Invariant NKT cells inhibit development of the Th17 lineage

PubMed Central

Mars, Lennart T.; Araujo, Luiza; Kerschen, Philippe; Diem, Séverine; Bourgeois, Elvire; Van, Linh Pham; Carrié, Nadège; Dy, Michel; Liblau, Roland S.; Herbelin, André

2009-01-01

T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th1 and Th2 responses. Recently, a new subset of CD4+ T helper cells, called Th17, was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4+ T cells. Transferred naïve CD25−CD62L+ CD4+ T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th17 differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th17 lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-γ in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th17 response in mice lacking iNKT cells. This invigorated Th17 response reverts to physiological levels when iNKT cells are introduced into Jα18−/− mice by adoptive transfer, indicating that iNKT cells control the Th17 compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th17 lineage and suggest that iNKT cells provide a natural barrier against Th17 responses. PMID:19325124

Cigarette smoke alters the ability of human dendritic cells to promote anti-Streptococcus pneumoniae Th17 response.

PubMed

Le Rouzic, Olivier; Koné, Bachirou; Kluza, Jerome; Marchetti, Philippe; Hennegrave, Florence; Olivier, Cécile; Kervoaze, Gwenola; Vilain, Eva; Mordacq, Clémence; Just, Nicolas; Perez, Thierry; Bautin, Nathalie; Pichavant, Muriel; Gosset, Philippe

2016-07-26

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation and impaired immune response to pathogens leading to bacteria-induced exacerbation of the disease. A defect in Th17 cytokines in response to Streptococcus pneumoniae, a bacteria associated with COPD exacerbations, has been recently reported. Dendritic cells (DC) are professional antigen presenting cells that drive T-cells differentiation and activation. In this study, we hypothesized that exposure to cigarette smoke, the main risk factor of COPD, might altered the pro-Th17 response to S. pneumoniae in COPD patients and human DC. Pro-Th1 and -Th17 cytokine production by peripheral blood mononuclear cells (PBMC) from COPD patients was analyzed and compared to those from smokers and non-smokers healthy subjects. The effect of cigarette smoke extract (CSE) was analyzed on human monocyte-derived DC (MDDC) from controls exposed or not to S. pneumoniae. Bacteria endocytosis, maturation of MDDC and secretion of cytokines were assessed by flow cytometry and ELISA, respectively. Implication of the oxidative stress was analyzed by addition of antioxidants and mitochondria inhibitors. In parallel, MDDC were cocultured with autologous T-cells to analyze the consequence on Th1 and Th17 cytokine production. PBMC from COPD patients exhibited defective production of IL-1β, IL-6, IL-12 and IL-23 to S. pneumoniae compared to healthy subjects and smokers. CSE significantly reduced S. pneumoniae-induced MDDC maturation, secretion of pro-Th1 and -Th17 cytokines and activation of Th1 and Th17 T-cell responses. CSE exposure was also associated with sustained CXCL8 secretion, bacteria endocytosis and mitochondrial oxidative stress. Antioxidants did not reverse these effects. Inhibitors of mitochondrial electron transport chain partly reproduced inhibition of S. pneumoniae-induced MDDC maturation but had no effect on cytokine secretion and T cell activation. We observed a defective pro-Th1 and -Th17 response to bacteria in COPD patients. CSE exposure was associated with an inhibition of DC capacity to activate antigen specific T-cell response, an effect that seems to be not only related to oxidative stress. These results suggest that new therapeutics boosting this response in DC may be helpful to improve treatment of COPD exacerbations.

Expansion of Pathogen-Specific T-Helper 1 and T-Helper 17 Cells in Pulmonary Tuberculosis With Coincident Type 2 Diabetes Mellitus

PubMed Central

Kumar, Nathella Pavan; Sridhar, Rathinam; Banurekha, Vaithilingam V.; Jawahar, Mohideen S.; Nutman, Thomas B.; Babu, Subash

2013-01-01

Background. Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis, although the immunological mechanisms underlying this interaction remain unexplored. The influence of poorly controlled diabetes on pathogen-specific T-helper 1 (Th1) and T-helper 17 (Th17) responses have not been examined. Methods. To identify the role of Th1 and Th17 cells in tuberculosis with coincident DM, we examined mycobacteria-specific immune responses in the whole blood of individuals who had tuberculosis with DM and compared them to those in individuals who had tuberculosis without DM. Results. Tuberculosis coincident with DM is characterized by elevated frequencies of monofunctional and dual-functional CD4+ Th1 cells following Mycobacterium tuberculosis antigen stimulation and elevated frequencies of Th17 subsets at both baseline and following antigen stimulation. This was associated with increased systemic (plasma) levels of both Th1 and Th17 cytokines and decreased baseline frequencies of natural regulatory T cells but not interleukin 10 or transforming growth factor β. Conclusions. Therefore, our data reveal that tuberculosis in persons with DM is characterized by elevated frequencies of Th1 and Th17 cells, indicating that DM is associated with an alteration in the immune response to tuberculosis, leading to a biased induction of Th1- and Th17-mediated cellular responses and likely contributing to increased immune pathology in M. tuberculosis infection. PMID:23715661

In vitro generated Th17 cells support the expansion and phenotypic stability of CD4(+)Foxp3(+) regulatory T cells in vivo.

PubMed

Zhou, Qiong; Hu, Ya; Howard, O M Zack; Oppenheim, Joost J; Chen, Xin

2014-01-01

CD4(+) T cells stimulate immune responses through distinct patterns of cytokine produced by Th1, Th2 or Th17 cells, or inhibit immune responses through Foxp3-expressing regulatory T cells (Tregs). Paradoxically, effector T cells were recently shown to activate Tregs, however, it remains unclear which Th subset is responsible for this effect. In this study, we found that Th17 cells expressed the highest levels of TNF among in vitro generated Th subsets, and most potently promoted expansion and stabilized Foxp3 expression by Tregs when co-transferred into Rag1(-/-) mice. Both TNF and IL-2 produced by Th17 cells contributed to this effect. The stimulatory effect of Th17 cells on Tregs was largely abolished when co-transferred with TNFR2-deficient Tregs. Furthermore, Tregs deficient in TNFR2 also supported a much lower production of IL-17A and TNF expression by co-transferred Th17 cells. Thus, our data indicate that the TNF-TNFR2 pathway plays a crucial role in the reciprocal stimulatory effect of Th17 cells and Tregs. This bidirectional interaction should be taken into account when designing therapy targeting Th17 cells, Tregs, TNF and TNFR2. Copyright © 2013 Elsevier Ltd. All rights reserved.

Induction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection.

PubMed

Wang, Beinan; Dileepan, Thamotharampillai; Briscoe, Sarah; Hyland, Kendra A; Kang, Johnthomas; Khoruts, Alexander; Cleary, P Patrick

2010-03-30

Recurrent group A Streptococcus (GAS) tonsillitis and associated autoimmune diseases indicate that the immune response to this organism can be ineffective and pathological. TGF-beta1 is recognized as an essential signal for generation of regulatory T cells (Tregs) and T helper (Th) 17 cells. Here, the impact of TGF-beta1 induction on the T-cell response in mouse nasal-associated lymphoid tissue (NALT) following intranasal (i.n.) infections is investigated. ELISA and TGF-beta1-luciferase reporter assays indicated that persistent infection of mouse NALT with GAS sets the stage for TGF-beta1 and IL-6 production, signals required for promotion of a Th17 immune response. As predicted, IL-17, the Th17 signature cytokine, was induced in a TGF-beta1 signaling-dependent manner in single-cell suspensions of both human tonsils and NALT. Intracellular cytokine staining and flow cytometry demonstrated that CD4(+) IL-17(+) T cells are the dominant T cells induced in NALT by i.n. infections. Moreover, naive mice acquired the potential to clear GAS by adoptive transfer of CD4(+) T cells from immunized IL-17A(+)/(+) mice but not cells from IL-17A(-)/(-) mice. These experiments link specific induction of TGF-beta1 by a bacterial infection to an in vivo Th17 immune response and show that this cellular response is sufficient for protection against GAS. The association of a Th17 response with GAS infection reveals a potential mechanism for destructive autoimmune responses in humans.

CD4 T-helper cell cytokine phenotypes and antibody response following tetanus toxoid booster immunization

USDA-ARS?s Scientific Manuscript database

Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify tetanus toxoid- (TT) specific Th1, Th2, Th17 and IL10+ cells. Eight healthy subjects were given a TT booster vacci...

Comparison of Th1- and Th2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caulada-Benedetti, Z.; Al-Zamel, F.; Sher, A.

1991-03-01

Mice immunized against Schistosoma mansoni by a single percutaneous exposure to radiation-attenuated parasite larvae demonstrate partial resistance to challenge infection that has been shown to correlate with development of cell-mediated immunity, whereas mice hyperimmunized by multiple exposure to attenuated larvae produce antibodies capable of transferring partial protection to naive recipients. Measurement of Ag-specific lymphokine responses in these animals suggested that the difference in resistance mechanisms may be due to the differential induction of Th subset response by the two immunization protocols. Thus, upon Ag stimulation, singly immunized mice predominantly demonstrated responses associated with Th1 reactivity, including IL-2 and IFN-gamma production,more » whereas multiply immunized animals showed increased IL-5, IL-4, and IgG1 antibody production associated with enhanced Th2 response. These responses demonstrated some degree of organ compartmentalization, with splenocytes demonstrating higher Th1-related lymphokine production and cells from draining lymph nodes showing stronger proliferation and Th2 type reactivity. However, hyperimmunized mice also continued to demonstrate substantial Th1-associated immune reactivity. Moreover, in vivo Ag challenge elicited activated larvacidal macrophages in hyperimmunized animals. These observations indicate that protective cell-mediated mechanisms associated with induction of CD4+ Th1 cell reactivity predominate in singly vaccinated mice. Further vaccination stimulates Th2 responses, such as enhanced IgG1 production, that may also contribute to protective immunity.« less

Modulation of CD4+ and CD8+ T Cell Function and Cytokine Responses in Strongyloides stercoralis Infection by Interleukin-27 (IL-27) and IL-37.

PubMed

Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukthi; Dolla, Chandrakumar; Kumaran, Paul; Nutman, Thomas B; Babu, Subash

2017-11-01

Strongyloides stercoralis infection is associated with diminished antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4 + and CD8 + T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis -infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection. Copyright © 2017 American Society for Microbiology.

Crucial role of gamma interferon-producing CD4+ Th1 cells but dispensable function of CD8+ T cell, B cell, Th2, and Th17 responses in the control of Brucella melitensis infection in mice.

PubMed

Vitry, Marie-Alice; De Trez, Carl; Goriely, Stanislas; Dumoutier, Laure; Akira, Shizuo; Ryffel, Bernhard; Carlier, Yves; Letesson, Jean-Jacques; Muraille, Eric

2012-12-01

Brucella spp. are facultative intracellular bacterial pathogens responsible for brucellosis, a worldwide zoonosis that causes abortion in domestic animals and chronic febrile disease associated with serious complications in humans. There is currently no approved vaccine against human brucellosis, and antibiotic therapy is long and costly. Development of a safe protective vaccine requires a better understanding of the roles played by components of adaptive immunity in the control of Brucella infection. The importance of lymphocyte subsets in the control of Brucella growth has been investigated separately by various research groups and remains unclear or controversial. Here, we used a large panel of genetically deficient mice to compare the importance of B cells, transporter associated with antigen processing (TAP-1), and major histocompatibility complex class II-dependent pathways of antigen presentation as well as T helper 1 (Th1), Th2, and Th17-mediated responses on the immune control of Brucella melitensis 16 M infection. We clearly confirmed the key function played by gamma interferon (IFN-γ)-producing Th1 CD4(+) T cells in the control of B. melitensis infection, whereas IFN-γ-producing CD8(+) T cells or B cell-mediated humoral immunity plays only a modest role in the clearance of bacteria during primary infection. In the presence of a Th1 response, Th2 or Th17 responses do not really develop or play a positive or negative role during the course of B. melitensis infection. On the whole, these results could improve our ability to develop protective vaccines or therapeutic treatments against brucellosis.

The Combination of Early and Rapid Type I IFN, IL-1α, and IL-1β Production Are Essential Mediators of RNA-Like Adjuvant Driven CD4+ Th1 Responses

PubMed Central

Madera, Rachel F.; Wang, Jennifer P.; Libraty, Daniel H.

2011-01-01

There is a growing need for novel vaccine adjuvants that can provide safe and potent T-helper type 1 (Th1) activity. RNA-like immune response modifiers (IRMs) are candidate T-cell adjuvants that skew acquired immune responses towards a Th1 phenotype. We set out to delineate the essential signaling pathways by which the RNA-like IRMs, resiquimod (R-848) and polyinosinic:polycytidylic acid (poly I:C), augment CD4+ T-helper 1 (Th1) responses. Highly purified murine conventional dendritic cells (cDCs) and conventional CD4+ T-cells were co-cultured in allogeneic and MHC congenic mixed leukocyte reactions. The activation of CD4+ Th1 cells was examined utilizing cells from mice deficient in specific RNA-sensing pattern recognition receptors and signaling mediators. R-848 and poly I:C stimulation of Type I interferon production and signaling in cDCs was essential but not sufficient for driving CD4+ Th1 responses. The early and rapid production of IL-1α and IL-1β was equally critical for the optimal activation of Th1 CD4+ T-cells. R-848 activation of Toll-like receptor 7/MyD88-dependent signaling in cDCs led to a rapid upregulation of pro-IL-1α and pro-IL-1β production compared to poly I:C activation of MyD88-independent signaling pathways. The in vitro data show that CD4+ T-cell adjuvant activity of RNA-like IRMs is mediated by a critical combination of early and rapid Type I interferon, IL-1α and IL-1β production. These results provide important insights into the key signaling pathways responsible for RNA-like IRM CD4+ Th1 activation. A better understanding of the critical signaling pathways by which RNA-like IRMs stimulate CD4+ Th1 responses is relevant to the rational design of improved vaccine adjuvants. PMID:22206014

Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

PubMed

Datta, Jashodeep; Berk, Erik; Xu, Shuwen; Fitzpatrick, Elizabeth; Rosemblit, Cinthia; Lowenfeld, Lea; Goodman, Noah; Lewis, David A; Zhang, Paul J; Fisher, Carla; Roses, Robert E; DeMichele, Angela; Czerniecki, Brian J

2015-05-23

A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C. Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization. Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination. Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice.

PubMed

Zhang, Qian; Luan, Hong; Wang, Le; He, Fan; Zhou, Huan; Xu, Xiaoli; Li, Xingai; Xu, Qing; Niki, Toshiro; Hirashima, Mitsuomi; Xu, Gang; Lv, Yongman; Yuan, Jin

2014-04-15

Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4(+)Tim-3(+) T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury, and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the downregulation of CCL-20, CXCL-9, and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-γ and IL-17A declined in Gal-9-treated nephritic mice at days 21 and 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney.

Inflammasome and Fas-Mediated IL-1β Contributes to Th17/Th1 Cell Induction in Pathogenic Bacterial Infection In Vivo.

PubMed

Uchiyama, Ryosuke; Yonehara, Shin; Taniguchi, Shun'ichiro; Ishido, Satoshi; Ishii, Ken J; Tsutsui, Hiroko

2017-08-01

CD4 + Th cells play crucial roles in orchestrating immune responses against pathogenic microbes, after differentiating into effector subsets. Recent research has revealed the importance of IFN-γ and IL-17 double-producing CD4 + Th cells, termed Th17/Th1 cells, in the induction of autoimmune and inflammatory diseases. In addition, Th17/Th1 cells are involved in the regulation of infection caused by the intracellular bacterium Mycobacterium tuberculosis in humans. However, the precise mechanism of Th17/Th1 induction during pathogen infection is unclear. In this study, we showed that the inflammasome and Fas-dependent IL-1β induces Th17/Th1 cells in mice, in response to infection with the pathogenic intracellular bacterium Listeria monocytogenes In the spleens of infected wild-type mice, Th17/Th1 cells were induced, and expressed T-bet and Rorγt. In Pycard -/- mice, which lack the adaptor molecule of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain), Th17/Th1 induction was abolished. In addition, the Fas-mediated IL-1β production was required for Th17/Th1 induction during bacterial infection: Th17/Th1 induction was abolished in Fas -/- mice, whereas supplementation with recombinant IL-1β restored Th17/Th1 induction via IL-1 receptor 1 (IL-1R1), and rescued the mortality of Fas -/- mice infected with Listeria IL-1R1, but not apoptosis-associated speck-like protein containing a caspase recruitment domain or Fas on T cells, was required for Th17/Th1 induction, indicating that IL-1β stimulates IL-1R1 on T cells for Th17/Th1 induction. These results indicate that IL-1β, produced by the inflammasome and Fas-dependent mechanisms, contributes cooperatively to the Th17/Th1 induction during bacterial infection. This study provides a deeper understanding of the molecular mechanisms underlying Th17/Th1 induction during pathogenic microbial infections in vivo. Copyright © 2017 by The American Association of Immunologists, Inc.

HIV-1 Tat addresses dendritic cells to induce a predominant Th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection.

PubMed

Fanales-Belasio, Emanuele; Moretti, Sonia; Fiorelli, Valeria; Tripiciano, Antonella; Pavone Cossut, Maria R; Scoglio, Arianna; Collacchi, Barbara; Nappi, Filomena; Macchia, Iole; Bellino, Stefania; Francavilla, Vittorio; Caputo, Antonella; Barillari, Giovanni; Magnani, Mauro; Laguardia, Maria Elena; Cafaro, Aurelio; Titti, Fausto; Monini, Paolo; Ensoli, Fabrizio; Ensoli, Barbara

2009-03-01

Tat is an early regulatory protein that plays a major role in human HIV-1 replication and AIDS pathogenesis, and therefore, it represents a key target for the host immune response. In natural infection, however, Abs against Tat are produced only by a small fraction (approximately 20%) of asymptomatic individuals and are rarely seen in progressors, suggesting that Tat may possess properties diverting the adaptive immunity from generating humoral responses. Here we show that a Th1-type T cell response against Tat is predominant over a Th2-type B cell response in natural HIV-1 infection. This is likely due to the capability of Tat to selectively target and very efficiently enter CD1a-expressing monocyte-derived dendritic cells (MDDC), which represent a primary target for the recognition and response to virus Ag. Upon cellular uptake, Tat induces MDDC maturation and Th1-associated cytokines and beta-chemokines production and polarizes the immune response in vitro to the Th1 pattern through the transcriptional activation of TNF-alpha gene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF-alpha production are found with either an oxidized Tat, which does not enter MDDC, or with a Tat protein mutated in the cysteine-rich region (cys22 Tat), which enters MDDC as the wild-type Tat but is transactivation silent. Consistently with these data, inoculation of monkeys with the native wild-type Tat induced a predominant Th1 response, whereas cys22 Tat generated mostly Th2 responses, therefore providing evidence that Tat induces a predominant Th1 polarized adaptive immune response in the host.

CD4(+) T-cell responses to Epstein-Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV-associated non-Hodgkin lymphoma: Th1 in active disease but Tr1 in remission.

PubMed

Marshall, Neil A; Culligan, Dominic J; Johnston, Peter W; Millar, Colin; Barker, Robert N; Vickers, Mark A

2007-10-01

Primary infection with Epstein-Barr virus (EBV) in childhood is usually asymptomatic, whereas infection in adolescence may result in infectious mononucleosis (IM) often followed by a fatigue syndrome. EBV latent membrane protein 1 (LMP1) is expressed in latency and in many EBV-associated tumours, including non-Hodgkin lymphoma (NHL). Given the regulatory nature of the CD4(+) T-cell response against LMP1 previously reported in healthy donors, we investigated whether patients with active EBV-driven disease can nevertheless mount effector [T-helper cell, type 1 (Th1)] anti-LMP1 responses. We therefore performed a longitudinal study of the nature of CD4(+) T-cell responses to LMP1 in four patients with IM, and five patients with NHL. In both groups, responses changed with time. During symptomatic infection or active tumour growth, responses were dominated by a Th1 effector phenotype, but switched to a regulatory interleukin-10 response upon recovery. In addition, the fine specificities of the T cells driving these responses evolved. This study showed the dynamic nature of CD4(+) T-cell responses to LMP1, and demonstrated that, although patients can mount Th1 effector responses, recovery from IM and NHL is associated with regulatory responses.

A novel subset of helper T cells promotes immune responses by secreting GM-CSF

PubMed Central

Zhang, J; Roberts, A I; Liu, C; Ren, G; Xu, G; Zhang, L; Devadas, S; Shi, Yufang

2013-01-01

Helper T cells are crucial for maintaining proper immune responses. Yet, they have an undefined relationship with one of the most potent immune stimulatory cytokines, granulocyte macrophage-colony-stimulating factor (GM-CSF). By depleting major cytokines during the differentiation of CD4+ T cells in vitro, we derived cells that were found to produce large amounts of GM-CSF, but little of the cytokines produced by other helper T subsets. By their secretion of GM-CSF, this novel subset of helper T cells (which we have termed ThGM cells) promoted the production of cytokines by other T-cell subtypes, including type 1 helper T cell (Th1), type 2 helper T cell (Th2), type 1 cytotoxic T cell (Tc1), type 2 cytotoxic T cell (Tc2), and naive T cells, as evidenced by the fact that antibody neutralization of GM-CSF abolished this effect. ThGM cells were found to be highly prone to activation-induced cell death (AICD). Inhibitors of TRAIL or granzymes could not block AICD in ThGM cells, whereas inhibition of FasL/Fas interaction partially rescued ThGM cells from AICD. Thus, ThGM cells are a novel subpopulation of T helper cells that produce abundant GM-CSF, exhibit exquisite susceptibility to apoptosis, and therefore play a pivotal role in the regulation of the early stages of immune responses. PMID:24076588

Metabolism of murine TH 17 cells: Impact on cell fate and function.

PubMed

Wang, Ran; Solt, Laura A

2016-04-01

An effective adaptive immune response relies on the ability of lymphocytes to rapidly act upon a variety of insults. In T lymphocytes, this response includes cell growth, clonal expansion, differentiation, and cytokine production, all of which place a significant energy burden on the cell. Recent evidence shows that T-cell metabolic reprogramming is an essential component of the adaptive immune response and specific metabolic pathways dictate T-cell fate decisions, including the development of TH 17 versus T regulatory (Treg) cells. TH 17 cells have garnered significant attention due to their roles in the pathology of immune-mediated inflammatory diseases. Attempts to characterize TH 17 cells have demonstrated that they are highly dynamic, adjusting their function to environmental cues, which dictate their metabolic program. In this review, we highlight recent data demonstrating the impact of cellular metabolism on the TH 17/Treg balance and present factors that mediate TH 17-cell metabolism. Some examples of these include the differential impact of the mTOR signaling complexes on T-helper-cell differentiation, hypoxia inducible factor 1 alpha (HIF1α) promotion of glycolysis to favor TH 17-cell development, and ACC1-dependent de novo fatty acid synthesis favoring TH 17-cell development over Treg cells. Finally, we discuss the potential therapeutic options and the implications of modulating TH 17-cell metabolism for the treatment of TH 17-mediated diseases. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

T(reg) cells may regulate interlukin-17 production by modulating TH1 responses in 1,3-β-glucan-induced lung inflammation in mice.

PubMed

Chen, Ying; Liu, Fangwei; Weng, Dong; Song, Laiyu; Li, Cuiying; Tang, Wen; Yu, Ye; Dai, Wujing; Chen, Jie

2013-01-01

1,3-β-glucan is considered a fungal biomarker and exposure to this agent can induce lung inflammation. Complement activation plays an important role in early immune responses to β-glucan. Previous studies showed that T-regulatory cells (Tregs) regulated 1,3-β-glucan-induced lung inflammation by modulating the maintenance of immune homeostasis in the lung. Both interleukin (IL)-17 and TH17 cells play pivotal roles in inflammation associated with lung disease and share reciprocal developmental pathways with Tregs. However, the effect of Tregs on IL-17 and TH17 responses in 1,3-β-glucan-induced lung inflammation remains unclear. In this study, mice were exposed to 1,3-β-glucan by intratracheal instillation. To investigate the effects of Tregs on IL-17 and TH17 cells in the induced lung inflammation, a Treg-depleted mice model was generated by administration of anti-CD25 mAb. The results indicated that Treg-depleted mice showed more severe pathological inflammatory changes in lung tissues. Tregs depletion reduced IL-17 expression in these tissues, and increased those of TH1 cytokines. The expression of IL-17 increased at the early phase of the inflammation response. There were no significant effects of the Tregs on expression of RORγt and IL-6 or the amount of CD4(+)IL-17(+) cells in the lungs. When taken together, the late phase of the 1,3-β-glucan-induced inflammatory response in the mice was primarily mediated by TH1 cytokines rather than IL-17. In contrast, the early phase of the inflammatory response might be mediated in part by IL-17 along with activated complement. Tregs might be required for IL-17 expression during the late phase inflammatory response in mice. The increased IL-17 mRNA observed during the 1,3-β-glucan induced inflammatory response were attributed to cells other than TH17 cells.

Neuroimmune processes associated with Wallerian degeneration support neurotrophin-3-induced axonal sprouting in the injured spinal cord.

PubMed

Chen, Qin; Shine, H David

2013-10-01

Lesions of the spinal cord cause two distinctive types of neuroimmune responses, a response at the lesion site that leads to additional tissue destruction and a more subtle response, termed Wallerian degeneration (WD), that occurs distal to the lesion site. We have evidence that the neuroimmune response associated with WD may support tissue repair. Previously, we found that overexpression of neurotrophin-3 (NT-3) induced axonal growth in the spinal cord after a unilateral corticospinal tract (CST) lesion, but only if the immune system was intact and activated. We reasoned that a neuroimmune response associated with WD was involved in this neuroplasticity. To test this, we compared NT-3-induced axonal sprouting in athymic nude rats that lack functional T cells with rats with functional T cells and in nude rats grafted with CD4(+) T cells or CD8(+) T cells. There was no sprouting in nude rats and in nude rats grafted with CD8(+) T cells. However, nude rats grafted with CD4(+) T cells mounted a sprouting response. To determine which CD4(+) subtype, type 1 T helper (Th1) or type 2 T helper (Th2) cells, was responsible, we grafted Th1 and Th2 cells into nude rats and tested whether they would support sprouting. Axonal sprouting was greater in rats grafted with Th2 cells, demonstrating that the Th2 subtype was responsible for supporting axonal sprouting. These data suggest that WD activates Th2 cells that, along with the direct effects of NT-3 on CST axons, act to support axonal sprouting in the lesioned spinal cord. Copyright © 2013 Wiley Periodicals, Inc.

Role of DAF in protecting against T-cell autoreactivity that leads to experimental autoimmune uveitis.

PubMed

An, Fengqi; Li, Qing; Tu, Zhidan; Bu, Hong; Chan, Chi-Chao; Caspi, Rachel R; Lin, Feng

2009-08-01

To investigate the role of decay-accelerating factor (DAF), a cell surface complement regulator that recently has been linked to T-cell responses and autoimmunity in the pathogenesis of experimental autoimmune uveitis (EAU). EAU was induced in wild-type (WT) and Daf1(-/-) mice, and their disease severities, IRBP specific Th1/Th17 responses, and cytokine expression profiles were compared. In a test of the efficacy of treatment with soluble mouse DAF protein, EAU was induced in disease-susceptible B10.RIII mice, and they were treated with 0.5 mg soluble DAF protein or equal volume of PBS IP every other day. Retinal histology and IRBP-specific T-cell responses were compared after 14 days. Both EAU incidence and histopathology scores were significantly greater in Daf1(-/-) mice. There was a >10-fold greater mononuclear cell influx into the retina together with severe vasculitic lesions, retinal folding, and photoreceptor cell layer destruction. There were 5- to 7-fold greater Th1 and 3- to 4-fold greater Th17 responses against IRBP in Daf1(-/-) mice with EAU, and they expressed significantly elevated levels of GM-CSF, IL-2, IL-3, and IFN-gamma. WT B10.RIII mice that received soluble DAF protein treatments exhibited decreased IRBP-specific Th1/Th17 responses and were protected from retinal injury compared with the mice that received PBS treatments. DAF significantly influences IRBP-specific Th1 and Th17 responses and disease severity in EAU. Systemic upregulation of DAF levels could be used to suppress retinal antigen(s)-specific autoimmunity to treat autoimmune posterior uveitis.

Modulation of IL-33/ST2-TIR and TLR signalling pathway by fingolimod and analogues in immune cells.

PubMed

Rüger, K; Ottenlinger, F; Schröder, M; Zivković, A; Stark, H; Pfeilschifter, J M; Radeke, H H

2014-12-01

For the immune modulatory drug fingolimod (FTY720), lymphocyte sequestration has been extensively studied and accepted as mode of action. Further, direct effects on immune cell signalling are incompletely understood. Herein, we used the parent drug and newly synthesized analogues to investigate their effects on dendritic cell (DC) calcium signalling and on Th1, Th2 and Th17 responses. DC calcium signalling was determined with a single cell-based confocal assay and IL-33/ST2-TIR Th2-like response with ST2-transduced EL4-6.1 thymoma cells. The Th1/Th17 responses were examined with a LPS/TLR-enhanced antigen presentation assay with OVA-TCRtg CD4 and CD8 spleen cells. Our results revealed a comparable influence of fingolimod and S1P on intracellular calcium level in DC, while an oxy-derivative of fingolimod exhibited an EC50 of 3.3 nm, being 14 times more potent than FTY720-P. The IL-33/ST2-TIR Th2-like response in ST2-EL4 cells was inhibited by fingolimod and analogues at varying degrees. Using the OVA-TCRtg LPS/TLR-enhanced spleen cell assay, we found that fingolimod inhibited both IL-17 and IFN-γ production. In contrast, fingolimod phosphate failed to decrease Th1 cytokines. Interestingly, the effects of the parent compound fingolimod were modulated by the PP2A inhibitor okadaic acid, thus suggesting PP2A as relevant intracellular target. These studies describe detailed immune-modulating properties of fingolimod, including interference with a prototypical Th2 response via IL-33/ST2-TIR. Moreover, differential effects of fingolimod versus its phosphorylated derivative on TLR-activated and antigen-dependent Th1 activation suggest PP2A as an additional target of fingolimod immune therapy. Together with the analogues tested, these data may guide the development of more specific fingolimod derivatives. © 2014 John Wiley & Sons Ltd.

The Th1-promoting effects of dehydroepiandrosterone can provide an explanation for the stronger Th1-immune response of women.

PubMed

Namazi, Mohammad Reza

2009-03-01

Estrogens foster immunological processes driven by CD4+ Th2 cells and B cells and androgens foster Th1 CD4+ and CD8+ cell activity. Higher levels of IFN-gamma and IL-2 and lower levels of IL-4 and IL-10 are detected in the phytohemagglutinin-stimulated lymphocyte culture supernatants of men compared with women. It is documented that the physiologic levels of estrogens produced during the luteal phase of the menstrual cycle shift the female immune system toward a Th2-type response and that the Th1 cytokines are increased in postmenopausal women. However, the Th1 immune response is also surprisingly stronger in women, hence affording them a better protection against infections. Nickel sensitivity, a Th1 immune reaction, seems to be more common in women even if men wear earrings. Further, not only the Th2 but also the Th1 autoimmune diseases are generally more common in women than men. How do women advance a stronger Th1 response than men? It is suggested that in contrast to the paradigm that estrogens lead to a Th2 bias, estrogens can enhance Th1 cytokine production also. However, the discrepant effects of estrogens are difficult to be reconciled from a molecular viewpoint and hence are not advocated by all authors. This paper provides an explanation: The effects of dehydroepiandrosterone on Th1/Th2 balance seem to be model-specific; in humans dehydroepiandrosterone, represents a pivotal up-regulator of Th1 immune response. Steroid sulphatase is a microsomal enzyme that cleaves the sulphate group of dehydroepiandrosterone sulphate. This enzyme is controlled by an X-linked gene that escapes the Lyon effect of X-inactivation; as a result, women usually have about twice steroid sulphatase in their cells, including macrophages, as have men. Putting all these facts together, it could be concluded that women's macrophages, which contain higher steroid sulphatase levels and enter peripheral lymphoid organs through afferent lymphatic drainage, produce higher levels of dehydroepiandrosterone in these organs; and higher levels of this hormone produce stronger Th1 immune responses.

T-Helper 17 Cell Cytokine Responses in Lyme Disease Correlate With Borrelia burgdorferi Antibodies During Early Infection and With Autoantibodies Late in the Illness in Patients With Antibiotic-Refractory Lyme Arthritis

PubMed Central

Sulka, Katherine B.; Pianta, Annalisa; Crowley, Jameson T.; Arvikar, Sheila L.; Anselmo, Anthony; Sadreyev, Ruslan; Steere, Allen C.

2017-01-01

Abstract Background. Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (TH1) immune responses, whereas the role of T-helper 17 cell (TH17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme arthritis (LA) to elucidate their role early and late in the infection. Methods. Levels of 21 cytokines and chemokines, representative of innate, TH1, and TH17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay. Results. Compared with healthy subjects, EM patients had significantly higher levels of innate, TH1, and TH17-associated mediators (P ≤ .05) in serum. In these patients, the levels of inflammatory mediators, particularly TH17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P ≤ .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and TH1-associated mediators were often >10-fold higher in synovial fluid than serum. In contrast, the levels of TH17-associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in TH17 responses toward an autoimmune phenotype. Conclusions. Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA. PMID:28077518

STAT4 Deficiency Fails To Induce Lung Th2 or Th17 Immunity following Primary or Secondary Respiratory Syncytial Virus (RSV) Challenge but Enhances the Lung RSV-Specific CD8+ T Cell Immune Response to Secondary Challenge

PubMed Central

Dulek, Daniel E.; Newcomb, Dawn C.; Toki, Shinji; Goliniewska, Kasia; Cephus, Jacqueline; Reiss, Sara; Bates, John T.; Crowe, James E.; Boyd, Kelli L.; Moore, Martin L.; Zhou, Weisong

2014-01-01

ABSTRACT Immune-mediated lung injury is a hallmark of lower respiratory tract illness caused by respiratory syncytial virus (RSV). STAT4 plays a critical role in CD4+ Th1 lineage differentiation and gamma interferon (IFN-γ) protein expression by CD4+ T cells. As CD4+ Th1 differentiation is associated with negative regulation of CD4+ Th2 and Th17 differentiation, we hypothesized that RSV infection of STAT4−/− mice would result in enhanced lung Th2 and Th17 inflammation and impaired lung Th1 inflammation compared to wild-type (WT) mice. We performed primary and secondary RSV challenges in WT and STAT4−/− mice and used STAT1−/− mice as a positive control for the development of RSV-specific lung Th2 and Th17 inflammation during primary challenge. Primary RSV challenge of STAT4−/− mice resulted in decreased T-bet and IFN-γ expression levels in CD4+ T cells compared to those of WT mice. Lung Th2 and Th17 inflammation did not develop in primary RSV-challenged STAT4−/− mice. Decreased IFN-γ expression by NK cells, CD4+ T cells, and CD8+ T cells was associated with attenuated weight loss and enhanced viral clearance with primary challenge in STAT4−/− mice compared to WT mice. Following secondary challenge, WT and STAT4−/− mice also did not develop lung Th2 or Th17 inflammation. In contrast to primary challenge, secondary RSV challenge of STAT4−/− mice resulted in enhanced weight loss, an increased lung IFN-γ expression level, and an increased lung RSV-specific CD8+ T cell response compared to those of WT mice. These data demonstrate that STAT4 regulates the RSV-specific CD8+ T cell response to secondary infection but does not independently regulate lung Th2 or Th17 immune responses to RSV challenge. IMPORTANCE STAT4 is a protein critical for both innate and adaptive immune responses to viral infection. Our results show that STAT4 regulates the immune response to primary and secondary challenge with RSV but does not restrain RSV-induced lung Th2 or Th17 immune responses. These findings suggest that STAT4 expression may influence lung immunity and severity of illness following primary and secondary RSV infections. PMID:24920804

Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

PubMed Central

Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

2013-01-01

Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

Host Th1/Th2 immune response to Taenia solium cyst antigens in relation to cyst burden of neurocysticercosis.

PubMed

Tharmalingam, J; Prabhakar, A T; Gangadaran, P; Dorny, P; Vercruysse, J; Geldhof, P; Rajshekhar, V; Alexander, M; Oommen, A

2016-10-01

Neurocysticercosis (NCC), Taenia solium larval infection of the brain, is an important cause of acquired seizures in endemic countries, which relate to number, location and degenerating cysts in the brain. Multicyst infections are common in endemic countries although single-cyst infection prevails in India. Single-cyst infections in an endemic country suggest a role for host immunity limiting the infection. This study examined ex vivo CD4(+) T cells and in vitro Th1 and Th2 cytokine responses to T. solium cyst antigens of peripheral blood mononuclear cells of healthy subjects from endemic and nonendemic regions and of single- and multicyst-infected patients for association with cyst burden of NCC. T. solium cyst antigens elicited a Th1 cytokine response in healthy subjects of T. solium-endemic and T. solium-non-endemic regions and those with single-cyst infections and a Th2 cytokine response from subjects with multicyst neurocysticercosis. Multicyst neurocysticercosis subjects also exhibited low levels of effector memory CD4(+) T cells. Th1 cytokine response of T. solium exposure and low infectious loads may aid in limiting cyst number. Th2 cytokines and low effector T cells may enable multiple-cyst infections to establish and persist. © 2016 John Wiley & Sons Ltd.

Proanthocyanidins from the bark of Metasequoia glyptostroboides ameliorate allergic contact dermatitis through directly inhibiting T cells activation and Th1/Th17 responses.

PubMed

Chen, Fengyang; Ye, Xiaodi; Yang, Yadong; Teng, Tianli; Li, Xiaoyu; Xu, Shifang; Ye, Yiping

2015-04-15

The leaves and bark of Metasequoia glyptostroboides are used as anti-microbic, analgesic and anti-inflammatory drug for dermatic diseases in Chinese folk medicine. However, the pharmacological effects and material basis responsible for the therapeutic use of this herb have not yet been well studied. The objectives of this study were to evaluate the anti-inflammatory effects of the proanthocyanidin fraction from the bark of M. glyptostroboides (MGEB) and to elucidate its immunological mechanisms. The anti-inflammatory activity of MGEB was evaluated using 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in mice. Its potential mechanisms were further investigated by determining its effects on Con A-induced T cell activation and Th1/Th17 responses in vitro. Both intraperitoneal injection and oral administration of MGEB significantly reduced the ear swelling in DNFB-induced ACD mice. MGEB inhibited Con A-induced proliferation and the expression levels of cell surface molecules CD69 and CD25 of T cells in vitro. MGEB also significantly decreased the production of Th1/Th17 specific cytokines (IL-2, IFN-γ and IL-17) and down-regulated their mRNA expression levels in activated T-cells. MGEB could ameliorate ACD, at least in part, through directly inhibiting T cells activation and Th1/Th17 responses. Copyright © 2015 Elsevier GmbH. All rights reserved.

Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals.

PubMed

Ly, Judy; Lagman, Minette; Saing, Tommy; Singh, Manpreet Kaur; Tudela, Enrique Vera; Morris, Devin; Anderson, Jessica; Daliva, John; Ochoa, Cesar; Patel, Nishita; Pearce, Daniel; Venketaraman, Vishwanath

2015-11-01

Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.

Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice.

PubMed Central

Zhou, X; Paulsson, G; Stemme, S; Hansson, G K

1998-01-01

Atherosclerosis is an inflammatory-fibrotic response to accumulation of cholesterol in the artery wall. In hypercholesterolemia, low density lipoproteins (LDL) accumulate and are oxidized to proinflammatory compounds in the arterial intima, leading to activation of endothelial cells, macrophages, and T lymphocytes. We have studied immune cell activation and the autoimmune response to oxidized LDL in atherosclerotic apo E-knockout mice. Autoantibodies to oxidized LDL exhibited subclass specificities indicative of T cell help, and the increase in antibody titers in peripheral blood was associated with increased numbers of cytokine-expressing T cells in the spleen. In addition to T cell-dependent antibodies, IgM antibodies to oxidized LDL were also increased in apo E-knockout mice. This suggests that both T cell-dependent and T cell-independent epitopes may be present on oxidized LDL. In moderate hypercholesterolemia, IgG antibodies were largely of the IgG2a isotype, suggesting that T cell help was provided by proinflammatory T helper (Th) 1 cells, which are prominent components of atherosclerotic lesions. In severe hypercholesterolemia induced by cholesterol feeding of apo E-knockout mice, a switch to Th2-dependent help was evident. It was associated with a loss of IFN-gamma-producing Th1 cells in the spleen, whereas IL-4-producing Th2 cells were more resistant to hypercholesterolemia. IFN-gamma but not IL-4 mRNA was detected in atherosclerotic lesions of moderately hypercholesterolemic apo E-knockout mice, but IL-4 mRNA appeared in the lesions when mice were made severely hypercholesterolemic by cholesterol feeding. These data show that IFN-gamma-producing Th1 cells infiltrate atherosclerotic lesions and provide T cell help for autoimmune responses to oxidized LDL in apo E-knockout mice. However, severe hypercholesterolemia is associated with a switch from Th1 to Th2, which results not only in the formation of IgG1 autoantibodies to oxidized LDL, but also in the appearance of Th2-type cytokines in the atherosclerotic lesions. Since the two subsets of T cells counteract each other, this switch may have important consequences for the inflammatory/immune process in atherosclerosis. PMID:9541503

Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection

PubMed Central

Bizzell, Erica; Madan-Lala, Ranjna

2017-01-01

Mycobacterium tuberculosis (Mtb) impairs dendritic cell (DC) functions and induces suboptimal antigen-specific CD4 T cell immune responses that are poorly protective. Mucosal T-helper cells producing IFN-γ (Th1) and IL-17 (Th17) are important for protecting against tuberculosis (TB), but the mechanisms by which DCs generate antigen-specific T-helper responses during Mtb infection are not well defined. We previously reported that Mtb impairs CD40 expression on DCs and restricts Th1 and Th17 responses. We now demonstrate that CD40-dependent costimulation is required to generate IL-17 responses to Mtb. CD40-deficient DCs were unable to induce antigen-specific IL-17 responses after Mtb infection despite the production of Th17-polarizing innate cytokines. Disrupting the interaction between CD40 on DCs and its ligand CD40L on antigen-specific CD4 T cells, genetically or via antibody blockade, significantly reduced antigen-specific IL-17 responses. Importantly, engaging CD40 on DCs with a multimeric CD40 agonist (CD40LT) enhanced antigen-specific IL-17 generation in ex vivo DC-T cell co-culture assays. Further, intratracheal instillation of Mtb-infected DCs treated with CD40LT significantly augmented antigen-specific Th17 responses in vivo in the lungs and lung-draining lymph nodes of mice. Finally, we show that boosting CD40-CD40L interactions promoted balanced Th1/Th17 responses in a setting of mucosal DC transfer, and conferred enhanced control of lung bacterial burdens following aerosol challenge with Mtb. Our results demonstrate that CD40 costimulation by DCs plays an important role in generating antigen-specific Th17 cells and targeting the CD40-CD40L pathway represents a novel strategy to improve adaptive immunity to TB. PMID:28767735

Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis

PubMed Central

Chen, Liye; Ridley, Anna; Hammitzsch, Ariane; Al-Mossawi, Mohammad Hussein; Bunting, Helen; Georgiadis, Dimitris; Chan, Antoni; Kollnberger, Simon; Bowness, Paul

2016-01-01

Objective Human leucocyte antigen (HLA)-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly associated with ankylosing spondylitis (AS). ERAP1 is a key aminopeptidase in HLA class I presentation and can potentially alter surface expression of HLA-B27 free heavy chains (FHCs). We studied the effects of ERAP1 silencing/inhibition/variations on HLA-B27 FHC expression and Th17 responses in AS. Methods Flow cytometry was used to measure surface expression of HLA class I in peripheral blood mononuclear cells (PBMCs) from patients with AS carrying different ERAP1 genotypes (rs2287987, rs30187 and rs27044) and in ERAP1-silenced/inhibited/mutated HLA-B27-expressing antigen presenting cells (APCs). ERAP1-silenced/inhibited APCs were cocultured with KIR3DL2CD3ε-reporter cells or AS CD4+ T cells. Th17 responses of AS CD4+ T cells were measured by interleukin (IL)-17A ELISA and Th17 intracellular cytokine staining. FHC cell surface expression and Th17 responses were also measured in AS PBMCs following ERAP1 inhibition. Results The AS-protective ERAP1 variants, K528R and Q730E, were associated with reduced surface FHC expression by monocytes from patients with AS and HLA-B27-expressing APCs. ERAP1 silencing or inhibition in APCs downregulated HLA-B27 FHC surface expression, reduced IL-2 production by KIR3DL2CD3ε-reporter cells and suppressed the Th17 expansion and IL-17A secretion by AS CD4+ T cells. ERAP1 inhibition of AS PBMCs reduced HLA class I FHC surface expression by monocytes and B cells, and suppressed Th17 expansion. Conclusions ERAP1 activity determines surface expression of HLA-B27 FHCs and potentially promotes Th17 responses in AS through binding of HLA-B27 FHCs to KIR3DL2. Our data suggest that ERAP1 inhibition has potential for AS treatment. PMID:26130142

Retinoic Acid Is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program

PubMed Central

Brown, Chrysothemis C.; Esterhazy, Daria; Sarde, Aurelien; London, Mariya; Pullabhatla, Venu; Osma-Garcia, Ines; al-Bader, Raya; Ortiz, Carla; Elgueta, Raul; Arno, Matthew; de Rinaldis, Emanuele; Mucida, Daniel; Lord, Graham M.; Noelle, Randolph J.

2015-01-01

Summary CD4+ T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells. PMID:25769610

The immunological response and post-treatment survival of DC-vaccinated melanoma patients are associated with increased Th1/Th17 and reduced Th3 cytokine responses.

PubMed

Durán-Aniotz, Claudia; Segal, Gabriela; Salazar, Lorena; Pereda, Cristián; Falcón, Cristián; Tempio, Fabián; Aguilera, Raquel; González, Rodrigo; Pérez, Claudio; Tittarelli, Andrés; Catalán, Diego; Nervi, Bruno; Larrondo, Milton; Salazar-Onfray, Flavio; López, Mercedes N

2013-04-01

Immunization with autologous dendritic cells (DCs) loaded with a heat shock-conditioned allogeneic melanoma cell lysate caused lysate-specific delayed type hypersensitivity (DTH) reactions in a number of patients. These responses correlated with a threefold prolonged long-term survival of DTH(+) with respect to DTH(-) unresponsive patients. Herein, we investigated whether the immunological reactions associated with prolonged survival were related to dissimilar cellular and cytokine responses in blood. Healthy donors and melanoma patient's lymphocytes obtained from blood before and after vaccinations and from DTH biopsies were analyzed for T cell population distribution and cytokine release. Peripheral blood lymphocytes from melanoma patients have an increased proportion of Th3 (CD4(+) TGF-β(+)) regulatory T lymphocytes compared with healthy donors. Notably, DTH(+) patients showed a threefold reduction of Th3 cells compared with DTH(-) patients after DCs vaccine treatment. Furthermore, DCs vaccination resulted in a threefold augment of the proportion of IFN-γ releasing Th1 cells and in a twofold increase of the IL-17-producing Th17 population in DTH(+) with respect to DTH(-) patients. Increased Th1 and Th17 cell populations in both blood and DTH-derived tissues suggest that these profiles may be related to a more effective anti-melanoma response. Our results indicate that increased proinflammatory cytokine profiles are related to detectable immunological responses in vivo (DTH) and to prolonged patient survival. Our study contributes to the understanding of immunological responses produced by DCs vaccines and to the identification of follow-up markers for patient outcome that may allow a closer individual monitoring of patients.

Novel function of Extracellular matrix protein 1 in suppressing Th17 cell development in experimental autoimmune encephalomyelitis

PubMed Central

Su, Pan; Chen, Sheng; Zheng, Yu Han; Zhou, Hai Yan; Yan, Cheng Hua; Yu, Fang; Zhang, Ya Guang; He, Lan; Zhang, Yuan; Wang, Yanming; Wu, Lei; Wu, Xiaoai; Yu, Bingke; Ma, Li Yan; Yang, Zhiru; Wang, Jianhua; Zhao, Guixian; Zhu, Jinfang; Wu, Zhi-Ying; Sun, Bing

2016-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model for human MS. While Th17 cells are important for the disease induction, Th2 cells are inhibitory in this process. Here, we report the effect of a Th2 cell product, extracellular matrix protein 1 (ECM1), on the differentiation of Th17 cells and the development of experimental autoimmune encephalomyelitis (EAE). Our results demonstrated that ECM1 administration from day 1 to day 7 following the EAE induction could ameliorate the Th17 cell responses and EAE development in vivo. Further mechanism study revealed that ECM1 could interact with αv integrin on DC cells and block the αv integrin-mediated activation of latent TGF-β, resulting in an inhibition of Th17 differentiation at early stage of EAE induction. Furthermore, overexpression of ECM1 in vivo significantly inhibited Th17 cell response and EAE induction in ECM1 transgenic mouse. Overall, our work has identified a novel function of ECM1 in inhibiting Th17 differentiation in the EAE model, suggesting that ECM1 may have a potential to be used in clinical applications for understanding the pathogenesis of MS and its diagnosis. PMID:27316685

Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

PubMed Central

Lalor, Stephen J.; Leech, John M.; O’Keeffe, Kate M.; Mac Aogáin, Micheál; O’Halloran, Dara P.; Lacey, Keenan A.; Tavakol, Mehri; Hearnden, Claire H.; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P.; van Wamel, Willem J.; Foster, Timothy J.; Geoghegan, Joan A.; Lavelle, Ed C.; Rogers, Thomas R.; McLoughlin, Rachel M.

2015-01-01

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

Panax Notoginseng Saponin Controls IL-17 Expression in Helper T Cells

PubMed Central

Wei, Jia-Ru; Wen, Xiaofeng; Bible, Paul W.; Li, Zhiyu; Nussenblatt, Robert B.

2017-01-01

Abstract Purpose: Panax Notoginseng, a traditional Chinese medicine, is known as an anti-inflammatory herb. However, the molecular mechanism by which it controls helper T cell mediated immune responses is largely unknown. Methods: Naive CD4+ T cells isolated from healthy donors, patients with Behcet's disease, and C57BL/6 mice were polarized into Th1, Th17, and Treg cells. Proliferation and cytokine expression were measured in these cells with the presence or absence of Panax Notoginseng saponins (PNS). Genomewide expression profiles of Th1, Th17, and Treg cells were assessed using Affymetrix microarray analysis. Results: We found that PNS control the proliferation and differentiation of Th17 cells by globally downregulating the expression of inflammatory cytokines and cell cycle genes. Conclusions: These findings demonstrated that PNS function as an anti-inflammatory agent through directly targeting Th17 cell mediated immune response. PMID:28051353

Aspergillus fumigatus generates an enhanced Th2-biased immune response in mice with defective cystic fibrosis transmembrane conductance regulator.

PubMed

Allard, Jenna B; Poynter, Matthew E; Marr, Kieren A; Cohn, Lauren; Rincon, Mercedes; Whittaker, Laurie A

2006-10-15

Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20-40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftr(tm1Unc-)TgN(fatty acid-binding protein)CFTR) and mutant (DeltaF508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4+ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4+ T cells. The Th2 bias of CD4+ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4+ T cells.

Nasal delivery of chitosan-coated poly(lactide-co-glycolide)-encapsulated honeybee (Apis mellifera) venom promotes Th 1-specific systemic and local intestinal immune responses in weaned pigs.

PubMed

Lee, Jin-A; Kim, Yun-Mi; Kim, Tae-Hoon; Lee, Sang-Ho; Lee, Cho-A; Cho, Cheong-Weon; Jeon, Jong-Woon; Park, Jin-Kyu; Kim, Sang-Ki; Jung, Bock-Gie; Lee, Bong-Joo

2016-10-01

Nasal delivery is a convenient and acceptable route for drug administration, and has been shown to elicit a much more potent local and systemic response compared with other drug delivery routes. We previously demonstrated that rectal administration of poly(lactide-co-glycolide)-encapsulated honeybee venom (P-HBV) could enhance systemic Th 1-specific immune responses. We therefore synthesized chitosan-coated P-HBV (CP-HBV) and then evaluated the immune-boosting efficacy of nasally administered CP-HBV on systemic and local intestinal immunity compared with non-chitosan-coated P-HBV. The nasally delivered CP-HBV effectively enhanced Th 1-specific responses, eliciting a significant increase in the CD3(+)CD4(+)CD8(-) Th cell population, lymphocyte proliferation capacity, and expression of Th 1 cytokines (IFN-γ, IL-12, and IL-2) in peripheral blood mononuclear cells. Furthermore, these immune-boosting effects persisted up to 21days post CP-HBV administration. Nasal administration of CP-HBV also led to an increase of not only the CD4(+) Th 1 and IFN-γ secreting CD4(+) Th 1 cell population but also Th 1-specific cytokines and transcription factors, including IL-12, IFN-γ, STAT4, and T-bet, in isolated mononuclear cells from the spleen and ileum. Copyright © 2016 Elsevier B.V. All rights reserved.

Allergen-specific Th1 cells counteract efferent Th2 cell-dependent bronchial hyperresponsiveness and eosinophilic inflammation partly via IFN-gamma.

PubMed

Huang, T J; MacAry, P A; Eynott, P; Moussavi, A; Daniel, K C; Askenase, P W; Kemeny, D M; Chung, K F

2001-01-01

Th2 T cell immune-driven inflammation plays an important role in allergic asthma. We studied the effect of counterbalancing Th1 T cells in an asthma model in Brown Norway rats that favors Th2 responses. Rats received i.v. transfers of syngeneic allergen-specific Th1 or Th2 cells, 24 h before aerosol exposure to allergen, and were studied 18-24 h later. Adoptive transfer of OVA-specific Th2 cells, but not Th1 cells, and OVA, but not BSA exposure, induced bronchial hyperresponsiveness (BHR) to acetylcholine and eosinophilia in a cell number-dependent manner. Importantly, cotransfer of OVA-specific Th1 cells dose-dependently reversed BHR and bronchoalveolar lavage (BAL) eosinophilia, but not mucosal eosinophilia. OVA-specific Th1 cells transferred alone induced mucosal eosinophilia, but neither BHR nor BAL eosinophilia. Th1 suppression of BHR and BAL eosinophilia was allergen specific, since cotransfer of BSA-specific Th1 cells with the OVA-specific Th2 cells was not inhibitory when OVA aerosol alone was used, but was suppressive with OVA and BSA challenge. Furthermore, recipients of Th1 cells alone had increased gene expression for IFN-gamma in the lungs, while those receiving Th2 cells alone showed increased IL-4 mRNA. Importantly, induction of these Th2 cytokines was inhibited in recipients of combined Th1 and Th2 cells. Anti-IFN-gamma treatment attenuated the down-regulatory effect of Th1 cells. Allergen-specific Th1 cells down-regulate efferent Th2 cytokine-dependent BHR and BAL eosinophilia in an asthma model via mechanisms that depend on IFN-gamma. Therapy designed to control the efferent phase of established asthma by augmenting down-regulatory Th1 counterbalancing mechanisms should be effective.

Delayed Activation Kinetics of Th2- and Th17 Cells Compared to Th1 Cells.

PubMed

Duechting, Andrea; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

2017-09-12

During immune responses, different classes of T cells arise: Th1, Th2, and Th17. Mobilizing the right class plays a critical role in successful host defense and therefore defining the ratios of Th1/Th2/Th17 cells within the antigen-specific T cell repertoire is critical for immune monitoring purposes. Antigen-specific Th1, Th2, and Th17 cells can be detected by challenging peripheral blood mononuclear cells (PBMC) with antigen, and establishing the numbers of T cells producing the respective lead cytokine, IFN-γ and IL-2 for Th1 cells, IL-4 and IL-5 for Th2, and IL-17 for Th-17 cells, respectively. Traditionally, these cytokines are measured within 6 h in flow cytometry. We show here that 6 h of stimulation is sufficient to detect peptide-induced production of IFN-γ, but 24 h are required to reveal the full frequency of protein antigen-specific Th1 cells. Also the detection of IL-2 producing Th1 cells requires 24 h stimulation cultures. Measurements of IL-4 producing Th2 cells requires 48-h cultures and 96 h are required for frequency measurements of IL-5 and IL-17 secreting T cells. Therefore, accounting for the differential secretion kinetics of these cytokines is critical for the accurate determination of the frequencies and ratios of antigen-specific Th1, Th2, and Th17 cells.

Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukuyama, Yoshiko; Tokuhara, Daisuke; Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639

Highlights: Black-Right-Pointing-Pointer Nasal Ad-FL effectively up-regulates APC function by CD11c{sup +} DCs in mucosal tissues. Black-Right-Pointing-Pointer Nasal Ad-FL induces Notch ligand (L)-expressing CD11c{sup +} DCs. Black-Right-Pointing-Pointer Notch L-expressing DCs support the induction of Th1- and Th2-type cytokine responses. -- Abstract: Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c{sup +} dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c{sup +} DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FLmore » activated CD11c{sup +} DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c{sup +} DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4{sup +} T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-{gamma}, IL-2 and IL-4 producing CD4{sup +} T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch-Notch-L pathway. These results show that Ad-FL induces CD11c{sup +} DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.« less

Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions.

PubMed

Hegazy, Ahmed N; Peine, Michael; Helmstetter, Caroline; Panse, Isabel; Fröhlich, Anja; Bergthaler, Andreas; Flatz, Lukas; Pinschewer, Daniel D; Radbruch, Andreas; Löhning, Max

2010-01-29

Current T cell differentiation models invoke separate T helper 2 (Th2) and Th1 cell lineages governed by the lineage-specifying transcription factors GATA-3 and T-bet. However, knowledge on the plasticity of Th2 cell lineage commitment is limited. Here we show that infection with Th1 cell-promoting lymphocytic choriomeningitis virus (LCMV) reprogrammed otherwise stably committed GATA-3(+) Th2 cells to adopt a GATA-3(+)T-bet(+) and interleukin-4(+)interferon-gamma(+) "Th2+1" phenotype that was maintained in vivo for months. Th2 cell reprogramming required T cell receptor stimulation, concerted type I and type II interferon and interleukin-12 signals, and T-bet. LCMV-triggered T-bet induction in adoptively transferred virus-specific Th2 cells was crucial to prevent viral persistence and fatal immunopathology. Thus, functional reprogramming of unfavorably differentiated Th2 cells may facilitate the establishment of protective immune responses. Stable coexpression of GATA-3 and T-bet provides a molecular concept for the long-term coexistence of Th2 and Th1 cell lineage characteristics in single memory T cells. Copyright 2010 Elsevier Inc. All rights reserved.

Preventative effect of an herbal preparation (HemoHIM) on development of airway inflammation in mice via modulation of Th1/2 cells differentiation.

PubMed

Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

2013-01-01

HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4(+) T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4(+) T cells displayed increased Th1 (IFN-γ(+) cell) as well as decreased Th2 (IL-4(+) cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance.

Th1 differentiation drives the accumulation of intravascular, non-protective CD4 T cells during tuberculosis

PubMed Central

Sallin, Michelle A.; Sakai, Shunsuke; Kauffman, Keith D.; Young, Howard A.; Zhu, Jinfang; Barber, Daniel L.

2017-01-01

SUMMARY Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1 polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL-12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+CD103+ tissue resident phenotype effectors in lung. In contrast, Th1 cell-derived IFNγ inhibits the accumulation of intravascular CX3CR1+KLRG1+ Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis. PMID:28355562

Interferon-gamma and T-bet expression in a patient with toxoplasmic lymphadenopathy.

PubMed

Jöhrens, Korinna; Moos, Verena; Schneider, Thomas; Stein, Harald; Anagnostopoulos, Ioannis

2010-04-01

Infection with Toxoplasma gondii (TG) presents in some individuals as a self-limited disease with a predominant lymphadenopathy characterized by prominent B-cell activation. As this is in contrast to the in vitro based concept of a T(h)1-immune response against TG, we investigated native lymphoid tissue and peripheral blood of a patient with serologic evidence of toxoplasmosis to verify which cells show T(h)1-response features. High-level expression of T-bet in monocytoid B-cells, in germinal center B-cells, and in a lesser amount in T cells could be demonstrated by immunohistochemistry. In vitro stimulation of lymph node cells with either TG, staphylococcus enterotoxin B, or phorbol 12-myristate 13-acetate/ionomycin revealed an interferon-gamma expression in T-bet(+) B cells only in the patient and not in controls. Similar results were found for T-bet(+) T cells which were also present in controls. CD4(+) peripheral blood cells stimulated with TG antigens showed a TG-specific but attenuated T(h)1-reactivity in the patient associated with a reduced expression of IL-2 when compared with controls. We conclude that the pathogenesis and course of toxoplasmic lymphadenopathy is based on a T(h)1-cell defect, which becomes compensated by the B cells mounting a T(h)1-like immune response.

The Predominant CD4+ Th1 Cytokine Elicited to Chlamydia trachomatis Infection in Women Is Tumor Necrosis Factor Alpha and Not Interferon Gamma

PubMed Central

Gupta, Kanupriya; Ogendi, Brian M. O.; Bakshi, Rakesh K.; Kapil, Richa; Press, Christen G.; Sabbaj, Steffanie; Lee, Jeannette Y.

2017-01-01

ABSTRACT Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of C. trachomatis-specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-γ)-producing CD4+ T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited to C. trachomatis infection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia-infected women with C. trachomatis elementary bodies, Pgp3, and major outer membrane protein and measured IFN-γ-, tumor necrosis factor alpha (TNF-α)-, and interleukin-2 (IL-2)-producing CD4+ and CD8+ T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4+ TNF-α responses, with frequency and magnitude varying significantly depending on the C. trachomatis antigen used. CD4+ IFN-γ and IL-2 responses occurred infrequently, as did production of any of the three cytokines by CD8+ T cells. About one-third of TNF-α-producing CD4+ T cells coproduced IFN-γ or IL-2. In summary, the predominant Th1 cytokine response elicited to C. trachomatis infection in women was a CD4+ TNF-α response, not CD4+ IFN-γ, and a subset of the CD4+ TNF-α-positive cells produced a second Th1 cytokine. PMID:28100498

T-Helper 17 Cell Cytokine Responses in Lyme Disease Correlate With Borrelia burgdorferi Antibodies During Early Infection and With Autoantibodies Late in the Illness in Patients With Antibiotic-Refractory Lyme Arthritis.

PubMed

Strle, Klemen; Sulka, Katherine B; Pianta, Annalisa; Crowley, Jameson T; Arvikar, Sheila L; Anselmo, Anthony; Sadreyev, Ruslan; Steere, Allen C

2017-04-01

Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (TH1) immune responses, whereas the role of T-helper 17 cell (TH17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme arthritis (LA) to elucidate their role early and late in the infection. Levels of 21 cytokines and chemokines, representative of innate, TH1, and TH17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay. Compared with healthy subjects, EM patients had significantly higher levels of innate, TH1, and TH17-associated mediators (P ≤ .05) in serum. In these patients, the levels of inflammatory mediators, particularly TH17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P ≤ .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and TH1-associated mediators were often >10-fold higher in synovial fluid than serum. In contrast, the levels of TH17-associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in TH17 responses toward an autoimmune phenotype. Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells

PubMed Central

Moraes-Vieira, Pedro M.M.; Larocca, Rafael A.; Bassi, Enio J.; Peron, Jean Pierre S.; Andrade-Oliveira, Vinícius; Wasinski, Frederick; Araujo, Ronaldo; Thornley, Thomas; Quintana, Francisco J.; Basso, Alexandre S.; Strom, Terry B.; Câmara, Niels O.S.

2016-01-01

Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1-cell polarization and inhibit Th2-cell responses. Additionally, leptin induces Th17-cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg-cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL-12, TNF-α, and IL-6, (iii) increased DC production of TGF-β, and (iv) limited the capacity of DCs to induce syngeneic CD4+ T-cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin-free conditions induced Treg or TH17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs. PMID:24271843

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

PubMed Central

Tarasenko, Tatyana; Kole, Hemanta K.; Chi, Anthony W.; Mentink-Kane, Margaret M.; Wynn, Thomas A.; Bolland, Silvia

2007-01-01

The 5′-phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient T cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8+ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity. PMID:17585010

The Systemic Immune State of Super-shedder Mice Is Characterized by a Unique Neutrophil-dependent Blunting of TH1 Responses

PubMed Central

Johns, Jennifer; Nolan, Garry; Monack, Denise

2013-01-01

Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsible for 80% of disease transmission. However, very little is known about the immune state of these super-shedders. In this study, we used the model organism Salmonella enterica serovar Typhimurium, an important cause of disease in humans and animal hosts, to study the immune state of super-shedders. Compared to moderate shedders, super-shedder mice had an active inflammatory response in both the gastrointestinal tract and the spleen but a dampened TH1 response specific to the secondary lymphoid organs. Spleens from super-shedder mice had higher numbers of neutrophils, and a dampened T cell response, characterized by higher levels of regulatory T cells (Tregs), fewer T-bet+ (TH1) T cells as well as blunted cytokine responsiveness. Administration of the cytokine granulocyte colony stimulating factor (G-CSF) and subsequent neutrophilia was sufficient to induce the super-shedder immune phenotype in moderate-shedder mice. Similar to super-shedders, these G-CSF-treated moderate-shedders had a dampened TH1 response with fewer T-bet+ T cells and a loss of cytokine responsiveness. Additionally, G-CSF treatment inhibited IL-2-mediated TH1 expansion. Finally, depletion of neutrophils led to an increase in the number of T-bet+ TH1 cells and restored their ability to respond to IL-2. Taken together, we demonstrate a novel role for neutrophils in blunting IL-2-mediated proliferation of the TH1 immune response in the spleens of mice that are colonized by high levels of S. Typhimurium in the gastrointestinal tract. PMID:23754944

An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients.

PubMed

Wei, Ping; Hu, Guo-Hua; Kang, Hou-Yong; Yao, Hong-Bing; Kou, Wei; Liu, Hong; Zhang, Cheng; Hong, Su-Ling

2014-05-01

A predominant Th17 population is a marker of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR) exhibits strong immunomodulation potential via regulation of the differentiation of T lymphocytes and dendritic cells (DCs) after activation by its ligand, such as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). The aim of this study was to analyze the effect of AhR on Th17 differentiation by investigating the action of ITE on DCs and CD4(+) T cells from patients with AR. In all, 26 AR patients and 12 healthy controls were included in this study. The expression of interleukin (IL)-1β, IL-6, IL-10, and IL-17 in the culture supernatant and the presence of Th17 cells in CD4(+) T cells and DC-CD4(+) T-cell co-culture system were measured before and after treatment with ITE. We show that ITE significantly induced cell secretion of IL-10 and inhibited IL-1β and IL-6 production in DCs, and promoted IL-10 production and suppressed IL-17 expression in CD4(+) T cells in vitro. It also suppressed the expansion of Th17 cells in vitro. Our work demonstrates that ITE acts on DCs and CD4(+) T cells to inhibit the Th17 response that suppresses AR; the AhR-DC-Th17 axis may be an important pathway in the treatment of AR. ITE, a nontoxic AhR ligand, attenuated the Th17 response; thus, it appears to be a promising therapeutic candidate for suppressing the inflammatory responses associated with AR.

Role of Arginase 1 from Myeloid Cells in Th2-Dominated Lung Inflammation

PubMed Central

Barron, Luke; Smith, Amber M.; El Kasmi, Karim C.; Qualls, Joseph E.; Huang, Xiaozhu; Cheever, Allen; Borthwick, Lee A.; Wilson, Mark S.; Murray, Peter J.; Wynn, Thomas A.

2013-01-01

Th2-driven lung inflammation increases Arginase 1 (Arg1) expression in alternatively-activated macrophages (AAMs). AAMs modulate T cell and wound healing responses and Arg1 might contribute to asthma pathogenesis by inhibiting nitric oxide production, regulating fibrosis, modulating arginine metabolism and restricting T cell proliferation. We used mice lacking Arg1 in myeloid cells to investigate the contribution of Arg1 to lung inflammation and pathophysiology. In six model systems encompassing acute and chronic Th2-mediated lung inflammation we observed neither a pathogenic nor protective role for myeloid-expressed Arg1. The number and composition of inflammatory cells in the airways and lungs, mucus secretion, collagen deposition, airway hyper-responsiveness, and T cell cytokine production were not altered if AAMs were deficient in Arg1 or simultaneously in both Arg1 and NOS2. Our results argue that Arg1 is a general feature of alternative activation but only selectively regulates Th2 responses. Therefore, attempts to experimentally or therapeutically inhibit arginase activity in the lung should be examined with caution. PMID:23637937

Functional diversity of human vaginal APC subsets in directing T cell responses

PubMed Central

Duluc, Dorothée; Gannevat, Julien; Anguiano, Esperanza; Zurawski, Sandra; Carley, Michael; Boreham, Muriel; Stecher, Jack; Dullaers, Melissa; Banchereau, Jacques; Oh, SangKon

2012-01-01

Human vaginal mucosa is the major entry site of sexually transmitted pathogens and thus has long been attractive as a site for mounting mucosal immunity. It is also known as a tolerogenic microenvironment. Here, we demonstrate that immune responses in the vagina are orchestrated by the functional diversity of four major antigen-presenting cell (APC) subsets. Langerhans cells (LCs) and CD14− lamina propria (LP)-DCs polarize CD4+ and CD8+ T cells toward Th2, whereas CD14+ LP-DCs and macrophages polarize CD4+ T cells toward Th1. Both LCs and CD14− LP-DCs are potent inducers of Th22. Due to their functional specialties and the different expression levels of pattern-recognition receptors on the APC subsets, microbial products do not bias them to elicit common types of immune responses (Th1 or Th2). To evoke desired types of adaptive immune responses in the human vagina, antigens may need to be targeted to proper APC subsets with right adjuvants. PMID:23131784

HIV infection impairs Th1 and Th17 Mycobacterium tuberculosis-specific T cell responses

PubMed Central

Murray, Lyle W; Satti, Iman; Meyerowitz, Jodi; Jones, Matthew; Willberg, Christian B; Ussher, James E; Goedhals, Dominique; Hurst, Jacob; Phillips, Rodney E; McShane, Helen

2018-01-01

Background HIV-infected individuals have a higher risk of developing active tuberculosis than HIV-uninfected individuals, but the mechanisms underpinning this are unclear. We hypothesized that depletion of specific components of Mycobacterium tuberculosis (M.tb)-specific CD4+ and CD8+ T cell responses contributed to this increased risk. Methods M.tb-specific T cell responses in 147 HIV-infected and 44 HIV-uninfected control subjects in a TB-endemic setting in Bloemfontein, South Africa were evaluated. Using a whole-blood flow cytometry assay, we measured expression of IFNγ, TNFα, IL-2 and IL-17 in CD4+ and CD8+ T cells in response to M.tb antigens (PPD, ESAT-6/CFP-10 (EC) and DosR regulon-encoded α-crystallin (Rv2031c)). Results Fewer HIV-infected individuals had detectable CD4+ and CD8+ T cell responses to PPD and Rv2031c than HIV-uninfected subjects. M.tb-specific T cells showed distinct patterns of cytokine expression comprising both Th1 (CD4 and CD8) and Th17 (CD4) cytokines, the latter at highest frequency for Rv2031c. Th17 antigen-specific responses to all antigens tested were specifically impaired in HIV-infected individuals. Conclusions HIV-associated impairment of CD4+ and CD8+ M.tb-specific T cell responses is antigen-specific, particularly impacting responses to PPD and Rv2031c. Preferential depletion of Th17 cytokine-expressing CD4+ T cells suggests this T cell subset may be key to TB susceptibility in HIV-infected individuals. PMID:29546381

Predictive Computational Modeling of the Mucosal Immune Responses during Helicobacter pylori Infection

PubMed Central

Carbo, Adria; Bassaganya-Riera, Josep; Pedragosa, Mireia; Viladomiu, Monica; Marathe, Madhav; Eubank, Stephen; Wendelsdorf, Katherine; Bisset, Keith; Hoops, Stefan; Deng, Xinwei; Alam, Maksudul; Kronsteiner, Barbara; Mei, Yongguo; Hontecillas, Raquel

2013-01-01

T helper (Th) cells play a major role in the immune response and pathology at the gastric mucosa during Helicobacter pylori infection. There is a limited mechanistic understanding regarding the contributions of CD4+ T cell subsets to gastritis development during H. pylori colonization. We used two computational approaches: ordinary differential equation (ODE)-based and agent-based modeling (ABM) to study the mechanisms underlying cellular immune responses to H. pylori and how CD4+ T cell subsets influenced initiation, progression and outcome of disease. To calibrate the model, in vivo experimentation was performed by infecting C57BL/6 mice intragastrically with H. pylori and assaying immune cell subsets in the stomach and gastric lymph nodes (GLN) on days 0, 7, 14, 30 and 60 post-infection. Our computational model reproduced the dynamics of effector and regulatory pathways in the gastric lamina propria (LP) in silico. Simulation results show the induction of a Th17 response and a dominant Th1 response, together with a regulatory response characterized by high levels of mucosal Treg) cells. We also investigated the potential role of peroxisome proliferator-activated receptor γ (PPARγ) activation on the modulation of host responses to H. pylori by using loss-of-function approaches. Specifically, in silico results showed a predominance of Th1 and Th17 cells in the stomach of the cell-specific PPARγ knockout system when compared to the wild-type simulation. Spatio-temporal, object-oriented ABM approaches suggested similar dynamics in induction of host responses showing analogous T cell distributions to ODE modeling and facilitated tracking lesion formation. In addition, sensitivity analysis predicted a crucial contribution of Th1 and Th17 effector responses as mediators of histopathological changes in the gastric mucosa during chronic stages of infection, which were experimentally validated in mice. These integrated immunoinformatics approaches characterized the induction of mucosal effector and regulatory pathways controlled by PPARγ during H. pylori infection affecting disease outcomes. PMID:24039925

Heterogeneity of Human CD4(+) T Cells Against Microbes.

PubMed

Sallusto, Federica

2016-05-20

CD4(+) T helper (Th) cells play a central role in the adaptive immune response by providing help to B cells and cytotoxic T cells and by releasing different types of cytokines in tissues to mediate protection against a wide range of pathogenic microorganisms. These functions are performed by different types of Th cells endowed with distinct migratory capacities and effector functions. Here we discuss how studies of the human T cell response to microbes have advanced our understanding of Th cell functional heterogeneity, in particular with the discovery of a distinct Th1 subset involved in the response to Mycobacteria and the characterization of two types of Th17 cells specific for extracellular bacteria or fungi. We also review new approaches to dissect at the clonal level the human CD4(+) T cell response induced by pathogens or vaccines that have revealed an unexpected degree of intraclonal diversification and propose a progressive and selective model of CD4(+) T cell differentiation.

CD16+ monocytes control T-cell subset development in immune thrombocytopenia

PubMed Central

Zhong, Hui; Bao, Weili; Li, Xiaojuan; Miller, Allison; Seery, Caroline; Haq, Naznin; Bussel, James

2012-01-01

Immune thrombocytopenia (ITP) results from decreased platelet production and accelerated platelet destruction. Impaired CD4+ regulatory T-cell (Treg) compartment and skewed Th1 and possibly Th17 responses have been described in ITP patients. The trigger for aberrant T-cell polarization remains unknown. Because monocytes have a critical role in development and polarization of T-cell subsets, we explored the contribution of monocyte subsets in control of Treg and Th development in patients with ITP. Unlike circulating classic CD14hiCD16− subpopulation, the CD16+ monocyte subset was expanded in ITP patients with low platelet counts on thrombopoietic agents and positively correlated with T-cell CD4+IFN-γ+ levels, but negatively with circulating CD4+CD25hiFoxp3+ and IL-17+ Th cells. Using a coculture model, we found that CD16+ ITP monocytes promoted the expansion of IFN-γ+CD4+ cells and concomitantly inhibited the proliferation of Tregs and IL-17+ Th cells. Th-1–polarizing cytokine IL-12, secreted after direct contact of patient T-cell and CD16+ monocytes, was responsible for the inhibitory effect on Treg and IL-17+CD4+ cell proliferation. Our findings are consistent with ITP CD16+ monocytes promoting Th1 development, which in turn negatively regulates IL-17 and Treg induction. This underscores the critical role of CD16+ monocytes in the generation of potentially pathogenic Th responses in ITP. PMID:22915651

Virus Infection Stages and Distinct Th1 or Th17/Th22 T-Cell Responses in Malaria/SHIV Coinfection Correlate with Different Outcomes of Disease

PubMed Central

Ryan-Payseur, Bridgett; Ali, Zahida; Huang, Dan; Chen, Crystal Y.; Yan, Lin; Wang, Richard C.; Collins, William E.; Wang, Yunqi

2011-01-01

Background. Malaria and AIDS represent 2 leading causes of death from infectious diseases worldwide, and their high geographic overlap means coinfection is prevalent. It remains unknown whether distinct immune responses during coinfection with malaria and human immunodeficiency virus (HIV) affect clinical outcomes. Methods. We tested this hypothesis by employing macaque models of coinfection with malaria and simian-human immunodeficiency virus (SHIV). Results. Plasmodium fragile malaria coinfection of acutely SHIV-infected macaques induced hyperimmune activation and remarkable expansion of CD4+ and CD8+ T effector cells de novo producing interferon γ or tumor necrosis factor α. Malaria-driven cellular hyperactivation/expansion and high-level Th1-cytokines enhanced SHIV disease characterized by increasing CD4+ T-cell depletion, profound lymphoid depletion or destruction, and even necrosis in lymph nodes and spleens. Importantly, malaria/SHIV-mediated depletion, destruction, and necrosis in lymphoid tissues led to bursting parasite replication and fatal virus-associated malaria. Surprisingly, chronically SHIV-infected macaques without AIDS employed different defense mechanisms during malaria coinfection, and mounted unique ∼200-fold expansion of interleukin 17+/interleukin 22+ T effectors with profound Th1 suppression. Such remarkable expansion of Th17/Th22 cells and inhibition of Th1 response coincided with development of immunity against fatal virus-associated malaria without accelerating SHIV disease. Conclusions. These novel findings suggest that virus infection status and selected Th1 or Th17/Th22 responses after malaria/AIDS-virus coinfection correlate with distinct outcomes of virus infection and malaria. PMID:21921207

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Xiaodan; School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Science, Jinan; Guo, Yuqi

Purpose: Inefficient T-cell reconstitution from x-ray–induced immune damage reduces antitumor response. To understand the profile of T-cell reconstitution after irradiation will overcome the barrier of antitumor immunity. This study aimed to identify the recovery profile of T-cell subsets following x-ray irradiation and to highlight the role of cinnamon on efficient T-cell restoration postexposure in the antitumor response. Methods and Materials: CD3{sup +}, CD8{sup +}, and CD4{sup +} T cells and Th1, Th2, Th17, and regulatory T (Treg) cells were evaluated at different time points after single low-dose total body irradiation (SLTBI) with or without cinnamon treatments. T-bet, GATA3, RORγt, and Foxp3more » signaling specific for Th1, Th2, Th17, and Treg were also analyzed by RT-PCR assay. The effects of cinnamon on efficient T-cell subset reconstitution was confirmed in a lung melanoma model in irradiated mice. Results: Reconstitution of CD4{sup +} T cells was delayed more than that of CD8{sup +} T cells in T-cell restoration after SLTBI. The production of IFNγ by Th1 or Tc1 cells was sharply decreased and was accompanied by reduced T-bet mRNA, even when total T-cell numbers had recovered; the frequencies of Th17 and Treg cells and their specific transcription factors (RORγt and Foxp3, respectively) were obviously increased. Irradiation-induced inefficient T-cell reconstitution impaired the antitumor capacities in the lung melanoma model. Pretreatment with cinnamon in irradiated mice accelerated the generation of Th1 and reduced the differentiation of Treg cells by activating T-bet and limiting transcriptions of Foxp3. Improvement resulting from cinnamon pretreatment on the efficient T-cell recovery profile from SLTBI promoted antitumor immunity in the lung melanoma model. Conclusions: T-cell reconstitution from SLTBI was characterized by impaired Th1 and elevated Th17 and Treg cells. Cinnamon effectively improved the imbalance of T-cell subsets by promoting the proliferation of Th1 and by suppressing expansions of Th17 and Tregs. The role of cinnamon in efficient T-cell reconstitution from SLTBI is effective in antitumor immunity.« less

Suppression of allergic airway inflammation in a mouse model by Der p2 recombined BCG.

PubMed

Ou-Yang, Hai-Feng; Hu, Xing-Bin; Ti, Xin-Yu; Shi, Jie-Ran; Li, Shu-Jun; Qi, Hao-Wen; Wu, Chang-Gui

2009-09-01

Allergic asthma is a chronic inflammatory disease mediated by T helper (Th)2 cell immune responses. Currently, immunotherapies based on both immune deviation and immune suppression, including the development of recombinant mycobacteria as immunoregulatory vaccines, are attractive treatment strategies for asthma. In our previous studies, we created a genetically recombinant form of bacille Calmette-Guerin (rBCG) that expressed Der p2 of house dust mites and established that it induced a shift from a Th2 response to a Th1 response in naive mice. However, it is unclear whether rBCG could suppress allergic airway inflammation in a mouse model. In this article we report that rBCG dramatically inhibited airway inflammation, eosinophilia, mucus production and mast cell degranulation in allergic mice. Analysis of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in bronchoalveolar lavage fluid (BALF) and lung tissue revealed that the suppression was associated with a shift from a Th2 response to a Th1 response. At the same time, rBCG induced a CD4(+) CD25(+) Foxp3(+) T-cell subtype that could suppress the proliferation of Th2 effector cells in vitro in an antigen-specific manner. Moreover, suppression of CD4(+) CD25(+) T cells could be adoptively transferred. Thus, our results demonstrate that rBCG induces both generic and specific immune responses. The generic immune response is associated with a shift from a Th2 to a Th1 cytokine response, whereas the specific immune response against Der p2 appears to be related to the expansion of transforming growth factor-beta (TGF-beta)-producing CD4(+) CD25(+) Foxp3(+) regulatory T cells. rBCG can suppress asthmatic airway inflammation through both immune deviation and immune suppression and may be a feasible, efficient immunotherapy for asthma.

Preventative Effect of an Herbal Preparation (HemoHIM) on Development of Airway Inflammation in Mice via Modulation of Th1/2 Cells Differentiation

PubMed Central

Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

2013-01-01

HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4+ T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4+ T cells displayed increased Th1 (IFN-γ+ cell) as well as decreased Th2 (IL-4+ cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance. PMID:23844220

Valsartan Attenuates KIR2.1 by Downregulating the Th1 Immune Response in Rats Following Myocardial Infarction.

PubMed

Li, Xinran; Hu, Hesheng; Wang, Ye; Xue, Mei; Li, Xiaolu; Cheng, Wenjuan; Xuan, Yongli; Yin, Jie; Yang, Na; Yan, Suhua

2016-03-01

Myocardial infarction (MI) results in decreased inward-rectifier K⁺ current (IK1), which is mediated primarily by the Kir2.1 protein and is accompanied by upregulated T cells. Interferon γ (IFN-γ), secreted predominantly by Th1 cells, causes a decrease in IK1 in microglia. Whether Th1 cells can induce IK1/Kir2.1 remodeling following MI and whether valsartan can ameliorate this phenomenon remain unclear. Rats experiencing MI received either valsartan or saline for 7 days. Th1-enriched lymphocytes and myocytes were cocultured with or without valsartan treatment. Th1 cells were monitored by flow cytometry. The protein levels of Kir2.1 were detected by Western blot analyses. IK1 was recorded through whole-cell patch clamping. The plasma levels of IFN-γ, interleukin 2, and tumor necrosis factor α were detected by enzyme-linked immunosorbent assay. Th1 cell number and cytokine expression levels were higher following MI, and the Kir2.1 protein level was decreased. In MI rats, valsartan reduced Th1 cell number and cytokine expression levels and increased the Kir2.1 expression and the IK1 current compared with the rats that received saline treatment; these results are consistent with the effect of valsartan in cocultured lymphocytes and myocytes. In vitro, IFN-γ overexpression suppressed the IK1 current, whereas interleukin 2 and tumor necrosis factor α had no significant effect on the current, establishing that Th1 cell regulation of IK1/Kir2.1 expression is mainly dependent on IFN-γ. Valsartan ameliorates IK1/Kir2.1 remodeling by downregulating the Th1 immune response following MI.

Establishment of HLA-DR4 Transgenic Mice for the Identification of CD4+ T Cell Epitopes of Tumor-Associated Antigens

PubMed Central

Harada, Kumiko; Michibata, Yayoi; Tsukamoto, Hirotake; Senju, Satoru; Tomita, Yusuke; Yuno, Akira; Hirayama, Masatoshi; Abu Sayem, Mohammad; Takeda, Naoki; Shibuya, Isao; Sogo, Shinji; Fujiki, Fumihiro; Sugiyama, Haruo; Eto, Masatoshi; Nishimura, Yasuharu

2013-01-01

Reports have shown that activation of tumor-specific CD4+ helper T (Th) cells is crucial for effective anti-tumor immunity and identification of Th-cell epitopes is critical for peptide vaccine-based cancer immunotherapy. Although computer algorithms are available to predict peptides with high binding affinity to a specific HLA class II molecule, the ability of those peptides to induce Th-cell responses must be evaluated. We have established HLA-DR4 (HLA-DRA*01:01/HLA-DRB1*04:05) transgenic mice (Tgm), since this HLA-DR allele is most frequent (13.6%) in Japanese population, to evaluate HLA-DR4-restricted Th-cell responses to tumor-associated antigen (TAA)-derived peptides predicted to bind to HLA-DR4. To avoid weak binding between mouse CD4 and HLA-DR4, Tgm were designed to express chimeric HLA-DR4/I-Ed, where I-Ed α1 and β1 domains were replaced with those from HLA-DR4. Th cells isolated from Tgm immunized with adjuvant and HLA-DR4-binding cytomegalovirus-derived peptide proliferated when stimulated with peptide-pulsed HLA-DR4-transduced mouse L cells, indicating chimeric HLA-DR4/I-Ed has equivalent antigen presenting capacity to HLA-DR4. Immunization with CDCA155-78 peptide, a computer algorithm-predicted HLA-DR4-binding peptide derived from TAA CDCA1, successfully induced Th-cell responses in Tgm, while immunization of HLA-DR4-binding Wilms' tumor 1 antigen-derived peptide with identical amino acid sequence to mouse ortholog failed. This was overcome by using peptide-pulsed syngeneic bone marrow-derived dendritic cells (BM-DC) followed by immunization with peptide/CFA booster. BM-DC-based immunization of KIF20A494-517 peptide from another TAA KIF20A, with an almost identical HLA-binding core amino acid sequence to mouse ortholog, successfully induced Th-cell responses in Tgm. Notably, both CDCA155-78 and KIF20A494-517 peptides induced human Th-cell responses in PBMCs from HLA-DR4-positive donors. Finally, an HLA-DR4 binding DEPDC1191-213 peptide from a new TAA DEPDC1 overexpressed in bladder cancer induced strong Th-cell responses both in Tgm and in PBMCs from an HLA-DR4-positive donor. Thus, the HLA-DR4 Tgm combined with computer algorithm was useful for preliminary screening of candidate peptides for vaccination. PMID:24386437

The expanding universe of T-cell subsets: Th1, Th2 and more.

PubMed

Mosmann, T R; Sad, S

1996-03-01

Since their discovery nearly ten years ago, T helper 1 (Th1) and Th2 subsets have been implicated in the regulation of many immune responses. In this article, Tim Mosmann and Subash Sad discuss the increasing number of T-cell subsets defined by cytokine patterns; the differentiation pathways of CD4+ and CD8+ T cells; the contribution of other cell types to these patterns; and the cytokine interactions during infection and pregnancy.

The dominant roles of ICAM-1-encoding gene in DNA vaccination against Japanese encephalitis virus are the activation of dendritic cells and enhancement of cellular immunity.

PubMed

Zhai, Yong-Zhen; Zhou, Yan; Ma, Li; Feng, Guo-He

2013-01-01

We investigated the cellular immune responses elicited by a plasmid DNA vaccine encoding prM-E protein from the Japanese encephalitis (JE) virus (JEV) with or without various forms of intercellular adhesion molecule (ICAM)-1 gene to maximize the immune responses evoked by the JE DNA vaccine. We observed that co-immunization with the construct containing murine ICAM-1 gene (pICAM-1) resulted in a significant increase in the percentage of CD4(+)T cells, high level of JEV-specific cytotoxic T lymphocyte response, and high production of T helper 1 (Th1)-type cytokines in splenic T cells. Furthermore, the co-expression of ICAM-1 and DNA immunogens was found to be more effective in generating T cell-mediated immune responses than those induced by immunization with pJME in combination with pICAM-1. Our results suggested that ICAM-1 enhanced T cell receptor signaling and activated Th1 immune responses in the JEV model system by increasing the induction of CD4(+)Th1 cell subset and activating dendritic cells. Copyright © 2013 Elsevier Inc. All rights reserved.

Phenytoin promotes Th2 type immune response in mice

PubMed Central

Okada, K; Sugiura, T; Kuroda, E; Tsuji, S; Yamashita, U

2001-01-01

The effects of chronic administration of phenytoin, a common anticonvulsive drug, on immune responses were studied in mice. Anti-keyhole limpet haemocyanin (KLH) IgE antibody response after KLH-immunization was enhanced in phenytoin-treated mice. Proliferative responses of spleen cells induced with KLH, concanavalin A (ConA), lipopolysaccharide and anti-CD3 antibody were reduced in phenytoin-treated mice. Accessory function of spleen adherent cells on ConA-induced T cell proliferative response was reduced in phenytoin-treated mice. KLH-induced IL-4 production of spleen cells was enhanced, while IFN-γ production was reduced in phenytoin-treated mice. In addition, production of IL-1α, but not IL-6 and IL-12 by spleen adherent cells from phenytoin-treated mice was reduced. Natural killer cell activity was reduced in phenytoin-treated mice. These results suggest that phenytoin treatment preferentially induces a Th2 type response. We also observed that plasma ACTH and corticosterone levels were increased in phenytoin-treated mice, and speculated that phenytoin might act directly and indirectly, through HPA axis activation, on the immune system to modulate Th1/Th2 balance. PMID:11472401

Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization.

PubMed

Renand, Amedee; Archila, Luis D; McGinty, John; Wambre, Erik; Robinson, David; Hales, Belinda J; Thomas, Wayne R; Kwok, William W

2015-12-01

In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood. We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced. Fel d 1-, Fel d 4-, Fel d 7-, and Fel d 8-specific T-cell responses were characterized by CD154 expression after antigen stimulation. In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)-specific TH2 (sTH2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sTH2 cells, which correlates with higher IgG4 levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG4 are present in allergic subjects and (2) cat allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages.

PubMed

Barros, Mário Henrique M; Hauck, Franziska; Dreyer, Johannes H; Kempkes, Bettina; Niedobitek, Gerald

2013-01-01

Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn's disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a suitable tool for the characterisation of macrophage polarisation in situ. Furthermore, CD163 cannot be considered a reliable M2 marker when used on its own.

Microenvironmental Regulation of Mammary Carcinogenesis

DTIC Science & Technology

2009-06-01

cells, leukocytes 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...metastatic spread to sentinel LNs and increased primary tumor size13. Perhaps more significant, the ratio of CD4+ to CD8+ T cells or TH2 to TH1 cells...present in primary tumors, where CD4+ or TH2 cells are more frequent than CD8+ or TH1 cells, correlates with LN metastasis and reduced overall patient

Down-regulation of Notch signaling pathway reverses the Th1/Th2 imbalance in tuberculosis patients.

PubMed

Li, Qifeng; Zhang, Hui; Yu, Liang; Wu, Chao; Luo, Xinhui; Sun, He; Ding, Jianbing

2018-01-01

Th1/Th2 imbalance to Th2 is of significance in the peripheral immune responses in Tuberculosis (TB) development. However, the mechanisms for Th1/Th2 imbalance are still not well determined. Notch signaling pathway is involved in the peripheral T cell activation and effector cell differentiation. However, whether it affects Th1/Th2 imbalance in TB patients is still not known. Here, we used γ-secretase inhibitor (DAPT) to treat the peripheral blood mononuclear cells (PBMCs) from healthy people or individuals with latent or active TB infection in vitro, respectively. Then, the Th1/Th2 ratios were determined by flow cytometry, and cytokines of IFN-γ, IL-4, IL-10 in the culture supernatant were measured by CBA method. The Notch signal pathway associated proteins Hes1, GATA3 and T-bet were quantitated by real-time PCR or immunoblotting. Our results showed that DAPT effectively inhibited the protein level of Hes1. In TB patients, the Th2 ratio increased in the PBMCs, alone with the high expression of GATA3 and IL-4, resulting in the high ratios of Th2/Th1 and GATA3/T-bet in TB patients. However, Th2 cells ratio decreased after blocking the Notch signaling pathway by DAPT and the Th2/Th1 ratio in TB patients were DAPT dose-dependent, accompanied by the decrease of IL-4 and GATA3. But, its influence on Th1 ratio and Th1 related T-bet and IFN-γ levels were not significant. In conclusion, our results suggest that blocking Notch signaling by DAPT could inhibit Th2 responses and restore Th1/Th2 imbalance in TB patients. Copyright © 2017. Published by Elsevier B.V.

CD4+ T-cell clones obtained from cattle chronically infected with Fasciola hepatica and specific for adult worm antigen express both unrestricted and Th2 cytokine profiles.

PubMed Central

Brown, W C; Davis, W C; Dobbelaere, D A; Rice-Ficht, A C

1994-01-01

The well-established importance of helper T (Th)-cell subsets in immunity and immunoregulation of many experimental helminth infections prompted a detailed study of the cellular immune response against Fasciola hepatica in the natural bovine host. T-cell lines established from two cattle infected with F. hepatica were characterized for the expression of T-cell surface markers and proliferative responses against F. hepatica adult worm antigen. Parasite-specific T-cell lines contained a mixture of CD4+, CD8+, and gamma/delta T-cell-receptor-bearing T cells. However, cell lines containing either fewer than 10% CD8+ T cells or depleted of gamma/delta T cells proliferated vigorously against F. hepatica antigen, indicating that these T-cell subsets are not required for proliferative responses in vitro. Seventeen F. hepatica-specific CD4+ Th-cell clones were examined for cytokine expression following concanavalin A stimulation. Biological assays to measure interleukin-2 (IL-2) or IL-4, gamma interferon (IFN-gamma), and tumor necrosis factor and Northern (RNA) blot analysis to verify the expression of IL-2, IL-4, and IFN-gamma revealed that the Th-cell clones expressed a spectrum of cytokine profiles. Several Th-cell clones were identified as Th2 cells by the strong expression of IL-4 but little or no IL-2 or IFN-gamma mRNA. The majority of Th-cell clones were classified as Th0 cells by the expression of either all three cytokines or combinations of IL-2 and IL-4 or IL-4 and IFN-gamma. No Th1-cell clones were obtained. All of the Th-cell clones expressed a typical memory cell surface phenotype, characterized as CD45Rlow, and all expressed the lymph node homing receptor (L selectin). These results are the first to describe cytokine responses of F. hepatica-specific T cells obtained from infected cattle and extend our previous analysis of Th0 and Th1 cells from cattle immune to Babesia bovis (W. C. Brown, V. M. Woods, D. A. E. Dobbelaere, and K. S. Logan, Infect. Immun. 61:3273-3281, 1993) to include F. hepatica-specific Th2 cells. Images PMID:7509319

BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Prevents Experimental Autoimmune Encephalomyelitis Disease Progression

PubMed Central

Timilshina, Maheshwor; Kang, Youra; Dahal, Ishmit; You, Zhiwei; Nam, Tae-gyu; Kim, Keuk-Jun

2017-01-01

CD4+ T cells are essential in inflammation and autoimmune diseases. Interferon-γ (IFN-γ) secreting T helper (Th1) and IL-17 secreting T helper (Th17) cells are critical for several autoimmune diseases. To assess the inhibitory effect of a given compound on autoimmune disease, we screened many compounds with an in vitro Th differentiation assay. BJ-3105, a 6-alkoxypyridin-3-ol analog, inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells which were activated by T cell receptor (TCR) engagement. BJ-3105 ameliorated the experimental autoimmune encephalomyelitis (EAE) model by reducing Th1 and Th17 generation. Notably, Th cell differentiation was significantly suppressed by BJ-3105 treatment without inhibiting in vitro proliferation of T cells or inducing programmed cell death. Mechanistically, BJ-3105 inhibited the phosphorylation of JAK and its downstream signal transducer and activator of transcription (STAT) that is critical for Th differentiation. These results demonstrated that BJ-3105 inhibits the phosphorylation of STAT in response to cytokine signals and subsequently suppressed the differentiation of Th cell responses. PMID:28095433

Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review.

PubMed

Asadi-Samani, Majid; Bagheri, Nader; Rafieian-Kopaei, Mahmoud; Shirzad, Hedayatollah

2017-08-01

Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Granulocytic myeloid-derived suppressor cells from human cord blood modulate T-helper cell response towards an anti-inflammatory phenotype.

PubMed

Köstlin, Natascha; Vogelmann, Margit; Spring, Bärbel; Schwarz, Julian; Feucht, Judith; Härtel, Christoph; Orlikowsky, Thorsten W; Poets, Christian F; Gille, Christian

2017-09-01

Infections are a leading cause of perinatal morbidity and mortality. The outstandingly high susceptibility to infections early in life is mainly attributable to the compromised state of the neonatal immune system. One important difference to the adult immune system is a bias towards T helper type 2 (Th2) responses in newborns. However, mechanisms regulating neonatal T-cell responses are incompletely understood. Granulocytic myeloid-derived suppressor cells (GR-MDSC) are myeloid cells with a granulocytic phenotype that suppress various functions of other immune cells and accumulate under physiological conditions during pregnancy in maternal and fetal blood. Although it has been hypothesized that GR-MDSC accumulation during fetal life could be important for the maintenance of maternal-fetal tolerance, the influence of GR-MDSC on the immunological phenotype of neonates is still unclear. Here, we investigated the impact of GR-MDSC isolated from cord blood (CB-MDSC) on the polarization of Th cells. We demonstrate that CB-MDSC inhibit Th1 responses and induced Th2 responses and regulatory T (Treg) cells. Th1 inhibition was cell-contact dependent and occurred independent of other cell types, while Th2 induction was mediated independently of cell contact through expression of ArgI and reactive oxygen species by CB-MDSC and partially needed the presence of monocytes. Treg cell induction by CB-MDSC also occurred cell-contact independently but was partially mediated through inducible nitric oxide synthase. These results point towards a role of MDSC in regulating neonatal immune responses. Targeting MDSC function in neonates could be a therapeutic opportunity to improve neonatal host defence. © 2017 John Wiley & Sons Ltd.

Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with allergic asthma.

PubMed

Shi, Yu-heng; Shi, Guo-chao; Wan, Huan-ying; Jiang, Li-hua; Ai, Xiang-yan; Zhu, Hai-xing; Tang, Wei; Ma, Jia-yun; Jin, Xiao-yan; Zhang, Bo-ying

2011-07-05

Recent recognition is that Th2 response is insufficient to fully explain the aetiology of asthma. Other CD4(+) T cells subsets might play a role in asthma. We investigated the relative abundance and activities of Th1, Th2, Th17 and CD4(+)CD25(+) Treg cells in patients with allergic asthma. Twenty-two patients with mild asthma, 17 patients with moderate to severe asthma and 20 healthy donors were enrolled. All patients were allergic to house dust mites. Plasma total IgE, pulmonary function and Asthma Control Questionnaire were assessed. The proportions of peripheral blood Th1, Th2, Th17 and CD4(+)CD25(+) Treg cells were determined by flow cytometry. The expression of cytokines in plasma and in the culture supernatant of peripheral blood mononuclear cells was determined by enzyme linked, immunosorbent assay. The frequency of blood Th2 cells and IL-4 levels in plasma and culture supernatant of peripheral blood mononuclear cells were increased in all patients with allergic asthma. The frequency of Th17 cells and the plasma and culture supernatant levels of IL-17 were increased, whereas the frequency of CD4(+)CD25(+) Treg cells and plasma IL-10 levels were decreased in patients with moderate to severe asthma. Dermatophagoides pteronyssinus specific IgE levels were positively correlated with the percentage of blood Th2 cells and plasma IL-4 levels. Forced expiratory volume in the first second was negatively correlated with the frequency of Th17 cells and plasma IL-17 levels, and positively correlated with the frequency of Treg cells. However, mean Asthma Control Questionnaire scores were positively correlated with the frequency of Th17 cells and plasma IL-17 levels, and negatively correlated with the frequency of Treg cells. Imbalances in Th1/Th2 and Th17/Treg were found in patients with allergic asthma. Furthermore, elevated Th17 cell responses, the absence of Tregs and an imbalance in Th17/Treg levels were associated with moderate to severe asthma.

Cell-mediated immune response and Th/Th cytokine profile of B-T constructs of F1 and V antigen of Yersinia pestis.

PubMed

Gupta, G; Khan, A A; Rao, D N

2010-03-01

Yersinia pestis, a Gram-negative bacterium, is the etiological agent of pneumonic and bubonic plague and still active in various regions of the world. Because plague is highly infectious and can readily spread by aerosolization, it poses a bioterrorism threat. The effective induction of mucosal as well as systemic immunity is an important attribute of an improved vaccine for plague. An alternative approach described here is the use of protective epitopes derived from immunodominant antigens (F1 and V) of Yersinia pestis. As T-cell immunity is also a major contributor of protection, microencapsulated B-T constructs of F1 and V antigen were used to immunize outbred and inbred mice through intranasal route, and lympho-proliferative response and cytokine profile of both Th(1) and Th(2) arms were measured in spleen, lamina propria and Peyer's patches. Three B-T constructs of F1 antigen and seven of V antigen showed significantly high T-cell response in terms of inducing systemic as well as mucosal response when compared to constituent peptides. These ten conjugates showed Th(1) cytokine profile whereas rest of the conjugates showed mixed Th(1)/Th(2) response. Four conjugates of V antigen showed high level of IL-10 production. In present study, microencapsulated B-T constructs after intranasal immunization generated systemic as well as mucosal immune response in all three sites, which offers an alternative approach for plague vaccine.

The active contribution of Toll-like receptors to allergic airway inflammation.

PubMed

Chen, Keqiang; Xiang, Yi; Yao, Xiaohong; Liu, Ying; Gong, Wanghua; Yoshimura, Teizo; Wang, Ji Ming

2011-10-01

Epithelia lining the respiratory tract represent a major portal of entry for microorganisms and allergens and are equipped with innate and adaptive immune signaling receptors for host protection. These include Toll-like receptors (TLRs) that recognize microbial components and evoke diverse responses in cells of the respiratory system. TLR stimulation by microorganism-derived molecules activates antigen presenting cells, control T helper (Th) 1, Th2, and Th17 immune cell differentiation, cytokine production by mast cells, and activation of eosinophils. It is clear that TLR are involved in the pathophysiology of allergic airway diseases such as asthma. Dendritic cells (DCs), a kind of antigen presenting cells, which play a key role in the induction of allergic airway inflammation, are privileged targets for pathogen associated molecular patterns (PAMPs). During the allergic responses, engagement of TLRs on DCs determines the Th2 polarization of the T cells. TLR signaling in mast cells increases the release of IL-5, and TLR activation of airway epithelial cells forces the generation of proallergic Th2 type of cytokines. Although these responses aim to protect the host, they may also result in inflammatory tissue damage in the airway. Under certain conditions, stimulation of TLRs, in particular, TLR9, may reduce Th2-dependent allergic inflammation by induction of Th1 responses. Therefore, understanding the complex regulatory roles of TLRs in the pathogenesis of allergic airway inflammation should facilitate the development of preventive and therapeutic measures for asthmatic patients. Copyright © 2011 Elsevier B.V. All rights reserved.

Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry.

PubMed

Kunicki, Matthew A; Amaya Hernandez, Laura C; Davis, Kara L; Bacchetta, Rosa; Roncarolo, Maria-Grazia

2018-01-01

Human CD3 + CD4 + Th cells, FOXP3 + T regulatory (Treg) cells, and T regulatory type 1 (Tr1) cells are essential for ensuring peripheral immune response and tolerance, but the diversity of Th, Treg, and Tr1 cell subsets has not been fully characterized. Independent functional characterization of human Th1, Th2, Th17, T follicular helper (Tfh), Treg, and Tr1 cells has helped to define unique surface molecules, transcription factors, and signaling profiles for each subset. However, the adequacy of these markers to recapitulate the whole CD3 + CD4 + T cell compartment remains questionable. In this study, we examined CD3 + CD4 + T cell populations by single-cell mass cytometry. We characterize the CD3 + CD4 + Th, Treg, and Tr1 cell populations simultaneously across 23 memory T cell-associated surface and intracellular molecules. High-dimensional analysis identified several new subsets, in addition to the already defined CD3 + CD4 + Th, Treg, and Tr1 cell populations, for a total of 11 Th cell, 4 Treg, and 1 Tr1 cell subsets. Some of these subsets share markers previously thought to be selective for Treg, Th1, Th2, Th17, and Tfh cells, including CD194 (CCR4) + FOXP3 + Treg and CD183 (CXCR3) + T-bet + Th17 cell subsets. Unsupervised clustering displayed a phenotypic organization of CD3 + CD4 + T cells that confirmed their diversity but showed interrelation between the different subsets, including similarity between Th1-Th2-Tfh cell populations and Th17 cells, as well as similarity of Th2 cells with Treg cells. In conclusion, the use of single-cell mass cytometry provides a systems-level characterization of CD3 + CD4 + T cells in healthy human blood, which represents an important baseline reference to investigate abnormalities of different subsets in immune-mediated pathologies. Copyright © 2017 by The American Association of Immunologists, Inc.

On the Mechanism Determining the Th1/Th2 Phenotype of an Immune Response, and its Pertinence to Strategies for the Prevention, and Treatment, of Certain Infectious Diseases

PubMed Central

Bretscher, P A

2014-01-01

It is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, are often critically dependent on the class of immunity generated. Here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates Th1 or Th2 cells. We refer to this mechanism as the ‘decision criterion’ controlling the Th1/Th2 phenotype of the immune response. A plausible decision criterion should account for the variables of immunization known to affect the Th1/Th2 phenotype of the ensuing immune response. Documented variables include the nature of the antigen, in terms of its degree of foreignness, the dose of antigen and the time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. These are quantitative variables made at the level of the system. In addition, the route of immunization is also critical. I describe a quantitative hypothesis as to the nature of the decision criterion, referred to as the Threshold Hypothesis. This hypothesis accounts for the quantitative variables of immunization known to affect the Th1/Th2 phenotype of the immune response generated. I suggest and illustrate how this is not true of competing, contemporary hypotheses. I outline studies testing predictions of the hypothesis and illustrate its potential utility in designing strategies to prevent or treat medical situations where a predominant Th1 response is required to contain an infection, such as those caused by HIV-1 and by Mycobacterium tuberculosis, or to contain cancers. PMID:24684592

Follicular helper T cell in immunity and autoimmunity.

PubMed

Mesquita, D; Cruvinel, W M; Resende, L S; Mesquita, F V; Silva, N P; Câmara, N O S; Andrade, L E C

2016-01-01

The traditional concept that effector T helper (Th) responses are mediated by Th1/Th2 cell subtypes has been broadened by the recent demonstration of two new effector T helper cells, the IL-17 producing cells (Th17) and the follicular helper T cells (Tfh). These new subsets have many features in common, such as the ability to produce IL-21 and to express the IL-23 receptor (IL23R), the inducible co-stimulatory molecule ICOS, and the transcription factor c-Maf, all of them essential for expansion and establishment of the final pool of both subsets. Tfh cells differ from Th17 by their ability to home to B cell areas in secondary lymphoid tissue through interactions mediated by the chemokine receptor CXCR5 and its ligand CXCL13. These CXCR5+ CD4+ T cells are considered an effector T cell type specialized in B cell help, with a transcriptional profile distinct from Th1 and Th2 cells. The role of Tfh cells and its primary product, IL-21, on B-cell activation and differentiation is essential for humoral immunity against infectious agents. However, when deregulated, Tfh cells could represent an important mechanism contributing to exacerbated humoral response and autoantibody production in autoimmune diseases. This review highlights the importance of Tfh cells by focusing on their biology and differentiation processes in the context of normal immune response to infectious microorganisms and their role in the pathogenesis of autoimmune diseases.

Downregulation of CXCR6 and CXCR3 in lymphocytes from birch-allergic patients.

PubMed

Casas, R; Lindau, C; Zetterström, O; Duchén, K

2008-09-01

Preferential expression of chemokine receptors on Th1 or Th2 T-helper cells has mostly been studied in cell lines generated in vitro or in animal models; however, results are less well characterized in humans. We determined T-cell responses through chemokine receptor expression on lymphocytes, and cytokine secretion in plasma from birch-allergic and healthy subjects. The expression of CCR2, CCR3, CCR4, CCR5, CCR7, CXCR3, CXCR4, CXCR6, IL-12 and IL-18R receptors was studied on CD4(+) and CD8(+) cells from birch-allergic (n = 14) and healthy (n = 14) subjects by flow cytometry. The concentration of IL-4, IL-5, IL-10, IL-12, IFN-gamma and TNF-alpha cytokines was measured in plasma from the same individuals using a cytometric bead array human cytokines kit. The similar expression of CCR4 in T cells from atopic and healthy individuals argues against the use of the receptor as an in vivo marker of Th2 immune responses. Reduced percentages of CD4(+) cells expressing IL-18R, CXCR6 and CXCR3 were found in the same group of samples. TNF-alpha, IFN-gamma, IL-10, IL-5, IL-4 and IL-12 cytokines were elevated in samples from allergic individuals. Reduced expression of Th1-associated chemokine receptors together with higher levels of Th1, Th2 and anti-inflammatory cytokines in samples from allergic patients indicate that immune responses in peripheral blood in atopic diseases are complex and cannot be simplified to the Th1/Th2 paradigm. Not only the clinical picture of atopic diseases but also the clinical state at different time points of the disease might influence the results of studies including immunological markers associated with Th1- or Th2-type immune responses.

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis.

PubMed

Martin, Nina M; Griffin, Diane E

2018-03-15

Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash, and encephalomyelitis. Previous studies in mice with a virulent strain (neuroadapted SINV [NSV]) of the alphavirus Sindbis virus (SINV) identified a role for Th17 cells and regulation by interleukin-10 (IL-10) in the pathogenesis of fatal encephalomyelitis (K. A. Kulcsar, V. K. Baxter, I. P. Greene, and D. E. Griffin, Proc Natl Acad Sci U S A 111:16053-16058, 2014, https://doi.org/10.1073/pnas.1418966111). To determine the role of virus virulence in generation of immune responses, we analyzed the modulatory effects of IL-10 on disease severity, virus clearance, and the CD4 + T cell response to infection with a recombinant strain of SINV of intermediate virulence (TE12). The absence of IL-10 during TE12 infection led to longer morbidity, more weight loss, higher mortality, and slower viral clearance than in wild-type mice. More severe disease and impaired virus clearance in IL-10 -/- mice were associated with more Th1 cells, fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells, and B cells, and delayed production of antiviral antibody in the central nervous system (CNS) without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain. IMPORTANCE Alphaviruses cause mosquito-borne outbreaks of encephalomyelitis, but determinants of outcome are incompletely understood. We analyzed the effects of the anti-inflammatory cytokine IL-10 on disease severity and virus clearance after infection with an alphavirus strain of intermediate virulence. The absence of IL-10 led to longer illness, more weight loss, more death, and slower viral clearance than in mice that produced IL-10. IL-10 influenced development of disease-causing T cells and entry into the brain of B cells producing antiviral antibody. The Th1 pathogenic cell subtype that developed in IL-10-deficient mice infected with a less virulent virus was distinct from the Th17 subtype that developed in response to a more virulent virus, indicating a role for virus strain in determining the immune response. Slow production of antibody in the nervous system led to delayed virus clearance. Therefore, both the virus strain and the host response to infection are important determinants of outcome. Copyright © 2018 American Society for Microbiology.

Lenalidomide Synergistically Enhances the Effect of Dendritic Cell Vaccination in a Model of Murine Multiple Myeloma.

PubMed

Nguyen-Pham, Thanh-Nhan; Jung, Sung-Hoon; Vo, Manh-Cuong; Thanh-Tran, Huong-Thi; Lee, Youn-Kyung; Lee, Hyun-Ju; Choi, Nu-Ri; Hoang, My-Dung; Kim, Hyeoung-Joon; Lee, Je-Jung

2015-10-01

We investigated the efficacy of lenalidomide (LEN) in combination with dendritic cell (DC) vaccination in the MOPC-315 murine myeloma model. After tumor growth, LEN was injected intraperitoneally for 4 consecutive days in combination with DC vaccination. The combination of LEN and vaccination efficiently inhibited tumor growth compared with the single agents alone. A cytotoxic assay revealed that the anticancer effects of DC vaccination plus LEN involved not only generation of antigen-specific cytotoxic T lymphocytes but also NK cells. Vaccinated mice had reduced numbers of suppressor cells, including both myeloid-derived suppressor cells and regulatory T cells, in the spleen. The proportions of CD4+ and CD8+ T cells increased in the spleen, and a Th1 cytokine (interferon-γ) rather than a Th2 cytokine (interleukin-10) was synthesized in response to tumor antigens. LEN enhanced the innate immune response by modulating NK cell numbers and function. In addition, LEN reduced the production levels of angiogenesis-inducing factors in tumor-bearing mice. Together, these results suggest that a combination of LEN and DC vaccination may synergistically enhance anticancer immunity in the murine myeloma model, by inhibiting immunosuppressor cells and stimulating effector cells, as well as effectively polarizing the Th1/Th2 balance in favor of a Th1-specific immune response.

Use of a LiESP/QA-21 Vaccine (CaniLeish) Stimulates an Appropriate Th1-Dominated Cell-Mediated Immune Response in Dogs

PubMed Central

Moreno, Javier; Vouldoukis, Ioannis; Martin, Virginie; McGahie, David; Cuisinier, Anne-Marie; Gueguen, Sylvie

2012-01-01

Canine leishmaniasis is an important zoonotic disease of dogs. The clinical outcome of infection is variable, with the efficiency of the immune response being the key determining factor. There is now a general consensus that a predominant Th1 immune profile in an overall mixed Th1/Th2 response is associated with resistance in dogs, and the absence of a strong Th1 influence is associated with a progression to clinical disease. As a result, there has been a growing demand for vaccines that can induce a specific, strong Th1 response. In this study, we measured the impact of a primary course of a newly available LiESP/QA-21 vaccine on selected humoral and cellular markers of the canine immune response during the onset of immunity. All vaccinated dogs developed a humoral response characterised by IgG2 production. More importantly, vaccinated dogs developed significantly stronger cell-mediated immunity responses than did control dogs. Vaccination induced specific cellular reactivity to soluble Leishmania antigens, with a Leishmania-specific lymphoproliferation (p = 0.0072), characterised by an increased population of T lymphocytes producing IFN-γ (p = 0.0021) and a significant ability of macrophages to reduce intracellular parasite burdens in vitro after co-culture with autologous lymphocytes (p = 0.0014). These responses were correlated with induction of the NOS pathway and production of NO derivatives, which has been shown to be an important leishmanicidal mechanism. These results confirm that vaccination with LiESP/QA-21 induces an appropriate Th1-profile cell-mediated response within three weeks of completing the primary course, and that this response effectively reduces the parasite load in pre-infected macrophages in vitro. PMID:22724031

Dendritic Cells Induce a Subpopulation of IL-12Rβ2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses

PubMed Central

Sela, Uri; Park, Chae Gyu; Park, Andrew; Olds, Peter; Wang, Shu; Fischetti, Vincent A.

2016-01-01

Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response. In the current study we used the mixed leukocyte reaction (MLR) to investigate the effect of allospecific Treg on IL-12, TNFα and IL-6 secretion by DCs. Treg cells were found to markedly down-regulate IL-12 secretion from DCs following stimulation with TLR7/8 agonist. This down-regulation of IL-12 was neither due to a direct suppression of its production by the DCs nor a result of marked DC death. We found that IL-12 was rather actively consumed by Treg cells. IL-12 consumption was mediated by a subpopulation of IL-12Rβ2-expressing Treg cells and was dependent on MHC class-II expressed on dendritic cells. Furthermore, IL-12 consumption by Tregs increased their suppressive effect on T cell proliferation and Th1 activation. These results provide a new pathway of Th1 response regulation where IL-12 secreted by DCs is consumed by a sub-population of IL-12Rβ2-expressing Treg cells. Consumption of IL-12 by Tregs not only reduces the availability of IL-12 to Th effector cells but also enhances the Treg immunosuppressive effect. This DC-induced IL-12Rβ2-expressing Treg subpopulation may have a therapeutic advantage in suppressing Th1 mediated autoimmunity. PMID:26745371

Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses

PubMed Central

Chen, Qian-Qian; Yan, Li; Wang, Chang-Zheng; Wang, Wei-Hua; Shi, Hui; Su, Bin-Bin; Zeng, Qing-Huan; Du, Hai-Tao; Wan, Jun

2013-01-01

AIM: To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD. METHODS: A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by measuring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined. RESULTS: Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by down-regulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4+CD25+Foxp3+ regulatory T cells (TGF-β, IL-10, Foxp3) with a suppressive capacity on Th1-Th17 effecter responses and promoted Th2 differentiation in vivo (P < 0.05). CONCLUSION: MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD. PMID:23922467

Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage.

PubMed

Hendricks, Deborah W; Fink, Pamela J

2011-01-27

After intrathymic development, T cells exit the thymus and join the peripheral T-cell pool. Such recent thymic emigrants (RTEs) undergo both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. Using a well-controlled in vitro polarization scheme, we now show that CD4(+) RTEs are defective in T-helper (Th) type 0 (Th0), Th1, Th17, and regulatory T-cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, CD4(+) RTES are biased toward the Th2 lineage both in vitro and in vivo, with more robust interleukin-4, interleukin-5, and interleukin-13 production than their mature naive counterparts. Coculture experiments demonstrate that mature naive T cells influence neighboring RTEs in their Th responses. In adoptive hosts, CD4(+) RTEs drive production of the Th2-associated antibody isotype immunoglobulin G1 and mediate airway inflammatory disease. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4(+) RTEs thus represent a transitional population with a distinct interpretation of, and response to, immunologic cues. These characteristics may be beneficial during the postthymic maturation period by leading to the avoidance of inappropriate immune responses, particularly in lymphopenic neonates and adults.

Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination

PubMed Central

Pedotti, Rosetta; DeVoss, Jason J.; Youssef, Sawsan; Mitchell, Dennis; Wedemeyer, Jochen; Madanat, Rami; Garren, Hideki; Fontoura, Paulo; Tsai, Mindy; Galli, Stephen J.; Sobel, Raymond A.; Steinman, Lawrence

2003-01-01

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc ɛ receptor 1 (FcɛRI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig FcγRIII or both FcγRIII and FcɛRI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and “allergic” responses. PMID:12576552

Eosinophils are required to suppress Th2 responses in Peyer's patches during intestinal infection by nematodes.

PubMed

Strandmark, J; Steinfelder, S; Berek, C; Kühl, A A; Rausch, S; Hartmann, S

2017-05-01

Infections with enteric nematodes result in systemic type 2 helper T (Th2) responses, expansion of immunoglobulin (Ig)G1 antibodies, and eosinophilia. Eosinophils have a supportive role in mucosal Th2 induction during airway hyperreactivity. Whether eosinophils affect the local T-cell and antibody response in the gut-associated lymphoid tissue during enteric infections is unknown. We infected eosinophil-deficient ΔdblGATA-1 mice with the Th2-inducing small intestinal nematode Heligmosomoides polygyrus and found that parasite fecundity was decreased in the absence of eosinophils. A lack of eosinophils resulted in significantly augmented expression of GATA-3 and IL-4 by CD4 + T cells during acute infection, a finding strictly limited to Peyer's patches (PP). The increase in IL-4-producing cells in ΔdblGATA-1 mice was particularly evident within the CXCR5 + PD-1 + T-follicular helper cell population and was associated with a switch of germinal centre B cells to IgG1 production and elevated serum IgG1 levels. In contrast, infected wild-type mice had a modest IgG1 response in the PP, whereas successfully maintaining a population of IgA + germinal center B cells. Our results suggest a novel role for eosinophils during intestinal infection whereby they restrict IL-4 responses by follicular T helper cells and IgG1 class switching in the PP to ensure maintenance of local IgA production.

Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice.

PubMed

Elhaik Goldman, Shirin; Dotan, Shahar; Talias, Amir; Lilo, Amit; Azriel, Shalhevet; Malka, Itay; Portnoi, Maxim; Ohayon, Ariel; Kafka, Daniel; Ellis, Ronald; Elkabets, Moshe; Porgador, Angel; Levin, Ditza; Azhari, Rosa; Swiatlo, Edwin; Ling, Eduard; Feldman, Galia; Tal, Michael; Dagan, Ron; Mizrachi Nebenzahl, Yaffa

2016-04-01

Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co-cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA‑pulsed APCs. The levels of the Th1-type cytokines, interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17-type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA‑immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1 involvement. In addition, rabbit and mouse anti-rFBA antisera significantly protected the mice against a lethal S. pneumoniae challenge in comparison with preimmune sera. Our results emphasize the mixed involvement of the Th1, Th2 and Th17 arms of the immune system in response to immunization with pneumococcal rFBA, a potential vaccine candidate.

The relevance of TH1 and TH2 cells in immediate and nonimmediate reactions to gelatin-containing vaccine.

PubMed

Ohsaki, M; Tsutsumi, H; Kumagai, T; Yamanaka, T; Wataya, Y; Furukawa, H; Kojima, H; Saito, A; Yano, S; Chiba, S

1999-02-01

The immune mechanism of gelatin allergy, especially the participation of TH1 and TH2 cells and their cytokine secretion, has not been investigated. We investigated the characteristics of T lymphocytes from patients allergic to gelatin-containing vaccine by secondary in vitro stimulation of circulating mononuclear cells with gelatin. We studied 8 children with a history of immediate-type reactions and 8 with nonimmediate-type reactions after inoculation of gelatin-containing vaccine. The expression of IFN-gamma (TH1 ), IL-2 (TH1 ), IL-4 (TH2 ), and IL-13 (TH2 ) mRNA was examined semiquantitatively by using a reverse transcriptase PCR. IgE antibody to bovine gelatin was measured with the fluorometric ELISA system, and gelatin-specific T-cell responses were detected by an in vitro lymphocyte proliferation assay. Patients with an immediate reaction all had gelatin-specific IgE antibody, whereas others did not. However, all patients exhibited positive T-lymphocyte responses specific to gelatin. Lymphocytes from subjects with nonimmediate-type reactions generally expressed very weak or sometimes no IFN-gamma, IL-2, or IL-13 genes and especially no IL-4 gene. On the other hand, the lymphocytes of subjects with immediate-type reactions significantly expressed not only IL-4 and IL-13 but also IFN-gamma and IL-2 mRNA. Our observations suggest that both gelatin-specific TH2 and TH1 responses are involved in the pathogenesis of the immediate reaction to gelatin. The gelatin-specific IL-4 and/or IL-13 responses consistently observed in patients with an immediate reaction may be associated with the production of gelatin-specific IgE antibody.

Interleukin-4 production by Follicular Helper T cells requires the conserved Il4 enhancer HS V

PubMed Central

Vijayanand, Pandurangan; Seumois, Grégory; Simpson, Laura J.; Abdul-Wajid, Sarah; Baumjohann, Dirk; Panduro, Marisella; Huang, Xiaozhu; Interlandi, Jeneen; Djuretic, Ivana M.; Brown, Daniel R.; Sharpe, Arlene H.; Rao, Anjana; Ansel, K. Mark

2012-01-01

SUMMARY Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that HS V (also known as CNS2), a 3’ enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in Th2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation, and increased accessibility of the Il4 promoter. Thus Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of Th2 mediated allergic diseases. PMID:22326582

CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model

PubMed Central

Connolly, Michael; Marketon, Anthony

2016-01-01

Allergies caused by Japanese Red Cedar (JRC) pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1) to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naïve mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-γ and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4+ T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses. PMID:27239481

Desmoglein 3-specific T regulatory 1 cells consist of two subpopulations with differential expression of the transcription factor Foxp3

PubMed Central

Veldman, Christian; Pahl, Andreas; Hertl, Michael

2009-01-01

Pemphigus vulgaris (PV) is an autoimmune bullous skin disorder associated with autoantibodies against desmoglein (Dsg) 3. An imbalance of type 1 regulatory T (Tr1) cells and T helper type 2 (Th2) cells specific for Dsg3 may be critical for the loss of tolerance against Dsg3 in PV. Within the population of Dsg3-responsive, interleukin (IL)-10-secreting Tr1 cell clones, two major subpopulations were identified and sorted by fluorescence-activated cell sorting (FACS) based on their size and granularity. Upon in vitro culture, the larger subpopulation differentiated back into the two former subpopulations of the Tr1 cell clones, while the smaller subpopulation died within 2 weeks. The smaller subpopulation of the Tr1 cell clones was characterized by the expression of Foxp3, the secretion of IL-10, transforming growth factor (TGF)-β and IL-5 upon stimulation with Dsg3, a proliferative response to IL-2 but not to Dsg3 or mitogenic stimuli, and an inhibitory effect on the proliferative response of Dsg3-responsive Th clones in a Dsg3-specific manner. In contrast, the larger subpopulation showed a Th-like phenotype, lacking Foxp3, cytotoxic T-lymphocyte antigen 4 (CTLA4) and glucocorticoid-induced tumour necrosis factor receptor (GITR) expression and IL-2 secretion, and did not mount a proliferative response to Dsg3 and mitogenic stimuli. The two Tr1 subpopulations showed expression of identical T-cell receptor (TCR) Vβ chains which varied among the PV patients studied. Upon inhibition of Foxp3, the smaller Tr1 subpopulation developed a proliferate response to Dsg3 and mitogenic stimuli, no longer suppressed Dsg3-specific Th cells, lost expression of GITR and CTLA4 and secreted IL-2. Thus, our observations suggest a distinct relationship between Dsg3-specific Tr1 and Th-like cells which may be critical for the continuous generation and survival of Dsg3-specific Tr1 cells. PMID:18800988

Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

PubMed Central

Carbo, Adria; Hontecillas, Raquel; Kronsteiner, Barbara; Viladomiu, Monica; Pedragosa, Mireia; Lu, Pinyi; Philipson, Casandra W.; Hoops, Stefan; Marathe, Madhav; Eubank, Stephen; Bisset, Keith; Wendelsdorf, Katherine; Jarrah, Abdul; Mei, Yongguo; Bassaganya-Riera, Josep

2013-01-01

Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa. PMID:23592971

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Ying; Li, Cuiying; Weng, Dong

Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentagemore » of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung inflammation and fibrosis.« less

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model.

PubMed

Banerjee, Antara; Bhattacharya, Parna; Dagur, Pradeep K; Karmakar, Subir; Ismail, Nevien; Joshi, Amritanshu B; Akue, Adovi D; KuKuruga, Mark; McCoy, John Philip; Dey, Ranadhir; Nakhasi, Hira L

2018-01-01

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani ( LdCen -/- ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen -/- -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen -/- parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen -/- Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen -/- -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-γ-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-γ abrogated LdCen -/- -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R -/- mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen -/- parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen -/- parasite-induced immunity and subsequent protection against visceral leishmaniasis.

Immunopathology of leishmaniasis: an update.

PubMed

Mansueto, P; Vitale, G; Di Lorenzo, G; Rini, G B; Mansueto, S; Cillari, E

2007-01-01

Leishmaniasis represents a severe, increasing, public health problem. The perspective of its control is highly dependent on research progress, on therapeutic manipulations of the immune system, and on vaccine development. There is a correlation between the clinical outcome of Leishmania infection and the cytokine response profile. While a protective immune response against Leishmania has been clearly identified to be related to the influence of a type-1 response and IFN-gamma production, the precise role of T helper (TH) 2 cytokines in non-healing infections requires further exploration. IL-4 and IL-13 (TH2 cytokines) can promote disease progression in cutaneous leishmaniasis, whereas IL-4 would appear to enhance protective type-1 responses in visceral leishmaniasis. Thus, the TH1/TH2 paradigm of resistance/susceptibility to intracellular parasites is probably an oversimplification of a more complicated network of regulatory/counter regulatory interactions. Moreover, the presence of antigen specific regulatory T cell subsets may provide an environment that contributes to the balance between TH1 and TH2 cells. Finally, the involvement of CD8 positive T cells has been described, but the modality of their function in this kind of infection has not been so far elucidated.

Role of Th17 Cells in the Pathogenesis of Human IBD

PubMed Central

Gálvez, Julio

2014-01-01

The gastrointestinal tract plays a central role in immune system, being able to mount efficient immune responses against pathogens, keeping the homeostasis of the human gut. However, conditions like Crohn's disease (CD) or ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD), are related to an excessive and uncontrolled immune response against normal microbiota, through the activation of CD4+ T helper (Th) cells. Classically, IBD was thought to be primarily mediated by Th1 cells in CD or Th2 cells in UC, but it is now known that Th17 cells and their related cytokines are crucial mediators in both conditions. Th17 cells massively infiltrate the inflamed intestine of IBD patients, where they produce interleukin- (IL-) 17A and other cytokines, triggering and amplifying the inflammatory process. However, these cells show functional plasticity, and they can be converted into either IFN-γ producing Th1 cells or regulatory T cells. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut. Deeper insights into their plasticity in inflammatory conditions will contribute to advancing our understanding of the mechanisms that regulate mucosal homeostasis and inflammation in the gut, promoting the design of novel therapeutic approaches for IBD. PMID:25101191

Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases.

PubMed Central

Lucey, D R; Clerici, M; Shearer, G M

1996-01-01

In the mid-1980s, Mosmann, Coffman, and their colleagues discovered that murine CD4+ helper T-cell clones could be distinguished by the cytokines they synthesized. The isolation of human Th1 and Th2 clones by Romagnani and coworkers in the early 1990s has led to a large number of reports on the effects of Th1 and Th2 on the human immune system. More recently, cells other than CD4+ T cells, including CD8+ T cells, monocytes, NK cells, B cells, eosinophils, mast cells, basophils, and other cells, have been shown to be capable of producing "Th1" and "Th2" cytokines. In this review, we examine the literature on human diseases, using the nomenclature of type 1 (Th1-like) and type 2 (Th2-like) cytokines, which includes all cell types producing these cytokines rather than only CD4+ T cells. Type 1 cytokines include interleukin-2 (IL-2), gamma interferon, IL-12 and tumor necrosis factor beta, while type 2 cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. In general, type 1 cytokines favor the development of a strong cellular immune response whereas type 2 cytokines favor a strong humoral immune response. Some of these type 1 and type 2 cytokines are cross-regulatory. For example, gamma interferon and IL-12 decrease the levels of type 2 cytokines whereas IL-4 and IL-10 decrease the levels of type 1 cytokines. We use this cytokine perspective to examine human diseases including infections due to viruses, bacteria, parasites, and fungi, as well as selected neoplastic, atopic, rheumatologic, autoimmune, and idiopathic-inflammatory conditions. Clinically, type 1 cytokine-predominant responses should be suspected in any delayed-type hypersensitivity-like granulomatous reactions and in infections with intracellular pathogens, whereas conditions involving hypergammaglobulinemia, increased immunoglobulin E levels, and/or eosinophilia are suggestive of type 2 cytokine-predominant conditions. If this immunologic concept is relevant to human diseases, the potential exists for novel cytokine-based therapies and novel cytokine-directed preventive vaccines for such diseases. PMID:8894351

Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity.

PubMed

Querec, Troy; Bennouna, Soumaya; Alkan, Sefik; Laouar, Yasmina; Gorden, Keith; Flavell, Richard; Akira, Shizuo; Ahmed, Rafi; Pulendran, Bali

2006-02-20

The live attenuated yellow fever vaccine 17D (YF-17D) is one of the most effective vaccines available, with a 65-yr history of use in >400 million people globally. Despite this efficacy, there is presently no information about the immunological mechanisms by which YF-17D acts. Here, we present data that suggest that YF-17D activates multiple Toll-like receptors (TLRs) on dendritic cells (DCs) to elicit a broad spectrum of innate and adaptive immune responses. Specifically, YF-17D activates multiple DC subsets via TLRs 2, 7, 8, and 9 to elicit the proinflammatory cytokines interleukin (IL)-12p40, IL-6, and interferon-alpha. Interestingly, the resulting adaptive immune responses are characterized by a mixed T helper cell (Th)1/Th2 cytokine profile and antigen-specific CD8+ T cells. Furthermore, distinct TLRs appear to differentially control the Th1/Th2 balance; thus, whilst MyD88-deficient mice show a profound impairment of Th1 cytokines, TLR2-deficient mice show greatly enhanced Th1 and Tc1 responses to YF-17D. Together, these data enhance our understanding of the molecular mechanism of action of YF-17D, and highlight the potential of vaccination strategies that use combinations of different TLR ligands to stimulate polyvalent immune responses.

Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway.

PubMed

Chen, Dandan; Tang, Ping; Liu, Linxiang; Wang, Fang; Xing, Haizhou; Sun, Ling; Jiang, Zhongxing

2018-05-21

This study aims to explore the effect of bone marrow mesenchymal stem cells (BMSCs) on multiple myeloma (MM) development and the underlying mechanism. BMSCs from C57BL/6 J mice were isolated and the third passage was used for subsequent experiments. Additionally, a series of in vitro transwell coculture assays were performed to explore the effects of BMSCs on the proliferation of MM cells 5TGM1 and CD4 + T cells. Furthermore, a 5TGM1-induced MM mice model was established. Moreover, PD-L1 shRNA was transfected into BMSCs to investigate whether PD-1/PD-L1 pathway involved in BMSCs-mediated regulation of T cells and MM growth. Data revealed that BMSCs significantly promoted 5TGM1 proliferation in a dose-dependent manner. Furthermore, BMSCs administration exerted stimulatory effects on MM development in terms of shortening the mouse survival rate, promoting tumor growth, and enhancing inflammatory infiltration in the MM model mice. Moreover, BMSCs decreased the percentage of Th1 and Th17 cells, whereas increased that of Th2 and Treg cells. Their corresponding cytokines of these T cell subsets showed similar alteration in the presence of BMSCs. Additionally, BMSCs significantly suppressed CD4 + T cell proliferation. We also found that PD-L1 shRNA inhibited 5TGM1 proliferation likely through activation of CD4 + T cells. Further in vivo experiments confirmed that PD-L1 inhibition attenuated BMSCs-induced MM growth, inflammation infiltration and imbalance of Th1/Th2 and Th17/Treg. In summary, our findings demonstrated that BMSCs promoted cell proliferation of MM through inhibiting T cell immune responses via PD-1/PD-L1 pathway.

Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract following Mucosal Herpes Simplex Virus 2 Vaccination

PubMed Central

Bagri, Puja; Anipindi, Varun C.; Nguyen, Philip V.; Vitali, Danielle; Stämpfli, Martin R.

2017-01-01

ABSTRACT It is well established that interferon gamma (IFN-γ) production by CD4+ T cells is critical for antiviral immunity against herpes simplex virus 2 (HSV-2) genital infection. However, the role of interleukin-17A (IL-17A) production by CD4+ T cells in HSV-2 antiviral immunity is yet to be elucidated. Here we demonstrate that IL-17A plays an important role in enhancing antiviral T helper type 1 (Th1) responses in the female genital tract (FGT) and is essential for effective protection conferred by HSV-2 vaccination. While IL-17A did not play a critical role during primary genital HSV-2 infection, seen by lack of differences in susceptibility between IL-17A-deficient (IL-17A−/−) and wild-type (WT) C57BL/6 mice, it was critical for mediating antiviral responses after challenge/reexposure. Compared to WT mice, IL-17A−/− mice (i) infected intravaginally and reexposed or (ii) vaccinated intranasally and challenged intravaginally demonstrated poor outcomes. Following intravaginal HSV-2 reexposure or challenge, vaccinated IL-17A−/− mice had significantly higher mortality, greater disease severity, higher viral shedding, and higher levels of proinflammatory cytokines and chemokines in vaginal secretions. Furthermore, IL-17A−/− mice had impaired Th1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ+ CD4+ T cells. The impaired Th1 cell responses in IL-17A−/− mice coincided with smaller populations of IFN-γ+ CD4+ tissue resident memory T (TRM) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ+ Th1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination. IMPORTANCE T helper type 1 (Th1) immunity, specifically interferon gamma (IFN-γ) production by CD4+ T cells, is critical for protection against genital herpesvirus (HSV-2) infection, and enhancing this response can potentially help improve disease outcomes. Our study demonstrated that interleukin-17A (IL-17A) plays an essential role in enhancing antiviral Th1 responses in the female genital tract (FGT). We found that in the absence of IL-17A, preexposed and vaccinated mice showed poor disease outcomes and were unable to overcome HSV-2 reexposure/challenge. IL-17A-deficient mice (IL-17A−/−) had smaller populations of IFN-γ+ CD4+ tissue resident memory T (TRM) cells in the genital tract postimmunization than did wild-type (WT) mice, which coincided with attenuated Th1 responses postchallenge. This has important implications for developing effective vaccines against HSV-2, as we propose that strategies inducing IL-17A in the genital tract may promote more effective Th1 cell immunity and better overall protection. PMID:28956763

IL-33 expands suppressive CD11b+ Gr-1int and regulatory T cells (Treg), including ST2L+ Foxp3+ cells, and mediates Treg-dependent promotion of cardiac allograft survival

PubMed Central

Turnquist, Hēth R.; Zhao, Zhenlin; Rosborough, Brian R.; Liu, Quan; Castellaneta, Antonino; Isse, Kumiko; Wang, Zhiliang; Lang, Megan; Stolz, Donna Beer; Zheng, Xin Xiao; Demetris, A. Jake; Liew, Foo Y.; Wood, Kathryn J.; Thomson, Angus W.

2011-01-01

IL-33 administration is associated with facilitation of Th type-2 (Th2) responses and cardioprotective properties in rodent models. However, in heart transplantation, the mechanism by which IL-33, signaling through ST2L, the membrane-bound form of ST2, promotes transplant survival is unclear. We report that IL-33 administration, while facilitating Th2 responses, also increases immunoregulatory myeloid cells and CD4+ Foxp3+ regulatory T cells (Treg) in mice. IL-33 expands functional myeloid-derived suppressor cells (MDSC), -CD11b+ cells that exhibit intermediate (int) levels of Gr-1 and potent T cell suppressive function. Furthermore, IL-33 administration causes a St2-dependent expansion of suppressive CD4+ Foxp3+ Treg, including a ST2L+ population. IL-33 monotherapy following fully allogeneic mouse heart transplantation resulted in significant graft prolongation, associated with increased Th2-type responses and decreased systemic CD8+ IFN-γ+ cells. Also, despite reducing overall CD3+ cell infiltration of the graft, IL-33 administration markedly increased intragraft Foxp3+ cells. Whereas control graft recipients displayed increases in systemic CD11b+ Gr-1hi cells, IL-33-treated recipients exhibited increased CD11b+ Gr-1int cells. Enhanced ST2 expression was observed in the myocardium and endothelium of rejecting allografts, however the therapeutic effect of IL-33 required recipient St2 expression and was dependent on Treg. These findings reveal a new immunoregulatory property of IL-33. Specifically, in addition to supporting Th2 responses, IL-33 facilitates regulatory cells, particularly functional CD4+ Foxp3+ Treg that underlie IL-33-mediated cardiac allograft survival. PMID:21949025

Induction of appropriate Th-cell phenotypes: cellular decision-making in heterogeneous environments.

PubMed

van den Ham, H-J; Andeweg, A C; de Boer, R J

2013-11-01

Helper T (Th)-cell differentiation is a key event in the development of the adaptive immune response. By the production of a range of cytokines, Th cells determine the type of immune response that is raised against an invading pathogen. Th cells can adopt many different phenotypes, and Th-cell phenotype decision-making is crucial in mounting effective host responses. This review discusses the different Th-cell phenotypes that have been identified and how Th cells adopt a particular phenotype. The regulation of Th-cell phenotypes has been studied extensively using mathematical models, which have explored the role of regulatory mechanisms such as autocrine cytokine signalling and cross-inhibition between self-activating transcription factors. At the single cell level, Th responses tend to be heterogeneous, but corrections can be made soon after T-cell activation. Although pathogens and the innate immune system provide signals that direct the induction of Th-cell phenotypes, these instructive mechanisms could be easily subverted by pathogens. We discuss that a model of success-driven feedback would select the most appropriate phenotype for clearing a pathogen. Given the heterogeneity in the induction phase of the Th response, such a success-driven feedback loop would allow the selection of effective Th-cell phenotypes while terminating incorrect responses. © 2013 John Wiley & Sons Ltd.

Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease.

PubMed

Kidd, Parris

2003-08-01

One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and T-helper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1- and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway ("cellular immunity") to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway ("humoral immunity") and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro-Th1 or -Th2 patterns. The non-helper regulatory T cells, or the antigen-presenting cells (APC), likely influence immunity in a manner comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or Th2 dominant fail to meet the set criteria. Experimentally, Th1 polarization is readily transformed to Th2 dominance through depletion of intracellular glutathione, and vice versa. Mercury depletes glutathione and polarizes toward Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2 balance, including plant sterols/sterolins, melatonin, probiotics, progesterone, and the minerals selenium and zinc. The long-chain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect. Th1/Th2-based immunotherapies, e.g., T-cell receptor (TCR) peptides and interleukin-4 (IL-4) injections, have produced mixed results to date.

Antiviral function of tilapia hepcidin 1-5 and its modulation of immune-related gene expressions against infectious pancreatic necrosis virus (IPNV) in Chinook salmon embryo (CHSE)-214 cells.

PubMed

Rajanbabu, Venugopal; Chen, Jyh-Yih

2011-01-01

Antimicrobial peptides, small cysteine-rich molecules, play vital roles in host defense mechanisms against pathogen infection. Recently, tilapia hepcidin (TH)1-5, was characterized, and its antimicrobial functions against several pathogens were reported. Herein, we investigated the antiviral functions of TH1-5 against infectious pancreatic necrosis virus (IPNV) in Chinook salmon embryo (CHSE)-214 cells. The presence of TH1-5 enhanced the survival of CHSE-214 cells infected with IPNV. Additionally, the number of plaques formed by the cytopathic effect of IPNV in CHSE-214 cells decreased when IPNV was preincubated with TH1-5. This observation demonstrates the antiviral function of TH1-5. Real-time PCR studies showed the modulation of interleukin, annexin, and other viral-responsive gene expressions by TH1-5. When TH1-5 and IPNV were used to co-treat CHSE-214 cells, then cells were re-challenged with IPNV at 24h, the cells did not survive the IPNV infection. This shows that in the absence of TH1-5, viral re-challenge killed CHSE-214 cells. In conclusion TH1-5 protected CHSE-214 cells against IPNV by direct antimicrobial and immunomodulatory functions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Production and function of cytokines in natural and acquired immunity to Candida albicans infection.

PubMed Central

Ashman, R B; Papadimitriou, J M

1995-01-01

Host resistance against infections caused by the yeast Candida albicans is mediated predominantly by polymorphonuclear leukocytes and macrophages. Antigens of Candida stimulate lymphocyte proliferation and cytokine synthesis, and in both humans and mice, these cytokines enhance the candidacidal functions of the phagocytic cells. In systemic candidiasis in mice, cytokine production has been found to be a function of the CD4+ T helper (Th) cells. The Th1 subset of these cells, characterized by the production of gamma interferon and interleukin-2, is associated with macrophage activation and enhanced resistance against reinfection, whereas the Th2 subset, which produces interleukins-4, -6, and -10, is linked to the development of chronic disease. However, other models have generated divergent data. Mucosal infection generally elicits Th1-type cytokine responses and protection from systemic challenge, and identification of cytokine mRNA present in infected tissues of mice that develop mild or severe lesions does not show pure Th1- or Th2-type responses. Furthermore, antigens of C. albicans, mannan in particular, can induce suppressor cells that modulate both specific and nonspecific cellular and humoral immune responses, and there is an emerging body of evidence that molecular mimicry may affect the efficiency of anti-Candida responses within defined genetic contexts. PMID:8531890

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

PubMed Central

Carvalho, Agostinho; Giovannini, Gloria; De Luca, Antonella; D'Angelo, Carmen; Casagrande, Andrea; Iannitti, Rossana G; Ricci, Giovanni; Cunha, Cristina; Romani, Luigina

2012-01-01

The recognition of β-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor-dependent IL-22 production and in adaptive Th1 responses. In contrast, the resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/noncanonical NF-κB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling. PMID:22543832

Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis.

PubMed

Muñoz, Leticia; Albillos, Agustín; Nieto, Mónica; Reyes, Eduardo; Lledó, Lourdes; Monserrat, Jorge; Sanz, Eva; de la Hera, Antonio; Alvarez-Mon, Melchor

2005-08-01

A systemic inflammatory state with increased circulating tumor necrosis factor alpha (TNF-alpha) has been related to the bacterial infection susceptibility and hemodynamic derangement of patients with cirrhosis. We compared the activation status of immune cell subpopulations defined by 4-color cytometry in mesenteric and peripheral lymph nodes and blood of rats with CCl(4)-cirrhosis to define the immune response initiation site, the T-cell and monocyte contribution to pro-inflammatory cytokine production, as well as the pathogenic role of enteric bacteria in the cirrhosis immune response. Th1 cells and monocytes were expanded in the mesenteric nodes (P < .001) and blood (P < .001) of rats with cirrhosis, and activated to produce interferon gamma (P < .0001) and TNF-alpha (P < .0001), respectively. The greater numbers of recently activated CD134(+) Th cells in mesenteric nodes compared with blood, the correlation between their numbers in mesenteric nodes and blood (r = 0.66, P < .001), and the expansion of activated CD45RC(-) Th cells, which are unable to re-enter lymph nodes, in mesenteric nodes but not in blood or axillary nodes points to mesenteric nodes as the origin site of activated Th cells. Abrogation of bacterial translocation by bowel decontamination reduced the number of activated Th cells and monocytes, and normalized interferon gamma production by Th cells and TNF-alpha production by monocytes in mesenteric nodes and blood, respectively. In conclusion, in cirrhosis, enteric bacteria start off an orchestrated immune response cascade in mesenteric nodes involving Th1 polarization and monocyte activation to TNF-alpha production. Later, the recirculation of these activated effector immune cells into blood promotes systemic inflammation.

Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response To Promote a Tumor-Tolerant Immune Microenvironment

PubMed Central

Delitto, Daniel; Delitto, Andrea E.; DiVita, Bayli B.; Pham, Kien; Han, Song; Hartlage, Emily R.; Newby, Brittney N.; Gerber, Michael H.; Behrns, Kevin E.; Moldawer, Lyle L.; Thomas, Ryan M.; George, Thomas J.; Brusko, Todd M.; Mathews, Clayton E.; Liu, Chen; Trevino, Jose G.; Hughes, Steven J.; Wallet, Shannon M.

2016-01-01

Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared to healthy controls. The TAS response also directly suppressed CD8+ T cell-mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. PMID:27864347

Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases.

PubMed

Finlay, Conor M; Walsh, Kevin P; Mills, Kingston H G

2014-05-01

Helminth parasites are highly successful pathogens, chronically infecting a quarter of the world's population, causing significant morbidity but rarely causing death. Protective immunity and expulsion of helminths is mediated by T-helper 2 (Th2) cells, type 2 (M2) macrophages, type 2 innate lymphoid cells, and eosinophils. Failure to mount these type 2 immune responses can result in immunopathology mediated by Th1 or Th17 cells. Helminths have evolved a wide variety of approaches for immune suppression, especially the generation of regulatory T cells and anti-inflammatory cytokines interleukin-10 and transforming growth factor-β. This is a very effective strategy for subverting protective immune responses to prolong their survival in the host but has the bystander effect of modulating immune responses to unrelated antigens. Epidemiological studies in humans have shown that infection with helminth parasites is associated with a low incidence of allergy/asthma and autoimmunity in developing countries. Experimental studies in mice have demonstrated that regulatory immune responses induced by helminth can suppress Th2 and Th1/Th17 responses that mediate allergy and autoimmunity, respectively. This has provided a rational explanation of the 'hygiene hypothesis' and has also led to the exploitation of helminths or their immunomodulatory products in the development of new immunosuppressive therapies for inflammatory diseases in humans. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Turned on by danger: activation of CD1d-restricted invariant natural killer T cells

PubMed Central

Lawson, Victoria

2012-01-01

CD1d-restricted invariant natural killer T (iNKT) cells bear characteristics of innate and adaptive lymphocytes, which allow them to bridge the two halves of the immune response and play roles in many disease settings. Recent work has characterized precisely how their activation is initiated and regulated. Novel antigens from important pathogens have been identified, as has an abundant self-antigen, β-glucopyranosylcaramide, capable of mediating an iNKT-cell response. Studies of the iNKT T-cell receptor (TCR)–antigen–CD1d complex show how docking between CD1d–antigen and iNKT TCR is highly conserved, and how small sequence differences in the TCR establish intrinsic variation in iNKT TCR affinity. The sequence of the TCR CDR3β loop determines iNKT TCR affinity for ligand–CD1d, independent of ligand identity. CD1d ligands can promote T helper type 1 (Th1) or Th2 biased cytokine responses, depending on the composition of their lipid tails. Ligands loaded into CD1d on the cell surface promote Th2 responses, whereas ligands with long hydrophobic tails are loaded endosomally and promote Th1 responses. This information is informing the design of synthetic iNKT-cell antigens. The iNKT cells may be activated by exogenous antigen, or by a combination of dendritic cell-derived interleukin-12 and iNKT TCR–self-antigen–CD1d engagement. The iNKT-cell activation is further modulated by recent foreign or self-antigen encounter. Activation of dendritic cells through pattern recognition receptors alters their antigen presentation and cytokine production, strongly influencing iNKT-cell activation. In a range of bacterial infections, dendritic cell-dependent innate activation of iNKT cells through interleukin-12 is the dominant influence on their activity. PMID:22734667

IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice

PubMed Central

Oriss, Timothy B.; Raundhal, Mahesh; Morse, Christina; Huff, Rachael E.; Das, Sudipta; Hannum, Rachel; Gauthier, Marc C.; Scholl, Kathryn L.; Chakraborty, Krishnendu; Nouraie, Seyed M.; Wenzel, Sally E.; Ray, Prabir

2017-01-01

Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1–dominated (IFN-γ–dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ– and IL-17–producing CD4+ T cells and IRF5–/– mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage disease in a subset of severe asthmatics. PMID:28515358

Immunomodulation and T Helper TH1/TH2 Response Polarization by CeO2 and TiO2 Nanoparticles

PubMed Central

Schanen, Brian C.; Das, Soumen; Reilly, Christopher M.; Warren, William L.; Self, William T.; Seal, Sudipta; Drake, Donald R.

2013-01-01

Immunomodulation by nanoparticles, especially as related to the biochemical properties of these unique materials, has scarcely been explored. In an in vitro model of human immunity, we demonstrate two catalytic nanoparticles, TiO2 (oxidant) and CeO2 (antioxidant), have nearly opposite effects on human dendritic cells and T helper (TH) cells. For example, whereas TiO2 nanoparticles potentiated DC maturation that led towards TH1-biased responses, treatment with antioxidant CeO2 nanoparticles induced APCs to secrete the anti-inflammatory cytokine, IL-10, and induce a TH2-dominated T cell profile. In subsequent studies, we demonstrate these results are likely explained by the disparate capacities of the nanoparticles to modulate ROS, since TiO2, but not CeO2 NPs, induced inflammatory responses through an ROS/inflammasome/IL-1β pathway. This novel capacity of metallic NPs to regulate innate and adaptive immunity in profoundly different directions via their ability to modulate dendritic cell function has strong implications for human health since unintentional exposure to these materials is common in modern societies. PMID:23667525

Blockade of tumour necrosis factor-α in experimental autoimmune encephalomyelitis reveals differential effects on the antigen-specific immune response and central nervous system histopathology.

PubMed

Batoulis, H; Recks, M S; Holland, F O; Thomalla, F; Williams, R O; Kuerten, S

2014-01-01

In various autoimmune diseases, anti-tumour necrosis factor (TNF)-α treatment has been shown to reduce both clinical disease severity and T helper type 1 (Th1)1/Th17 responses. In experimental autoimmune encephalomyelitis (EAE), however, the role of TNF-α has remained unclear. Here, C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 and treated with anti-TNF-α, control antibody or vehicle. The clinical disease course, incidence and severity were assessed. On day 20 after immunization the antigen-specific Th1/Th17 response was evaluated by enzyme-linked immunospot (ELISPOT) in spleen and central nervous system (CNS). Also, the extent of spinal cord histopathology was analysed on semi- and ultrathin sections. Our results demonstrate that anti-TNF-α treatment reduced the incidence and delayed the onset of EAE, but had no effect on disease severity once EAE had been established. Whereas anti-TNF-α treatment induced an increase in splenic Th1/Th17 responses, there was no effect on the number of antigen-specific Th1/Th17 cells in the spinal cord. Accordingly, the degree of CNS histopathology was comparable in control and anti-TNF-α-treated mice. In conclusion, while the anti-TNF-α treatment had neither immunosuppressive effects on the Th1/Th17 response in the CNS nor histoprotective properties in EAE, it enhanced the myelin-specific T cell response in the immune periphery. © 2013 British Society for Immunology.

High frequencies of Th1-type CD4(+) T cells specific to HTLV-1 Env and Tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

PubMed

Goon, Peter K C; Hanon, Emmanuel; Igakura, Tadahiko; Tanaka, Yuetsu; Weber, Jonathan N; Taylor, Graham P; Bangham, Charles R M

2002-05-01

CD4(+) T cells are critical for inducing and maintaining efficient humoral and cellular immune responses to pathogens. The CD4(+) T-cell response in human T-lymphotropic virus 1 (HTLV-1) infection has not been studied in detail. However, CD4(+) T cells have been shown to predominate in early lesions in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We present direct estimates of HTLV-1 Env- and Tax-specific CD4(+) T-cell frequencies in patients infected with HTLV-1. We first showed that there was a strong bias toward the Th1 phenotype in these HTLV-1-specific CD4(+) T cells in patients with HAM/TSP. We then demonstrated significantly higher frequencies of HTLV-1-specific Th1-type CD4(+) T cells in HAM/TSP patients than in asymptomatic HTLV-1 carriers. The majority of these HTLV-1-specific CD4(+) T cells did not express HTLV-1 Tax and were therefore unlikely to be infected by HTLV-1. High frequencies of activated HTLV-1-specific CD4(+) T cells of the Th1 phenotype might contribute to the initiation or pathogenesis of HAM/TSP and other HTLV-1-associated inflammatory diseases.

A New Adjuvant Combined with Inactivated Influenza Enhances Specific CD8 T Cell Response in Mice and Decreases Symptoms in Swine Upon Challenge.

PubMed

Bouguyon, Edwige; Goncalves, Elodie; Shevtsov, Alexander; Maisonnasse, Pauline; Remyga, Stepan; Goryushev, Oleg; Deville, Sebastien; Bertho, Nicolas; Ben Arous, Juliette

2015-11-01

Vaccination is the most effective way to control swine influenza virus (SIV) in the field. Classical vaccines are based on inactivated antigens formulated with an oil emulsion or a polymeric adjuvant. Standard adjuvants enhance the humoral response and orient the immune response toward a Th2 response. An important issue is that current vaccines do not protect against new strains. One approach to improve cross-protection is to enhance Th1 and cytotoxic responses. The development of adjuvants orienting the immune response of inactivated vaccines toward Th1/Cytotoxic responses would be highly beneficial. This study shows that the water in oil in water emulsion adjuvant Montanide™ ISA 201 VG allows the induction of anti-influenza CD8 T cell in mice and induces homologous protection against an H1N1 challenge in swine. Such adjuvants that induce both humoral and cell-mediated immunity could improve the protection conferred by SIV vaccines in the field.

Induction of immunoglobulin G1, interleukin-6 and interleukin-10 by Taenia crassiceps metacestode carbohydrates

PubMed Central

Dissanayake, Senarath; Khan, Nasir; Shahin, Allen; Wijesinghe, Shanaka; Lukic, Miodrag

2002-01-01

T helper type 2 (Th2) -polarized immune responses are characteristically dominant in helminth infections. Two murine models that show a Th1 to Th2 polarization with infection progression are those of Schistosoma mansoni and Taenia crassiceps. In both, an early Th1 response is replaced by a late Th2 response. We report that the nucleic acid-, protein- and lipid-free carbohydrate fraction of T. crassiceps metacestodes (denoted T-CHO) possesses Th2-like immunomodulatory activity. Immunization of two strains of rats (Dark Agouti and Albino Oxford) and BALB/c mice with chicken albumin in the presence of T-CHO resulted in selective enhancement of immunoglobulin G1 (IgG1) antibodies, considered to be associated with Th2 responses in both rats and mice. Interleukin-6 (IL-6) followed by IL-10 were the dominant cytokines detected in in vitro cultures of mouse spleen cells stimulated with T-CHO. IL-4 and IL-5 were not detected in these culture supernates. Furthermore, Taenia carbohydrates were mitogenic to spleen cells, activated serine phosphorylation of proteins and up-regulated the expression of the anti-apoptotic protein, Bcl-2. When mouse spleen cells were cultured in the presence of Taenia carbohydrates, a concentration-dependent down-regulation of IL-2 and an overlapping up-regulation of IL-6 secretion were seen. PMID:12460185

Dectin-1/2–induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses

PubMed Central

Kaisar, Maria M. M.; Jónasdóttir, Hulda S.; van der Ham, Alwin J.; Pelgrom, Leonard R.; Schramm, Gabriele; Layland, Laura E.; Sancho, David; Prazeres da Costa, Clarissa; Giera, Martin; Yazdanbakhsh, Maria

2018-01-01

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently—in an autocrine manner—induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1–independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2−/−, and to a lesser extent Dectin-1−/− mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced. PMID:29668708

A Novel Sphingomyelinase-Like Enzyme in Ixodes scapularis Tick Saliva Drives Host CD4+ T cells to Express IL-4

PubMed Central

Alarcon-Chaidez, F. J.; Boppana, V. D.; Hagymasi, A.T.; Adler, A. J.; Wikel, S. K.

2009-01-01

Tick feeding modulates host immune responses. Tick-induced skewing of host CD4+ T cells towards a Th2 cytokine profile facilitates transmission of tick-borne pathogens that would otherwise be neutralized by Th1 cytokines. Tick-derived factors that drive this Th2 response have not previously been characterized. In the current study, we examined an I. scapularis cDNA library prepared at 18-24 hours of feeding and identified and expressed a tick gene with homology to Loxosceles spider venom proteins with sphingomyelinase activity. This I. scapularis sphingomyelinase-like (IsSMase) protein is a Mg+2-dependent, neutral (pH 7.4) form of sphingomyelinase. Significantly, in an in vivo TCR transgenic adoptive transfer assay IsSMase programmed host CD4+ T cells to express the hallmark Th2 effector cytokine IL-4. IsSMase appears to directly program host CD4 T cell IL-4 expression (as opposed to its metabolic by-products) because induced IL-4 expression was not altered when enzymatic activity was neutralized. TCR transgenic CD4 T cell proliferation (CFSE-dilution) was also significantly increased by IsSMase. Furthermore, a Th2 response is superimposed onto a virally-primed Th1 response by IsSMase. Thus, IsSMase is the first identified tick molecule capable of programming host CD4+ T cells to express IL-4. PMID:19292772

Immunological Signatures after Bordetella pertussis Infection Demonstrate Importance of Pulmonary Innate Immune Cells

PubMed Central

Brummelman, Jolanda; van der Maas, Larissa; Tilstra, Wichard; Pennings, Jeroen L. A.; Han, Wanda G. H.; van Els, Cécile A. C. M.; van Riet, Elly; Kersten, Gideon F. A.; Metz, Bernard

2016-01-01

Effective immunity against Bordetella pertussis is currently under discussion following the stacking evidence of pertussis resurgence in the vaccinated population. Natural immunity is more effective than vaccine-induced immunity indicating that knowledge on infection-induced responses may contribute to improve vaccination strategies. We applied a systems biology approach comprising microarray, flow cytometry and multiplex immunoassays to unravel the molecular and cellular signatures in unprotected mice and protected mice with infection-induced immunity, around a B. pertussis challenge. Pre-existing systemic memory Th1/Th17 cells, memory B-cells, and mucosal IgA specific for Ptx, Vag8, Fim2/3 were detected in the protected mice 56 days after an experimental infection. In addition, pre-existing high activity and reactivation of pulmonary innate cells such as alveolar macrophages, M-cells and goblet cells was detected. The pro-inflammatory responses in the lungs and serum, and neutrophil recruitment in the spleen upon an infectious challenge of unprotected mice were absent in protected mice. Instead, fast pulmonary immune responses in protected mice led to efficient bacterial clearance and harbored potential new gene markers that contribute to immunity against B. pertussis. These responses comprised of innate makers, such as Clca3, Retlna, Glycam1, Gp2, and Umod, next to adaptive markers, such as CCR6+ B-cells, CCR6+ Th17 cells and CXCR6+ T-cells as demonstrated by transcriptome analysis. In conclusion, besides effective Th1/Th17 and mucosal IgA responses, the primary infection-induced immunity benefits from activation of pulmonary resident innate immune cells, achieved by local pathogen-recognition. These molecular signatures of primary infection-induced immunity provided potential markers to improve vaccine-induced immunity against B. pertussis. PMID:27711188

BALB/c mice display more enhanced BCG vaccine induced Th1 and Th17 response than C57BL/6 mice but have equivalent protection.

PubMed

Garcia-Pelayo, M Carmen; Bachy, Véronique S; Kaveh, Daryan A; Hogarth, Philip J

2015-01-01

It is generally assumed that the inbred mouse strains BALB/c (H-2(d)) and C57BL/6 (H-2(b)) respond to mycobacterial infection with distinct polarisation of T helper responses, with C57BL/6 predisposed to Th1 and BALB/c to Th2. We investigated this in a BCG-immunisation, Mycobacterium bovis challenge model. Following immunisation, lung and spleen cell cytokine responses to in vitro re-stimulation with a cocktail of seven secreted, immunogenic, recombinant mycobacterial proteins were determined. In both lung and spleen, BALB/c cells produced at least 2-fold more IFN-γ, and up to 7-fold more IL-2 and IL-17 than C57BL/6 cells, whereas IL-10 production was reciprocally increased in C57BL/6 mice. These data suggest that, contrary to reports in the literature, specific mycobacterial antigens are able to induce strong Th1 and Th17 responses in BALB/c mice following BCG vaccination, whilst in C57BL/6 mice, the Th1 response is partly counterbalanced by IL-10. After subsequent M. bovis low dose challenge, protection, as measured in the lungs and dissemination to the spleen, was equivalent in BALB/c and C57BL/6 mice, indicating that BCG-induced immunity was equivalent in both strains. Thus, the differential immune responses do not appear to have a role in protection, but further, as yet unidentified, specific immune responses play a significant role. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation.

PubMed

Bui, Thi Tho; Piao, Chun Hua; Song, Chang Ho; Shin, Hee Soon; Shon, Dong-Hwa; Chai, Ok Hee

2017-12-01

Piper nigrum (Piperaceae) is commonly used as a spice and traditional medicine in many countries. P. nigrum has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic asthma has not been known. This study investigated the effect of P. nigrum ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG 1 and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1β, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG 1 and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation. Copyright © 2017 Elsevier Inc. All rights reserved.

An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis

PubMed Central

Mikecz, Katalin; Glant, Tibor T.; Markovics, Adrienn; Rosenthal, Kenneth S.; Kurko, Julia; Carambula, Roy E.; Cress, Steve; Steiner, Harold L.; Zimmerman, Daniel H.

2017-01-01

Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPS™) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70-treated mice demonstrated a shift from a pro-inflammatory to an anti-inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA. PMID:28583308

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses.

PubMed

Chiurchiù, Valerio; Leuti, Alessandro; Dalli, Jesmond; Jacobsson, Anders; Battistini, Luca; Maccarrone, Mauro; Serhan, Charles N

2016-08-24

Resolution of inflammation is a finely regulated process mediated by specialized proresolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series resolvins (resolvin D1 and resolvin D2) and maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8(+) T cells and CD4(+) T helper 1 (TH1) and TH17 cells but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4(+) T cell differentiation into TH1 and TH17 by down-regulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3(+) regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2(-/-)) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild-type mice. Additionally, either DHA supplementation in Elovl2(-/-) mice or in vivo administration of resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation. Copyright © 2016, American Association for the Advancement of Science.

Commensal oral bacteria antigens prime human dendritic cells to induce Th1, Th2 or Treg differentiation.

PubMed

Kopitar, A N; Ihan Hren, N; Ihan, A

2006-02-01

In various immunopathologic conditions, bacterial flora induce an immune response which results in inflammatory manifestations, e.g. periapical granuloma. Dendritic cells provide the main orchestration of specific immune responses. The aim of our study was to test the capacity of distinct oral bacterial antigens (prepared from Streptococcus mitis, Propionibacterium acnes, and Bacteroides spp.) to prime human dendritic cells for stimulation of the T-lymphocyte response. To assess the T-lymphocyte response, the expression of CD25, CD69, intracellular interferon gamma (cIFN-gamma), and intracellular interleukin 4 (cIL-4) was determined. Dendritic cells were prepared from leukocyte buffy coat from healthy blood donors. Monocytes were stimulated with IL-4 and GM-CSF and dendritic cells activated with bacterial lysates. Cell suspensions contained up to 90% dendritic cells, which represented 2-12% of the initial number of mononuclear cells. Lymphocyte subsets that developed in lymphocyte cultures after 1 week of stimulation were analyzed by flow cytometry. Dendritic cells, primed with antigens of Bacteroides fragilis have shown significantly higher activation and expression of intercellular IFN-gamma by T lymphocytes compared to negative controls. The dendritic cells primed with antigens of P. acnes had no effect on T-lymphocyte activation or cytokine production; instead they induced differentiation of T lymphocytes into CD25bright cells (regulatory T cells) with a potentially inhibitory effect on immune response. Dendritic cells primed with antigens of S. mitis induced increased expression of cIL-4. We conclude that commensal oral bacteria antigens prepared from B. fragilis, S. mitis, and P. acnes prime human dendritic cells to induce Th1, Th2, and T(reg) differentiation, respectively. This may advance our understanding of immunopathologic manifestations in the oral cavity and offer new possibilities for redirecting immune responses in mucosal vaccination.

Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria

PubMed Central

Lönnberg, Tapio; Svensson, Valentine; James, Kylie R.; Fernandez-Ruiz, Daniel; Sebina, Ismail; Montandon, Ruddy; Soon, Megan S. F.; Fogg, Lily G.; Nair, Arya Sheela; Liligeto, Urijah; Stubbington, Michael J. T.; Ly, Lam-Ha; Bagger, Frederik Otzen; Zwiessele, Max; Lawrence, Neil D.; Souza-Fonseca-Guimaraes, Fernando; Bunn, Patrick T.; Engwerda, Christian R.; Heath, William R.; Billker, Oliver; Stegle, Oliver; Haque, Ashraful; Teichmann, Sarah A.

2017-01-01

Differentiation of naïve CD4+ T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection in vivo. By using single-cell transcriptomics and computational analysis using a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of Th1 and Tfh cells during blood-stage Plasmodium infection in mice. By tracking clonality using endogenous TCR sequences, we first demonstrated that Th1/Tfh bifurcation had occurred at both population and single-clone levels. Next, we identified genes whose expression was associated with Th1 or Tfh fates, and demonstrated a T-cell intrinsic role for Galectin-1 in supporting a Th1 differentiation. We also revealed the close molecular relationship between Th1 and IL-10-producing Tr1 cells in this infection. Th1 and Tfh fates emerged from a highly proliferative precursor that upregulated aerobic glycolysis and accelerated cell cycling as cytokine expression began. Dynamic gene expression of chemokine receptors around bifurcation predicted roles for cell-cell in driving Th1/Tfh fates. In particular, we found that precursor Th cells were coached towards a Th1 but not a Tfh fate by inflammatory monocytes. Thus, by integrating genomic and computational approaches, our study has provided two unique resources, a database www.PlasmoTH.org, which facilitates discovery of novel factors controlling Th1/Tfh fate commitment, and more generally, GPfates, a modelling framework for characterizing cell differentiation towards multiple fates. PMID:28345074

Th1 biased response to a novel Porphyromonas gingivalis protein aggravates bone resorption caused by this oral pathogen

PubMed Central

Leshem, Onir; Kashino, Suely S.; Gonçalves, Reginaldo B.; Suzuki, Noriyuki; Onodera, Masao; Fujimura, Akira; Sasaki, Hajime; Stashenko, Philip; Campos-Neto, Antonio

2013-01-01

In previous studies we showed that biasing the immune response to Porphyromonas gingivalis antigens to the Th1 phenotype increases inflammatory bone resorption caused by this organism. Using a T cell screening strategy we identified eight P. gingivalis genes coding for proteins that appear to be involved in T-helper cell responses. In the present study we characterized the protein, encoded by PG_1841 gene and evaluated its relevance in the in bone resorption caused by P. gingivalis because subcutaneous infection of mice with this organism resulted in the induction of Th1 biased response to the recombinant PG1841 antigen molecule. Using an immunization regime that strongly biases toward the Th1 phenotype followed by challenge with P. gingivalis in dental pulp tissue, we demonstrate that mice pre-immunized with rPG1841 developed severe bone loss compared with control immunized mice. Pre-immunization of mice with the antigen using a Th2 biasing regime resulted in no exacerbation of the disease. These results support the notion that selected antigens of P. gingivalis are involved in a biased Th1 host response that leads to the severe bone loss caused by this oral pathogen. PMID:18457976

T helper cells in leprosy: An update.

PubMed

Saini, Chaman; Tarique, Mohd; Rai, Reeta; Siddiqui, Anisuddin; Khanna, Neena; Sharma, Alpana

2017-04-01

Leprosy is an ancient disease caused by gram positive, rod shaped bacilli called Mycobacterium leprae. Patients present with varied clinico-pathological disease depending on the host immune response to Mycobacterium leprae. Thus tuberculoid (TT) and lepromatous (LL) patients represent two ends of a spectrum where the former shows limited disease, high T cell mediate immune (CMI) response and low antibody (HI) levels in serum. In contrast the latter has low T cell and high humoral immune response i.e antibody levels. The mechanisms underlying these differences have been investigated intensely; however, there is no consensus on the primary immunological basis. Over three decades, Th1 and Th2 paradigm were thought to underling tuberculoid and lepromatous disease respectively. However many patients were shown to have mixed Th1/Th2 pattern of (IFN-γ/IL-4) cytokines. The present review was undertaken with a view to understand the T cells and cytokine dysregulation in leprosy. In recent years the sub classes of T cells that are Regulatory in nature (Treg) have been implicated in immune diseases where they were shown to suppress T cell functions. Additionally Th17 cells secreting IL-17A, IL17F, were implicated in immune inflammation. Taken together these regulatory cells may play a part in influencing immune responses in leprosy. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Short exposure of maturing, bone marrow-derived dendritic cells to norepinephrine: impact on kinetics of cytokine production and Th development.

PubMed

Maestroni, Georges J M

2002-08-01

The information gathered by dendritic cells (DC) during the innate immune response to a pathogen is determinant for the type of adaptive response. Here we show that short-term (3 h) exposure of bone marrow-derived DC to norepinephrine (NE), at the beginning of lipopolysaccharide (LPS) or keyhole limpet hemocyanin (KLH) stimulation hampers IL-12 production and increases IL-10 release. The NE effect was mediated by both beta- and alpha2-adrenergic receptors. The capacity of NE-exposed DC to produce IL-12 upon CD40 cross-linking as well as to stimulate allogeneic T-helper (Th) lymphocytes was reduced. Adoptive transfer of NE-exposed DC induced a Th2 slanted response in vivo. Thus, a brief NE exposure of antigen-stimulated DC seems to limit their Th1 polarizing properties. Noteworthy, the ganglionic blocker pentolinium administered in mice before skin sensitization with fluoroscein isothiocyanate (FITC) could increase the Th1-type response in the draining lymph nodes. Our results suggest that the extent of Th differentiation in the response to an antigen might be influenced by the local sympathetic nervous activity in the early phase of dendritic cell stimulation.

Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-γ+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease.

PubMed

Globig, Anna-Maria; Hennecke, Nadine; Martin, Bianca; Seidl, Maximilian; Ruf, Günther; Hasselblatt, Peter; Thimme, Robert; Bengsch, Bertram

2014-12-01

Skewed T helper (TH) cell responses and specific functions of TH1, TH2, TH17, and Treg cells have been implicated in the pathogenesis of inflammatory bowel disease (IBD) that led to the establishment of the pathogenic TH1/TH2 and TH17/Treg cell imbalance paradigms. However, the relevant TH cell population driving mucosal inflammation is still unknown. We performed a comprehensive TH cell profiling of circulating and intestinal lymphocytes isolated from patients with Crohn's disease (CD; n = 69) and ulcerative colitis (UC; n = 41) undergoing endoscopy or surgical resection and compared them with healthy controls (n = 45). Mucosal inflammation was assessed endoscopically and histologically. TH cells were analyzed by flow cytometric evaluation of cytokine production and differentiation marker expression. Specialized TH cell populations were enriched in the intestinal mucosa compared with peripheral blood. Specifically, we observed a concomitant upregulation of TH17 cells and Tregs in active inflammatory lesions in patients with both CD and UC compared with quiescent/mildly inflamed lesions and healthy tissue. Of note, interferon γ+ interleukin (IL)-17+coproducing CD4+ T cells with high expression of T-bet, CD26, and IL-22 resembling recently described pathogenic TH17 cells were specifically enriched in the inflamed mucosal tissue. Our results argue against the controversial TH1/TH2 or TH17/Treg paradigms. In contrast, they suggest that a subpopulation of TH17 cells sharing a TH1 signature may be specifically involved in intestinal inflammation in CD and UC. These findings provide a better understanding of IBD pathogenesis and may help explain the efficacy of anti-IL-12p40/IL-23 and failure of anti-IL-17A therapies despite the enrichment of TH17 cells.

Amelioration of skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice by oral administration of Agaricus blazei extracts.

PubMed

Takimoto, Hiroaki; Kato, Hanano; Kaneko, Masahiro; Kumazawa, Yoshio

2008-01-01

We showed in a previous study that hot-water extracts of Agaricus blazei (Agaricus extracts) had anti-tumor activity to Meth A fibrosarcoma, but it remains unclear whether the Agaricus extracts ameliorate the skewed balance of type-1 T helper (Th1) and type-2 T helper (Th2) cells. We examined whether Agaricus extracts effect the skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice. When Meth A-bearing mice were given orally either Agaricus extracts or water once a day starting 5 days after tumor implantation, spleen T cells, prepared from tumor-bearing mice treated with Agaricus extracts, in response to anti-CD3 monoclonal antibody produced significantly higher levels of interferon gamma (IFN-gamma) than that of controls. The mRNA expression of IFN-gamma-inducing protein 10 and the frequency of CD69(+) or CD49d(+) cells, among activated T cells infiltrated into tumors, significantly increased in Agaricus-treated mice, compared with those of tumor-controls. In asthma-induced mice, treatment with the Agaricus extracts caused significant downregulation of OVA-specific antibody responses of IgG1 and IgE but not of IgG2a, and significantly decreased total cell numbers, levels of interleukin 5, and eosinophil numbers in bronchial alveolar lavage fluids. IFN-gamma production by anti-CD3-stimulated spleen cells, obtained from Agaricus-treated mice, significantly increased. Our results strongly suggest that oral administration of Agaricus extracts ameliorates the Th1/Th2 balance from the Th2-skewed conditions.

Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection

PubMed Central

Wiesner, Darin L.; Specht, Charles A.; Lee, Chrono K.; Smith, Kyle D.; Mukaremera, Liliane; Lee, S. Thera; Lee, Chun G.; Elias, Jack A.; Nielsen, Judith N.; Boulware, David R.; Bohjanen, Paul R.; Jenkins, Marc K.; Levitz, Stuart M.; Nielsen, Kirsten

2015-01-01

Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection. PMID:25764512

Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection.

PubMed

Wiesner, Darin L; Specht, Charles A; Lee, Chrono K; Smith, Kyle D; Mukaremera, Liliane; Lee, S Thera; Lee, Chun G; Elias, Jack A; Nielsen, Judith N; Boulware, David R; Bohjanen, Paul R; Jenkins, Marc K; Levitz, Stuart M; Nielsen, Kirsten

2015-03-01

Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.

Healthy human T-Cell Responses to Aspergillus fumigatus antigens.

PubMed

Chaudhary, Neelkamal; Staab, Janet F; Marr, Kieren A

2010-02-17

Aspergillus fumigatus is associated with both invasive and allergic pulmonary diseases, in different hosts. The organism is inhaled as a spore, which, if not cleared from the airway, germinates into hyphal morphotypes that are responsible for tissue invasion and resultant inflammation. Hyphae secrete multiple products that function as antigens, evoking both a protective (T(H)1-T(H)17) and destructive allergic (T(H)2) immunity. How Aspergillus allergens (Asp f proteins) participate in the development of allergic sensitization is unknown. To determine whether Asp f proteins are strictly associated with T(H)2 responses, or represent soluble hyphal products recognized by healthy hosts, human T cell responses to crude and recombinant products were characterized by ELISPOT. While responses (number of spots producing IFN-gamma, IL-4 or IL-17) to crude hyphal antigen preparations were weak, responses to recombinant Asp f proteins were higher. Recombinant allergens stimulated cells to produce IFN-gamma more so than IL-4 or IL-17. Volunteers exhibited a diverse CD4+ and CD8+ T cell antigen recognition profile, with prominent CD4 T(H)1-responses to Asp f3 (a putative peroxismal membrane protein), Asp f9/16 (cell wall glucanase), Asp f11 (cyclophilin type peptidyl-prolyl isomerase) and Asp f22 (enolase). Strong IFN-gamma responses were reproduced in most subjects tested over 6 month intervals. Products secreted after conidial germination into hyphae are differentially recognized by protective T cells in healthy, non-atopic individuals. Defining the specificity of the human T cell repertoire, and identifying factors that govern early responses may allow for development of novel diagnostics and therapeutics for both invasive and allergic Aspergillus diseases.

The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study.

PubMed

Martinez-Sanchez, Mariana E; Hiriart, Marcia; Alvarez-Buylla, Elena R

2017-06-26

Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGFβ producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGFβ in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment. This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.

Nanoparticles, [Gd@C82(OH)22]n, induces dendritic cell maturation and activates Th1 immune responses

PubMed Central

Yang, De; Zhao, Yuliang; Guo, Hua; Li, Yana; Tewary, Poonam; Xing, Gengmei; Hou, Wei; Oppenheim, Joost J.; Zhang, Ning

2010-01-01

Dendritic cells play a pivotal role in host immune defense, such as elimination of foreign pathogen and inhibition of tumorigenesis. In this paper, we report that [Gd@C82(OH)22]n could induce phenotypic maturation of dendritic cells by stimulating DC production of cytokines including IL-12p70, upregulating DC costimulatory (CD80, CD83, and CD86) and MHC (HLA-A,B,C and HLA-DR) molecules, and switching DCs from a CCL5-responsive to a CCL19-responsive phenotype. We found that [Gd@C82(OH)22]n can induce dendritic cells to become functionally mature as illustrated by their capacity to activate allogeneic T cells. Mice immunized with ovalbumin in the presence of [Gd@C82(OH)22]n exhibit enhanced ovalbumin-specific Th1-polarized immune response as evidenced by the predominantly increased production of IFNγ, IL-1β, and IL-2. The [Gd@C82(OH)22]n nanoparticle is a potent activator of dendritic cells and Th1 immune responses. These new findings also provide a rational understanding of the potent anticancer activities of [Gd@C82(OH)22]n nanoparticles reported previously. PMID:20121217

Adoptive Transfer of Tumor-Specific Th2 Cells Eradicates Tumors by Triggering an In Situ Inflammatory Immune Response.

PubMed

Lorvik, Kristina Berg; Hammarström, Clara; Fauskanger, Marte; Haabeth, Ole Audun Werner; Zangani, Michael; Haraldsen, Guttorm; Bogen, Bjarne; Corthay, Alexandre

2016-12-01

Adoptive cell therapy (ACT) trials to date have focused on transfer of autologous tumor-specific cytotoxic CD8 + T cells; however, the potential of CD4 + T helper (Th) cells for ACT is gaining interest. While encouraging results have been reported with IFNγ-producing Th1 cells, tumor-specific Th2 cells have been largely neglected for ACT due to their reported tumor-promoting properties. In this study, we tested the efficacy of idiotype-specific Th2 cells for the treatment of mice with MHC class II-negative myeloma. Th2 ACT efficiently eradicated subcutaneous myeloma in an antigen-specific fashion. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Cancer eradication mediated by tumor-specific Th2 cells did not require B cells, natural killer T cells, CD8 + T cells, or IFNγ. Th2 ACT was also curative against B-cell lymphoma. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. In vivo blockade of arginase strongly inhibited Th2 ACT, consistent with a key role of arginase and M2 macrophages in myeloma elimination by Th2 cells. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, ACT with tumor-specific Th2 cells may represent a highly efficient immunotherapy protocol against cancer. Cancer Res; 76(23); 6864-76. ©2016 AACR. ©2016 American Association for Cancer Research.

Turmeric (Curcuma longa) attenuates food allergy symptoms by regulating type 1/type 2 helper T cells (Th1/Th2) balance in a mouse model of food allergy.

PubMed

Shin, Hee Soon; See, Hye-Jeong; Jung, Sun Young; Choi, Dae Woon; Kwon, Da-Ae; Bae, Min-Jung; Sung, Ki-Seung; Shon, Dong-Hwa

2015-12-04

Turmeric (Curcuma longa) has traditionally been used to treat pain, fever, allergic and inflammatory diseases such as bronchitis, arthritis, and dermatitis. In particular, turmeric and its active component, curcumin, were effective in ameliorating immune disorders including allergies. However, the effects of turmeric and curcumin have not yet been tested on food allergies. Mice were immunized with intraperitoneal ovalbumin (OVA) and alum. The mice were orally challenged with 50mg OVA, and treated with turmeric extract (100mg/kg), curcumin (3mg/kg or 30 mg/kg) for 16 days. Food allergy symptoms including decreased rectal temperature, diarrhea, and anaphylaxis were evaluated. In addition, cytokines, immunoglobulins, and mouse mast cell protease-1 (mMCP-1) were evaluated using ELISA. Turmeric significantly attenuated food allergy symptoms (decreased rectal temperature and anaphylactic response) induced by OVA, but curcumin showed weak improvement. Turmeric also inhibited IgE, IgG1, and mMCP-1 levels increased by OVA. Turmeric reduced type 2 helper cell (Th2)-related cytokines and enhanced a Th1-related cytokine. Turmeric ameliorated OVA-induced food allergy by maintaining Th1/Th2 balance. Furthermore, turmeric was confirmed anti-allergic effect through promoting Th1 responses on Th2-dominant immune responses in immunized mice. Turmeric significantly ameliorated food allergic symptoms in a mouse model of food allergy. The turmeric as an anti-allergic agent showed immune regulatory effects through maintaining Th1/Th2 immune balance, whereas curcumin appeared immune suppressive effects. Therefore, we suggest that administration of turmeric including various components may be useful to ameliorate Th2-mediated allergic disorders such as food allergy, atopic dermatitis, and asthma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines.

PubMed

Banerjee, Antara; Bhattacharya, Parna; Joshi, Amritanshu B; Ismail, Nevien; Dey, Ranadhir; Nakhasi, Hira L

2016-11-01

The clinical outcome of Leishmania pathogenesis ranges from active skin lesions to fatal visceral dissemination and severely impaired T cell immunity. It is well established that a strong Th1 immune response is protective against cutaneous forms of the disease, however a mixed Th1/Th2 response is most commonly observed against visceral infections as evident from previous studies. Aside from Th1/Th2 cytokines, the pro-inflammatory IL-17 cytokine family plays an important role in the clearance of intracellular pathogens. In Leishmania induced skin lesions, IL-17 produced by Th17 cells is shown to exacerbate the disease, suggesting a role in pathogenesis. However, a protective role for IL-17 is indicated by the expansion of IL-17 producing cells in vaccine-induced immunity. In human visceral leishmaniasis (VL) it has been demonstrated that IL-17 and IL-22 are associated with protection against re-exposure to Leishmania, which further suggests the involvement of IL-17 in vaccine induced protective immunity. Although there is no vaccine against any form of leishmaniasis, the development of genetically modified live attenuated parasites as vaccine candidates prove to be promising, as they successfully induce a robust protective immune response in various animal models. However, the role of IL-17 producing cells and Th17 cells in response to these vaccine candidates remains unexplored. In this article, we review the role of IL-17 in Leishmania pathogenesis and the potential impact on vaccine induced immunity, with a special focus on live attenuated Leishmania parasites. Published by Elsevier Inc.

Unique Action of Interleukin-18 on T Cells and Other Immune Cells.

PubMed

Nakanishi, Kenji

2018-01-01

Interleukin (IL)-18 was originally discovered as a factor that enhances interferon (IFN)-γ production by anti-CD3-stimulated Th1 cells, particularly in association with IL-12. IL-12 is a cytokine that induces development of Th1 cells. IL-18 cannot induce Th1 cell development, but has the capacity to activate established Th1 cells to produce IFN-γ in the presence of IL-12. Thus, IL-18 is regarded as a proinflammatory cytokine that facilitates type 1 responses. However, in the absence of IL-12 but presence of IL-2, IL-18 stimulates natural killer cells, NKT cells, and even established Th1 cells to produce IL-3, IL-9, and IL-13. Thus, IL-18 also facilitates type 2 responses. This unique function of IL-18 contributes to infection-associated allergic diseases. Together with IL-3, IL-18 stimulates mast cells and basophils to produce IL-4, IL-13, and chemical mediators such as histamine. Thus, IL-18 also induces innate-type allergic inflammation. IL-18 belongs to the IL-1 family of cytokines, which share similar molecular structures, receptors structures, and signal transduction pathways. Nevertheless, IL-18 shows a unique function by binding to a specific receptor expressed on distinct types of cells. In this review article, I will focus on the unique features of IL-18 in lymphocytes, basophils, and mast cells, particularly in comparison with IL-33.

Impact of combined sodium chloride and saturated long-chain fatty acid challenge on the differentiation of T helper cells in neuroinflammation.

PubMed

Hammer, Anna; Schliep, Anne; Jörg, Stefanie; Haghikia, Aiden; Gold, Ralf; Kleinewietfeld, Markus; Müller, Dominik N; Linker, Ralf A

2017-09-12

There has been a marked increase in the incidence of autoimmune diseases like multiple sclerosis (MS) in the last decades which is most likely driven by a change in environmental factors. Here, growing evidence suggests that ingredients of a Western diet like high intake of sodium chloride (NaCl) or saturated fatty acids may impact systemic immune responses, thus increasing disease susceptibility. Recently, we have shown that high dietary salt or long-chain fatty acid (LCFA) intake indeed aggravates T helper (Th) cell responses and neuroinflammation. Naïve CD4 + T cells were treated with an excess of 40 mM NaCl and/or 250 μM lauric acid (LA) in vitro to analyze effects on Th cell differentiation, cytokine secretion, and gene expression. We employed ex vivo analyses of the model disease murine experimental autoimmune encephalomyelitis (EAE) to investigate whether salt and LCFA may affect disease severity and T cell activation in vivo. LCFA, like LA, together with NaCl enhance the differentiation of Th1 and Th17 cells as well as pro-inflammatory cytokine and gene expression in vitro. In cell culture, we observed an additive effect of LA and hypertonic extracellular NaCl (NaCl + LA) in Th17 differentiation assays as well as on IL-17, GM-CSF, and IL-2 gene expression. In contrast, NaCl + LA reduced Th2 frequencies. We employed EAE as a model of Th1/Th17 cell-mediated autoimmunity and show that the combination of a NaCl- and LA-rich diet aggravated the disease course and increased T cell infiltration into the central nervous system (CNS) to the same extent as dietary NaCl. Our findings demonstrate a partially additive effect of NaCl and LA on Th cell polarization in vitro and on Th cell responses in autoimmune neuroinflammation. These data may help to better understand the pathophysiology of autoimmune diseases such as MS.

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.

PubMed

Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita; Wyatt, Megan W; Dhar, Payal; Selvam, Shanmugam Panneer; Fu, Jianing; Zhang, Jinyu; Nguyen, Hung; Kang, Inhong; Toth, Kyle; Al-Homrani, Mazen; Husain, Mahvash; Beeson, Gyda; Ball, Lauren; Helke, Kristi; Husain, Shahid; Garrett-Mayer, Elizabeth; Hardiman, Gary; Mehrotra, Meenal; Nishimura, Michael I; Beeson, Craig C; Bupp, Melanie Gubbels; Wu, Jennifer; Ogretmen, Besim; Paulos, Chrystal M; Rathmell, Jeffery; Yu, Xue-Zhong; Mehrotra, Shikhar

2018-01-09

Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD + -dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD + , enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD + axis could increase the efficacy of anti-tumor adoptive T cell therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin.

PubMed

Rodríguez, Ernesto; Carasi, Paula; Frigerio, Sofía; da Costa, Valeria; van Vliet, Sandra; Noya, Verónica; Brossard, Natalie; van Kooyk, Yvette; García-Vallejo, Juan J; Freire, Teresa

2017-01-01

Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica , is a trematode zoonosis of interest in public health and livestock production. Like other helminths, F. hepatica modulates the host immune response by inducing potent polarized Th2 and regulatory T cell immune responses and by downregulating the production of Th1 cytokines. In this work, we show that F. hepatica glycans increase Th2 immune responses by immunomodulating TLR-induced maturation and function of dendritic cells (DCs). This process was mediated by the macrophage Gal/GalNAc lectin (MGL) expressed on DCs, which recognizes the Tn antigen (GalNAc-Ser/Thr) on parasite components. More interestingly, we identified MGL-expressing CD11c + cells in infected animals and showed that these cells are recruited both to the peritoneum and the liver upon F. hepatica infection. These cells express the regulatory cytokines IL-10, TNFα and TGFβ and a variety of regulatory markers. Furthermore, MGL + CD11c + cells expand parasite-specific Th2/regulatory cells and suppress Th1 polarization. The results presented here suggest a potential role of MGL in the immunomodulation of DCs induced by F. hepatica and contribute to a better understanding of the molecular and immunoregulatory mechanisms induced by this parasite.

Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin

PubMed Central

Rodríguez, Ernesto; Carasi, Paula; Frigerio, Sofía; da Costa, Valeria; van Vliet, Sandra; Noya, Verónica; Brossard, Natalie; van Kooyk, Yvette; García-Vallejo, Juan J.; Freire, Teresa

2017-01-01

Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is a trematode zoonosis of interest in public health and livestock production. Like other helminths, F. hepatica modulates the host immune response by inducing potent polarized Th2 and regulatory T cell immune responses and by downregulating the production of Th1 cytokines. In this work, we show that F. hepatica glycans increase Th2 immune responses by immunomodulating TLR-induced maturation and function of dendritic cells (DCs). This process was mediated by the macrophage Gal/GalNAc lectin (MGL) expressed on DCs, which recognizes the Tn antigen (GalNAc-Ser/Thr) on parasite components. More interestingly, we identified MGL-expressing CD11c+ cells in infected animals and showed that these cells are recruited both to the peritoneum and the liver upon F. hepatica infection. These cells express the regulatory cytokines IL-10, TNFα and TGFβ and a variety of regulatory markers. Furthermore, MGL+ CD11c+ cells expand parasite-specific Th2/regulatory cells and suppress Th1 polarization. The results presented here suggest a potential role of MGL in the immunomodulation of DCs induced by F. hepatica and contribute to a better understanding of the molecular and immunoregulatory mechanisms induced by this parasite. PMID:28360908

Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response.

PubMed

Charbonnier, Anne-Sophie; Hammad, Hamida; Gosset, Philippe; Stewart, Geoffrey A; Alkan, Sefik; Tonnel, André-Bernard; Pestel, Joël

2003-01-01

Although reports suggest that dendritic cells (DC) are involved in the allergic reaction characterized by a T helper cell type 2 (Th2) profile, the role of myeloid (M-DC) and plasmacytoid DC (P-DC), controlling the balance Th1/Th2, remains unknown. Here, we showed that in Dermatophagoides pteronyssinus (Dpt)-sensitized allergic patients and in healthy donors, M-DC displayed a higher capacity to capture Der p 1, a major allergen of Dpt, than did P-DC. However, Der p 1-pulsed M-DC from healthy subjects overexpressed CD80 and secreted interleukin (IL)-10, whereas M-DC from allergic patients did not. In contrast, with Der p 1-pulsed P-DC from both groups, no increase in human leukocyte antigen-DR, CD80, and CD86 and no IL-10 secretion were detected. When cocultured with allogeneic naive CD4(+) T cells from healthy donors, Der p 1-pulsed M-DC from allergic patients favored a Th1 profile [interferon (IFN)-gamma(high)/IL-4(low)] and Der p 1-pulsed P-DC, a Th2 profile (IFN-gamma(low)/IL-4(high)). In healthy donors, no T cell polarization (IFN-gamma(low)/IL-4(low)) was induced by Der p 1-pulsed M-DC or P-DC, but in response to Der p 1-pulsed M-DC, T cells secreted IL-10. The neutralization of IL-10 produced by Der p 1-pulsed M-DC from healthy donors led to an inhibition of IL-10 production by T cells and a polarization toward a type 1. Thus, IL-10 produced by M-DC might be an essential mediator controlling the balance between tolerance and allergic status. In addition, P-DC could contribute to the steady state in healthy donors or to the development of a Th2 response in allergic donors.

Concomitant Exposure to Ovalbumin and Endotoxin Augments Airway Inflammation but Not Airway Hyperresponsiveness in a Murine Model of Asthma

PubMed Central

Mac Sharry, John; Shalaby, Karim H.; Marchica, Cinzia; Farahnak, Soroor; Chieh-Li, Tien; Lapthorne, Susan; Qureshi, Salman T.; Shanahan, Fergus; Martin, James G.

2014-01-01

Varying concentrations of lipopolysaccharide (LPS) in ovalbumin (OVA) may influence the airway response to allergic sensitization and challenge. We assessed the contribution of LPS to allergic airway inflammatory responses following challenge with LPS-rich and LPS-free commercial OVA. BALB/c mice were sensitized with LPS-rich OVA and alum and then underwent challenge with the same OVA (10 µg intranasally) or an LPS-free OVA. Following challenge, bronchoalveolar lavage (BAL), airway responsiveness to methacholine and the lung regulatory T cell population (Treg) were assessed. Both OVA preparations induced BAL eosinophilia but LPS-rich OVA also evoked BAL neutrophilia. LPS-free OVA increased interleukin (IL)-2, IL-4 and IL-5 whereas LPS-rich OVA additionally increased IL-1β, IL-12, IFN-γ, TNF-α and KC. Both OVA-challenged groups developed airway hyperresponsiveness. TLR4-deficient mice challenged with either OVA preparation showed eosinophilia but not neutrophilia and had increased IL-5. Only LPS-rich OVA challenged mice had increased lung Tregs and LPS-rich OVA also induced in vitro Treg differentiation. LPS-rich OVA also induced a Th1 cytokine response in human peripheral blood mononuclear cells.We conclude that LPS-rich OVA evokes mixed Th1, Th2 and innate immune responses through the TLR-4 pathway, whereas LPS-free OVA evokes only a Th2 response. Contaminating LPS is not required for induction of airway hyperresponsiveness but amplifies the Th2 inflammatory response and is a critical mediator of the neutrophil, Th1 and T regulatory cell responses to OVA. PMID:24968337

SUMOylation-disrupting WAS mutation converts WASp from a transcriptional activator to a repressor of NF-κB response genes in T cells.

PubMed

Sarkar, Koustav; Sadhukhan, Sanjoy; Han, Seong-Su; Vyas, Yatin M

2015-10-01

In Wiskott-Aldrich syndrome (WAS), immunodeficiency and autoimmunity often comanifest, yet how WAS mutations misregulate chromatin-signaling in Thelper (TH) cells favoring development of auto-inflammation over protective immunity is unclear. Previously, we identified an essential promoter-specific, coactivator role of nuclear-WASp in TH1 gene transcription. Here we identify small ubiquitin-related modifier (SUMO)ylation as a novel posttranslational modification of WASp, impairment of which converts nuclear-WASp from a transcriptional coactivator to a corepressor of nuclear factor (NF)-κB response genes in human (TH)1-differentiating cells. V75M, one of many disease-causing mutations occurring in SUMO*motif (72-ψψψψKDxxxxSY-83) of WASp, compromises WASp-SUMOylation, associates with COMMD1 to attenuate NF-κB signaling, and recruits histone deacetylases-6 (HDAC6) to p300-marked promoters of NF-κB response genes that pattern immunity but not inflammation. Consequently, proteins mediating adaptive immunity (IFNG, STAT1, TLR1) are deficient, whereas those mediating auto-inflammation (GM-CSF, TNFAIP2, IL-1β) are paradoxically increased in TH1 cells expressing SUMOylation-deficient WASp. Moreover, SUMOylation-deficient WASp favors ectopic development of the TH17-like phenotype (↑IL17A, IL21, IL22, IL23R, RORC, and CSF2) under TH1-skewing conditions, suggesting a role for WASp in modulating TH1/TH17 plasticity. Notably, pan-histone deacetylase inhibitors lift promoter-specific repression imposed by SUMOylation-deficient WASp and restore misregulated gene expression. Our findings uncovering a SUMOylation-based mechanism controlling WASp's dichotomous roles in transcription may have implications for personalized therapy for patients carrying mutations that perturb WASp-SUMOylation. © 2015 by The American Society of Hematology.

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant.

PubMed

Schaut, Robert G; Grinnage-Pulley, Tara L; Esch, Kevin J; Toepp, Angela J; Duthie, Malcolm S; Howard, Randall F; Reed, Steven G; Petersen, Christine A

2016-10-17

Visceral leishmaniasis (VL), caused by infection with the obligate intracellular protozoan parasite Leishmania infantum, is a fatal disease of dogs and humans. Protection against VL requires a T helper 1 (Th1) skewed CD4 + T response, but despite this knowledge, there are currently no approved-to-market vaccines for humans and only three veterinary-use vaccines globally. As VL progresses from asymptomatic to symptomatic, L. infantum-specific interferon gamma (IFNγ) driven-Th1 responses become dampened and a state of immune exhaustion established. T cell exhaustion and other immunoregulatory processes, starting during asymptomatic disease, are likely to hinder vaccine-induced responses if vaccine is administered to infected, but asymptomatic and seronegative, individuals. In this study we evaluated how immune exhaustion, shown previously by our group to worsen in concert with VL progression, effected the capacity of vaccine candidate antigen/toll-like receptor (TLR) agonist combinations to promote protective CD4 + T cell responses during progressive VL. In conjunction with Th1 responses, we also evaluated concomitant stimulation of immune-balanced IL-10 regulatory cytokine production by these vaccine products in progressive VL canine T cells. Vaccine antigen L111f in combination with TLR agonists significantly recovered CD4 + T cell IFNγ intracellular production in T cells from asymptomatic VL dogs. Vaccine antigen NS with TLR agonists significantly recovered CD4 + T cell production in both endemic control and VL dogs. Combinations of TLR agonists and vaccine antigens overcame L. infantum induced cellular exhaustion, allowing robust Th1 CD4 + T cell responses from symptomatic dogs that previously had dampened responses to antigen alone. Antigen-agonist adjuvants can be utilized to promote more robust vaccine responses from infected hosts in endemic areas where vaccination of asymptomatic, L. infantum-infected animals is likely. Copyright © 2016. Published by Elsevier Ltd.

Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/CCL22.

PubMed

Hammad, Hamida; Smits, Hermelijn H; Ratajczak, Céline; Nithiananthan, Asokananthan; Wierenga, Eddy A; Stewart, Geoffrey A; Jacquet, Alain; Tonnel, Andre-Bernard; Pestel, Joël

2003-01-01

Dendritic cells (DC) are potent antigen - presenting cells that can orientate the immune response towards a Th1 or a Th2 type. DC produce chemokines that are involved in the recruitment of either Th1 cells, such as IP10 (CXCL10), Th2 cells such as TARC (CCL17) and MDC (CCL22), or non-polarized T cells such as RANTES (CCL5) and MIP-lalpha (CCL3). We investigated whether monocyte-derived DC (MD-DC) generated from healthy donors or from patients sensitive to Dermatophagoides pteronyssinus (Dpt) and exposed to the cysteine-protease Der p 1(allergen of Dpt), could upregulate the expression of chemokines involved in type 1 or type 2 T cell recruitment. MD-DC were pulsed with either Der p 1 or with LPS as the control and the chemokines produced were evaluated using ELISA and chemotaxis assays. Der p 1-pulsed DC from allergic patients showed increased TARC (CCL17) and MDC (CCL22) production without modifying IP-10 (CXCL10) release. Der p 1-pulsed DC from healthy donors showed only increased IP-10 (CXCL10) secretion. RANTES (CCL5) and MIP-lalpha (CCL3) production were similarly increased when DC were from healthy or allergic donors. The selective Th2 clone recruitment activity of supernatants from Der p 1-pulsed DC of allergic patients was inhibited by anti-TARC (CCL17) and anti-MDC (CCL22) neutralizing Abs. By using anti-IP10 (CXCL10) blocking Abs, supernatants of Der p 1-pulsed DC from healthy donors were shown to be involved in the recruitment of Th1 cells. These results suggest that in allergic patients exposed to house dust mites, DC may favour the exacerbation of the Th2 response via the increase in type 2 chemokine production. Copyright John Libbey Eurotext 2003.

Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses.

PubMed

Imamura, Emiko; Taguchi, Katsunari; Sasaki-Iwaoka, Haruna; Kubo, Satoshi; Furukawa, Shigetada; Morokata, Tatsuaki

2018-04-05

Experimental colitis studies, including T cell-mediated colitis, indicate that IL-23 rather than IL-12 orchestrates intestinal inflammation in inflammatory bowel disease (IBD). Previous studies have identified the roles of IL-12 and IL-23 using mice deficient for their specific subunits, p35 and p19, respectively. However, these studies do not completely reflect the difference in roles between IL-12 and IL-23, especially since the discovery of novel IL-12 family cytokines, which also include p35 or p19 subunits. Here, to clarify the contribution of IL-12 and IL-23 in T cell-mediated colitis, we compared the efficacy of a monoclonal antibody (mAb) to an IL-23-specific receptor subunit with that of an anti-IL-12/23p40 mAb in a naive CD4 + T cell transfer model of experimental colitis, which is associated with enhanced Th1 and Th17 responses. Both antibodies almost completely prevented the development of colitis and showed reduced associated histological changes, including mucosal hyperplasia, infiltration of inflammatory cells and loss of goblet cells. The anti-IL-23 receptor mAb inhibited not only the systemic Th17-response but also the Th1-response, both of which were up-regulated in this model. These results suggest that IL-23, but not IL-12, signaling is critical for the development of colitis. Blockade of IL-23 signaling is a promising therapeutic approach for IBD. Copyright © 2018 Elsevier B.V. All rights reserved.

T cell epitope immunotherapy ameliorates allergic responses in a murine model of shrimp allergy.

PubMed

Wai, C Y Y; Leung, N Y H; Leung, P S C; Chu, K H

2016-03-01

Shellfish allergy is one of the most common food hypersensitivities worldwide but allergen-specific immunotherapy for shellfish allergy is not yet available. We believe that T cell peptide-based immunotherapy holds the potential for modulating allergic responses without IgE cross-linking. We sought to identify the immunodominant T cell epitopes of tropomyosin, the major shrimp allergen of Metapenaeus ensis (Met e 1), and to evaluate their therapeutic effects in a Balb/c mouse model of Met e 1 hypersensitivity. T cell epitopes of Met e 1 were first identified based on the proliferation and cytokine responses of splenocytes isolated from Met e 1-sensitized Balb/c mice upon stimulation by 18 synthetic peptides that span the full-length Met e 1. The immunodominant T cell peptides identified were then fed orally to Met e 1-sensitized Balb/c mice twice a week for four weeks. Allergic responses, serological antibody levels, intestinal histology and systemic and local cytokine profiles were compared between the treated and the untreated groups. Six major Met e 1 T cell epitopes were identified. Mice treated with the T cell epitope peptide mixture demonstrated an amelioration of systemic allergic symptoms and a significant reduction in Th2-associated antibody and cytokine responses. These benefits were accompanied by a shift to a balanced Th1/Th2 response, induction of IgG2a antibodies possessing in vitro and in vivo blocking activities and the induction of regulatory T cell responses. T cell epitope-based oral immunotherapy is effective in reducing allergic responses towards shrimp tropomyosin. This is a novel strategy for clinical management of shellfish allergy and is a model for mechanistic studies of oral immunotherapy. © 2015 John Wiley & Sons Ltd.

Mesenchymal Stromal Cells Prevent Allostimulation In Vivo and Control Checkpoints of Th1 Priming: Migration of Human DC to Lymph Nodes and NK Cell Activation.

PubMed

Consentius, C; Akyüz, L; Schmidt-Lucke, J A; Tschöpe, C; Pinzur, L; Ofir, R; Reinke, P; Volk, H-D; Juelke, K

2015-10-01

Although the immunomodulatory potency of mesenchymal stromal cells (MSC) is well established, the mechanisms behind are still not clear. The crosstalk between myeloid dendritic cells (mDC) and natural killer (NK) cells and especially NK cell-derived interferon-gamma (IFN-γ) play a pivotal role in the development of type 1 helper (Th1) cell immune responses. While many studies explored the isolated impact of MSC on either in vitro generated DC, NK, or T cells, there are only few data available on the complex interplay between these cells. Here, we investigated the impact of MSC on the functionality of human mDC and the consequences for NK cell and Th1 priming in vitro and in vivo. In critical limb ischemia patients, who have been treated with allogeneic placenta-derived mesenchymal-like stromal cells (PLX-PAD), no in vivo priming of Th1 responses toward the major histocompatibility complex (MHC) mismatches could be detected. Further in vitro studies revealed that mDC reprogramming could play a central role for these effects. Following crosstalk with MSC, activated mDC acquired a tolerogenic phenotype characterized by reduced migration toward CCR7 ligand and impaired ability to stimulate NK cell-derived IFN-γ production. These effects, which were strongly related to an altered interleukin (IL)-12/IL-10 production by mDC, were accompanied by an effective prevention of Th1 priming in vivo. Our findings provide novel evidence for the regulation of Th1 priming by MSC via modulation of mDC and NK cell crosstalk and show that off-the-shelf produced MHC-mismatched PLX-PAD can be used in patients without any sign of immunogenicity. © 2015 AlphaMed Press.

PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

PubMed

Li, Pan; Asokanathan, Catpagavalli; Liu, Fang; Khaing, Kyi Kyi; Kmiec, Dorota; Wei, Xiaoqing; Song, Bing; Xing, Dorothy; Kong, Deling

2016-11-20

Poly(lactic-co-glycolic acid) (PLGA) based nano/micro particles were investigated as a potential vaccine platform for pertussis antigen. Presentation of pertussis toxoid as nano/micro particles (NP/MP) gave similar antigen-specific IgG responses in mice compared to soluble antigen. Notably, in cell line based assays, it was found that PLGA based nano/micro particles enhanced the phagocytosis of fluorescent antigen-nano/micro particles by J774.2 murine monocyte/macrophage cells compared to soluble antigen. More importantly, when mice were immunised with the antigen-nano/micro particles they significantly increased antigen-specific Th1 cytokines INF-γ and IL-17 secretion in splenocytes after in vitro re-stimulation with heat killed Bordetalla pertussis, indicating the induction of a Th1/Th17 response. Also, presentation of pertussis antigen in a NP/MP formulation is able to provide protection against respiratory infection in a murine model. Thus, the NP/MP formulation may provide an alternative to conventional acellular vaccines to achieve a more balanced Th1/Th2 immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

Differential Effects of Naja naja atra Venom on Immune Activity

PubMed Central

Kou, Jian-Qun; Han, Rong; Xu, Yin-Li; Ding, Xiao-Lan; Wang, Shu-Zhi; Chen, Cao-Xin; Ji, Hong-Zhang; Ding, Zhi-Hui; Qin, Zheng-Hong

2014-01-01

Previous studies reported that Naja naja atra venom (NNAV) inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1 phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-γ, IL-4) secretion and inhibition of Th17 cytokine (IL-17) production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases. PMID:25024726

Identification of a T-helper cell epitope on the rotavirus VP6 protein.

PubMed Central

Baños, D M; Lopez, S; Arias, C F; Esquivel, F R

1997-01-01

In this work, we have studied the T-helper (Th)-cell response against rotavirus, in a mouse model. Adult BALB/c mice were inoculated parenterally with porcine rotavirus YM, and the Th-cell response from spleen cells against the virus and two overlapping fragments of the major capsid protein VP6 (VP6(1-192) and VP6(171-397)) were evaluated in vitro. The Th cells recognized the YM virus and the two protein fragments, suggesting that there are at least two Th-cell epitopes on the VP6 molecule. To study the specificity of Th cells against VP6 at the clonal level, we established two Th-cell hybridomas cross-reactive for the VP6 protein of rotavirus strains YM and SA11. Both hybridomas recognized the VP6(171-397) polypeptide, and a synthetic peptide comprising the amino acids 289 to 302 (RLSFQLVRPPNMTP) of YM VP6 in the context of the major histocompatibility complex class II IEd molecule. The Th-cell hybridomas recognized rotavirus VP6 in a highly cross-reactive fashion, since they could be stimulated by eight different strains of rotavirus, including the murine rotavirus EDIM, that represent five G serotypes and at least two subgroups. The amino acid sequence of the VP6 epitope is highly conserved in most group A rotavirus strains sequenced so far. On the other hand, it was found that Th cells specific for the VP6 epitope may constitute an important proportion of the total polyclonal Th-cell response against rotavirus YM in spleen cells. These results demonstrate that VP6 can be a target for highly cross-reactive Th cells. PMID:8985366

Mannosylated Mucin-Type Immunoglobulin Fusion Proteins Enhance Antigen-Specific Antibody and T Lymphocyte Responses

PubMed Central

Johansson, Tomas; Nilsson, Anki; Chatzissavidou, Nathalie; Sjöblom, Magnus; Rova, Ulrika; Holgersson, Jan

2012-01-01

Targeting antigens to antigen-presenting cells (APC) improve their immunogenicity and capacity to induce Th1 responses and cytotoxic T lymphocytes (CTL). We have generated a mucin-type immunoglobulin fusion protein (PSGL-1/mIgG2b), which upon expression in the yeast Pichia pastoris became multivalently substituted with O-linked oligomannose structures and bound the macrophage mannose receptor (MMR) and dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) with high affinity in vitro. Here, its effects on the humoral and cellular anti-ovalbumin (OVA) responses in C57BL/6 mice are presented. OVA antibody class and subclass responses were determined by ELISA, the generation of anti-OVA CTLs was assessed in 51Cr release assays using in vitro-stimulated immune spleen cells from the different groups of mice as effector cells and OVA peptide-fed RMA-S cells as targets, and evaluation of the type of Th cell response was done by IFN-γ, IL-2, IL-4 and IL-5 ELISpot assays. Immunizations with the OVA − mannosylated PSGL-1/mIgG2b conjugate, especially when combined with the AbISCO®-100 adjuvant, lead to faster, stronger and broader (with regard to IgG subclass) OVA IgG responses, a stronger OVA-specific CTL response and stronger Th1 and Th2 responses than if OVA was used alone or together with AbISCO®-100. Also non-covalent mixing of mannosylated PSGL-1/mIgG2b, OVA and AbISCO®-100 lead to relatively stronger humoral and cellular responses. The O-glycan oligomannoses were necessary because PSGL-1/mIgG2b with mono- and disialyl core 1 structures did not have this effect. Mannosylated mucin-type fusion proteins can be used as versatile APC-targeting molecules for vaccines and as such enhance both humoral and cellular immune responses. PMID:23071675

Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer.

PubMed

Li, Li; Wang, Wei; Pan, Hong; Ma, Ge; Shi, Xinyi; Xie, Hui; Liu, Xiaoan; Ding, Qiang; Zhou, Wenbin; Wang, Shui

2017-01-31

Minimally invasive therapies, such as microwave ablation (MWA), are widely used for the treatment of solid tumors. Previous studies suggest that MWA is feasible for the treatment of small breast cancer, and thermal ablation may induce adaptive antitumor immunity. However, the induced immune responses are mostly weak, and the immunomodulation effects of MWA in breast cancer are unclear. Immunostimulant OK-432 can induce tumor-specific T-cell responses and may augment the immunity induced by MWA. We treated 4T1 breast cancer bearing BALB/c mice with MWA, OK-432, MWA plus OK-432, or left without treatment. Survival time was evaluated with the Kaplan-Meyer method comparing survival curves by log-rank test. On day 25 after ablation, surviving mice received tumor rechallenge, and the rechallenged tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were used to evaluate the T-cell immune responses in ablated tissues and spleens. The tumor-specific immunity was assessed by enzyme-linked immunospot assays. Besides, the cytokine patterns were identified from enzyme-linked immunosorbent assay. Microwave ablation plus OK-432 resulted in longer survival than single treatment and protect most surviving mice from tumor rechallenge. Both local and systemic T-cell responses were induced by MWA and were further enhanced by subsequent administration of OK-432. Moreover, the combination of MWA and OK-432 induced stronger tumor-specific immune responses than MWA alone. In addition, OK-432 and MWA synergistically promoted the production of Th1-type but not Th2-type cytokines, and polarized T-cell responses to Th1-dominant state. The T-cell immune responses were activated by MWA in breast cancer. Furthermore, the combination of MWA and OK-432 induced Th1-type response and elicited specific antitumor immunity.

Cognate interactions between helper T cells and B cells. IV. Requirements for the expression of effector phase activity by helper T cells.

PubMed

Bartlett, W C; McCann, J; Shepherd, D M; Roy, M; Noelle, R J

1990-12-15

After activation with anti-CD3, activated Th (THCD3), but not resting Th, fixed with paraformaldehyde induce B cell RNA synthesis when co-cultured with resting B cells. This activity is expressed by Th of both Th1 and Th2 subtypes, as well as a third Th clone that is not classified into either subtype. It is proposed that anti-CD3 activation of Th results in the expression of Th membrane proteins that trigger B cell cycle entry. Kinetic studies reveal that 4 to 8 h of activation with anti-CD3 is sufficient for ThCD3 to express B cell-activating function. However, activation of Th with anti-CD3 for extended periods of time results in reduced Th effector activity. Inhibition of Th RNA synthesis during the anti-CD3 activation period ablates the ability of ThCD3 to induce B cell cycle entry. This indicates that de novo synthesis of proteins is required for ThCD3 to express effector function. The ability of fixed ThCD3 to induce entry of B cell into cycle is not due to an increase in expression of CD3, CD4, LFA-1, ICAM-1, class I MHC or Thy-1. Other forms of Th activation (PMA and A23187, Con A) also induced Th effector function. Furthermore, purified plasma membranes from anti-CD3 activated, but not resting Th, induced resting B cells to enter cycle. The addition of IL-4, but not IL-2, IL-5, or IFN-gamma amplified the DNA synthetic response of B cells stimulated with PM from activated Th. Taken together these data indicate that de novo expression of Th surface proteins on activated Th is required for Th to induce B cell cycle entry into G1 and the addition of IL-4 is required for the heightened progression into S phase.

Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4.

PubMed

Im, S H; Barchan, D; Maiti, P K; Fuchs, S; Souroujon, M C

2001-06-01

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent Ab-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1-type cells and costimulatory factors such as CD40 ligand (CD40L) contribute to disease pathogenesis by producing proinflammatory cytokines and by activating autoreactive B cells. In this study we demonstrate the capacity of CD40L blockade to modulate EAMG, and analyze the mechanism underlying this disease suppression. Anti-CD40L Abs given to rats at the chronic stage of EAMG suppress the clinical progression of the autoimmune process and lead to a decrease in the AChR-specific humoral response and delayed-type hypersensitivity. The cytokine profile of treated rats suggests that the underlying mechanism involves down-regulation of AChR-specific Th1-regulated responses with no significant effect on Th2- and Th3-regulated AChR-specific responses. EAMG suppression is also accompanied by a significant up-regulation of CTLA-4, whereas a series of costimulatory factors remain unchanged. Adoptive transfer of splenocytes from anti-CD40L-treated rats does not protect recipient rats against subsequently induced EAMG. Thus it seems that the suppressed progression of chronic EAMG by anti-CD40L treatment does not induce a switch from Th1 to Th2/Th3 regulation of the AChR-specific immune response and does not induce generation of regulatory cells. The ability of anti-CD40L treatment to suppress ongoing chronic EAMG suggests that blockade of CD40L may serve as a potential approach for the immunotherapy of MG and other Ab-mediated autoimmune diseases.

Curcumin attenuates the scurfy-induced immune disorder, a model of IPEX syndrome, with inhibiting Th1/Th2/Th17 responses in mice.

PubMed

Lee, Gihyun; Chung, Hwan-Suck; Lee, Kyeseok; Lee, Hyeonhoon; Kim, Minhwan; Bae, Hyunsu

2017-09-15

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects. The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period. C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro. Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4 + T cells. Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases. Copyright © 2017 Elsevier GmbH. All rights reserved.

Theory-Driven Models for Correcting Fight or Flight Imbalance in Gulf War Illness

DTIC Science & Technology

2013-09-01

models require the inclusion of positive receptor feedback dynamics 483 to produce mutlistability, these effects become inherent in more coarse, but...separately. In this modified immune module innate immune cells (ICells) produce cytokines that regulate the innate immune response (IIR) including...Th1 type adaptive immune response (T1Cell), producing Th1 pro-inflammatory cytokines (T1Cyt) including IL-2, interferon-gamma (IFN-γ), and tumor

TET1 and TET3 are essential in induction of Th2-type immunity partly through regulation of IL-4/13A expression in zebrafish model.

PubMed

Yang, Chao; Li, Zhuo; Kang, Wei; Tian, Yu; Yan, Yuzhu; Chen, Wei

2016-10-10

It has been considered that epigenetic modulation can affect a diverse array of cellular activities, in which ten eleven translocation (TET) methylcytosine dioxygenase family members refer to a group of fundamental components involved in catalyzation of 5-hydroxymethylcytosine and modification of gene expression. Even though the function of TET proteins has been gradually revealed, their roles in immune regulation are still largely unknown. Recent studies provided clues that TET2 could regulate several innate immune-related inflammatory mediators in mammals. This study sought to explore the function of TET family members in potential T-helper (Th) cell differentiation involved in adaptive immunity by utilizing a zebrafish model. As shown by results, soluble antigens could induce expression of zebrafish IL-4/13A (i.e. a pivotal Th2-type cytokine essential in Th2 cell differentiation and functions), and further trigger the expression of Th1- and Th2-related genes. It is noteworthy that this response was accompanied by the up-regulation of two TET family members (TET1 and TET3) both in immune organs (spleen and kidney) and cells (peripheral lymphocytes). Knocking-down of TET1 and TET3 will give rise to the decreased responses of IL-4/13A induction against exogenous soluble antigen stimulation, and further restrain the expression of Th2-related genes, which indicates a restrained Th2 cell differentiation. Nonetheless, TET2 did not exhibit effect on the modification of Th1/Th2 related gene expression. Hence, these data showed that TET1 and TET3 might be two significant epigenetic regulators involved in Th2 differentiation through regulation of IL-4/13A expression. This is the first report to show that TET family members play indispensable roles in Th2-type immunity, indicating an epigenetic modulation manner involved in adaptive immune regulations and responses. Copyright © 2016 Elsevier B.V. All rights reserved.

Galectin-7 promotes proliferation and Th1/2 cells polarization toward Th1 in activated CD4+ T cells by inhibiting The TGFβ/Smad3 pathway.

PubMed

Luo, Zhenlong; Ji, Yudong; Tian, Dean; Zhang, Yong; Chang, Sheng; Yang, Chao; Zhou, Hongmin; Chen, Zhonghua Klaus

2018-06-08

Galectin-7 (Gal-7) has been associated with cell proliferation and apoptosis. It is known that Gal-7 antagonises TGFβ-mediated effects in hepatocytes by interacting with Smad3. Previously, we have demonstrated that Gal-7 is related to CD4+ T cells responses; nevertheless, its effect and functional mechanism on CD4+ T cells responses remain unclear. The murine CD4+ T cells were respectively cultured with Gal-7, anti-CD3/CD28 mAbs, or with anti-CD3/CD28 mAbs & Gal-7. The effects of Gal-7 on proliferation and the phenotypic changes in CD4+ T cells were assessed by flow cytometry. The cytokines from CD4+ T cells were analysed by quantitative real-time PCR. Subcellular localisation and expression of Smad3 were determined by immunofluorescence staining and Western blot, respectively. Gal-7 enhanced the proliferation of activated CD4+ T cells in a dose- and β-galactoside-dependent manner. Additionally, Gal-7 treatment did not change the ratio of Th2 cells in activated CD4+ T cells, while it increased the ratio of Th1 cells. Gal-7 also induced activated CD4+ T cells to produce a higher level of IFN-γ and TNF-α and a lower level of IL-10. Moreover, Gal-7 treatment significantly accelerated nuclear export of Smad3 in activated CD4+ T cells. These results revealed a novel role of Gal-7 in promoting proliferation and Th1/2 cells polarization toward Th1 in activated CD4+ T cells by inhibiting the TGFβ/Smad3 pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

DNA β-Amyloid1–42 Trimer Immunization for Alzheimer Disease in a Wild-Type Mouse Model

PubMed Central

Lambracht-Washington, Doris; Qu, Bao-Xi; Fu, Min; Eagar, Todd N.; Stüve, Olaf; Rosenberg, Roger N.

2010-01-01

Context DNA β-amyloid1–42 (Aβ42) trimer immunization was developed to produce specific T helper 2 cell (TH2)–type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Aβ42 peptide that occur in the brain of patients with AD. Objective To compare the immune response in wild-type mice after immunization with DNA Aβ42 trimer and Aβ42 peptide. Design and Intervention Wild-type mice received either 4 µg of DNA Aβ42 trimer immunization administered with gene gun (n=8) or intraperitoneal injection of 100 µg of human Aβ42 peptide with the adjuvant Quil A (n=8). Titers, epitope mapping, and isotypes of the Aβ42-specific antibodies were analyzed. Main Outcome Measures Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Aβ42-specific antibodies, and T-cell activation. Results DNA Aβ42 trimer immunization resulted in antibody titers with a mean of 15 µg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a TH2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed TH1/TH2 immune response (IgG1/IgG2a ratio of 1) (P<.001). No increased T-cell proliferation was observed in the DNA-immunized mice (P=.03). Conclusion In this preliminary study in a wild-type mouse model, DNA Aβ42 trimer immunization protocol produced a TH2 immune response and appeared to have low potential to cause an inflammatory T-cell response. PMID:19861672

DNA beta-amyloid(1-42) trimer immunization for Alzheimer disease in a wild-type mouse model.

PubMed

Lambracht-Washington, Doris; Qu, Bao-Xi; Fu, Min; Eagar, Todd N; Stüve, Olaf; Rosenberg, Roger N

2009-10-28

DNA beta-amyloid(1-42) (Abeta42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Abeta42 peptide that occur in the brain of patients with AD. To compare the immune response in wild-type mice after immunization with DNA Abeta42 trimer and Abeta42 peptide. Wild-type mice received either 4 microg of DNA Abeta42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 microg of human Abeta42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Abeta42-specific antibodies were analyzed. Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Abeta42-specific antibodies, and T-cell activation. DNA Abeta42 trimer immunization resulted in antibody titers with a mean of 15 microg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03). In this preliminary study in a wild-type mouse model, DNA Abeta42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response.

Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy.

PubMed

Nguyen-Pham, Thanh-Nhan; Yang, Deok-Hwan; Nguyen, Truc-Anh Thi; Lim, Mi-Seon; Hong, Cheol Yi; Kim, Mi-Hyun; Lee, Hyun Ju; Lee, Youn-Kyung; Cho, Duck; Bae, Soo-Young; Ahn, Jae-Sook; Kim, Yeo-Kyeoung; Chung, Ik-Joo; Kim, Hyeoung-Joon; Lee, Je-Jung

2012-01-01

Dendritic cell (DC)-based vaccines continue to be considered an attractive tool for cancer immunotherapy. DCs require an additional signal from the environment or other immune cells to polarize the development of immune responses toward T helper 1 (Th1) or Th2 responses. DCs play a role in natural killer (NK) cell activation, and NK cells are also able to activate and induce the maturation of DCs. We investigated the types of NK cells that can induce the maturation and enhanced function of DCs and the conditions under which these interactions occur. DCs that were activated by resting NK cells in the presence of inflammatory cytokines exhibited increased expression of several costimulatory molecules and an enhanced ability to produce IL-12p70. NK cell-stimulated DCs potently induced Th1 polarization and exhibited the ability to generate tumor antigen-specific cytotoxic T lymphocyte responses. Our data demonstrate that functional DCs can be generated by coculturing immature DCs with freshly isolated resting NK cells in the presence of Toll-like receptor agonists and proinflammatory cytokines and that the resulting DCs effectively present antigens to induce tumor-specific T-cell responses, which suggests that these cells may be useful for cancer immunotherapy.

Dendritic cell MST1 inhibits Th17 differentiation

PubMed Central

Li, Chunxiao; Bi, Yujing; Li, Yan; Yang, Hui; Yu, Qing; Wang, Jian; Wang, Yu; Su, Huilin; Jia, Anna; Hu, Ying; Han, Linian; Zhang, Jiangyuan; Li, Simin; Tao, Wufan; Liu, Guangwei

2017-01-01

Although the differentiation of CD4+T cells is widely studied, the mechanisms of antigen-presenting cell-dependent T-cell modulation are unclear. Here, we investigate the role of dendritic cell (DC)-dependent T-cell differentiation in autoimmune and antifungal inflammation and find that mammalian sterile 20-like kinase 1 (MST1) signalling from DCs negatively regulates IL-17 producing-CD4+T helper cell (Th17) differentiation. MST1 deficiency in DCs increases IL-17 production by CD4+T cells, whereas ectopic MST1 expression in DCs inhibits it. Notably, MST1-mediated DC-dependent Th17 differentiation regulates experimental autoimmune encephalomyelitis and antifungal immunity. Mechanistically, MST1-deficient DCs promote IL-6 secretion and regulate the activation of IL-6 receptor α/β and STAT3 in CD4+T cells in the course of inducing Th17 differentiation. Activation of the p38 MAPK signal is responsible for IL-6 production in MST1-deficient DCs. Thus, our results define the DC MST1–p38MAPK signalling pathway in directing Th17 differentiation. PMID:28145433

In vivo characterization of fusion protein comprising of A1 subunit of Shiga toxin and human GM-CSF: Assessment of its immunogenicity and toxicity.

PubMed

Oloomi, Mana; Bouzari, Saeid; Shariati, Elaheh

2010-10-01

Most cancer cells become resistant to anti-cancer agents. In the last few years, a new approach for targeted therapy of human cancer has been developed using immunotoxins which comprise both the cell targeting and the cell killing moieties. In the present study, the recombinant Shiga toxin A1 subunit fused to human granulocyte-macrophage colony stimulating factor (A1-GM-CSF), previously produced in E. coli, was further characterized. The recombinant protein could cause 50% cytotoxicity and induced apoptosis in cells bearing GM-CSF receptors. The non-specific toxicity of the fusion protein was assessed in C57BL/6 and BALB/c mice. No mortality was observed in either group of mice, with different concentration of fusion protein. The lymphocyte proliferation assay, induction of specific IgG response and a mixed (Th1/Th2) response were observed only in BALB/c mice. The mixed response in BALB/c mice (Th1/Th2) could be explained on the basis of the two components of the fusion protein i.e. A1 and GM-CSF.

The Aryl Hydrocarbon Receptor: Differential Contribution to T Helper 17 and T Cytotoxic 17 Cell Development

PubMed Central

Hayes, Mark D.; Ovcinnikovs, Vitalijs; Smith, Andrew G.; Kimber, Ian; Dearman, Rebecca J.

2014-01-01

The aryl hydrocarbon receptor (AhR) has been shown to be required for optimal Thelper (Th) 17 cell activation. Th17 cells provide immunity against extracellular pathogens and are implicated in autoimmune diseases. Herein, the role of the AhR in cytokine production by Th17, and by the analogous population of T cytotoxic (Tc)17 cells, has been examined. Lymph node Tc (CD8+) and Th (CD4+) cells were isolated by negative selection from naive AhR+/− and AhR−/− mice and polarised to Tc1/Th1 or Tc17/Th17 phenotypes with appropriate cytokines. Cell differentiation was assessed as a function of mRNA and protein (ELISA and flow cytometry) expression for interferon (IFN)-γ and for key Th17 cytokines. In AhR+/− mice, Th17 cells displayed an exclusive IL-17 profile, which was markedly inhibited by a selective AhR antagonist to levels observed in AhR knockout mice. Addition of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) markedly enhanced Th17 cell activity in the heterozygotes. In contrast, Tc17 cells polarised into 3 distinct subsets: producing either IL-17 or IFN-γ alone, or both cytokines. Blocking AhR was also detrimental to Tc17 development, with reduced responses recorded in AhR−/− mice and antagonist-mediated reduction of IL-17 expression in the heterozygotes. However, Tc17 cells were largely refractory to exogenous FICZ, presumably because Tc17 cells express baseline AhR mRNA, but unlike Th17 cells, there is no marked up-regulation during polarisation. Thus, Th17 cell development is more dependent upon AhR activation than is Tc17 cell development, suggesting that endogenous AhR ligands play a much greater role in driving Th17 cell responses. PMID:25203682

Influence of a cocoa-enriched diet on specific immune response in ovalbumin-sensitized rats.

PubMed

Pérez-Berezo, Teresa; Ramiro-Puig, Emma; Pérez-Cano, Francisco J; Castellote, Cristina; Permanyer, Joan; Franch, Angels; Castell, Margarida

2009-03-01

Previous studies in young rats have reported the impact of 3 weeks of high cocoa intake on healthy immune status. The present article describes the effects of a longer-term cocoa-enriched diet (9 weeks) on the specific immune response to ovalbumin (OVA) in adult Wistar rats. At 4 weeks after immunization, control rats produced anti-OVA antibodies, which, according their amount and isotype, were arranged as follows: IgG1 > IgG2a > IgM > IgG2b > IgG2c. Both cocoa diets studied (4% and 10%) down-modulated OVA-specific antibody levels of IgG1 (main subclass associated with the Th2 immune response in rats), IgG2a, IgG2c and IgM isotypes. Conversely, cocoa-fed rats presented equal or higher levels of anti-OVA IgG2b antibodies (subclass linked to the Th1 response). Spleen and lymph node cells from OVA-immunized control and cocoa-fed animals proliferated similarly under OVA stimulation. However, spleen cells from cocoa-fed animals showed decreased interleukin-4 secretion (main Th2 cytokine), and lymph node cells from the same rats displayed higher interferon-gamma secretion (main Th1 cytokine). These changes were accompanied by a reduction in the number of anti-OVA IgG-secreting cells in spleen. In conclusion, cocoa diets induced attenuation of antibody synthesis that may be attributable to specific down-regulation of the Th2 immune response.

IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age.

PubMed

Tsukamoto, Hirotake; Senju, Satoru; Matsumura, Keiko; Swain, Susan L; Nishimura, Yasuharu

2015-04-07

Decline in immune function and inflammation concomitantly develop with ageing. Here we focus on the impact of this inflammatory environment on T cells, and demonstrate that in contrast to successful tumour elimination in young mice, replenishment of tumour-specific CD4(+) T cells fails to induce tumour regression in aged hosts. The impaired antitumour effect of CD4(+) T cells with their defective Th1 differentiation in an aged environment is restored by interleukin (IL)-6 blockade or IL-6 deficiency. IL-6 blockade also restores the impaired ability of CD4(+) T cells to promote CD8(+) T-cell-dependent tumour elimination in aged mice, which requires IFN-γ. Furthermore, IL-6-stimulated production of IL-4/IL-21 through c-Maf induction is responsible for impaired Th1 differentiation. IL-6 also contributes to IL-10 production from CD4(+) T cells in aged mice, causing attenuated responses of CD8(+) T cells. These findings suggest that IL-6 serves as an extrinsic factor counteracting CD4(+) T-cell-mediated immunity against tumour in old age.

Blockade of PD-1 Signaling Enhances Th2 Cell Responses and Aggravates Liver Immunopathology in Mice with Schistosomiasis japonica

PubMed Central

Zhou, Sha; Jin, Xin; Li, Yalin; Li, Wei; Chen, Xiaojun; Xu, Lei; Zhu, Jifeng; Xu, Zhipeng; Zhang, Yang; Liu, Feng; Su, Chuan

2016-01-01

Background More than 220 million people worldwide are chronically infected with schistosomes, causing severe disease or even death. The major pathological damage occurring in schistosomiasis is attributable to the granulomatous inflammatory response and liver fibrosis induced by schistosome eggs. The inflammatory response is tightly controlled and parallels immunosuppressive regulation, constantly maintaining immune homeostasis and limiting excessive immunopathologic damage in important host organs. It is well known that the activation of programmed death 1 (PD-1) signaling causes a significant suppression of T cell function. However, the roles of PD-1 signaling in modulating CD4+ T cell responses and immunopathology during schistosome infection, have yet to be defined. Methodology/Principal Findings Here, we show that PD-1 is upregulated in CD4+ T cells in Schistosoma japonicum (S. japonicum)-infected patients. We also show the upregulation of PD-1 expression in CD4+ T cells in the spleens, mesenteric lymph nodes, and livers of mice with S. japonicum infection. Finally, we found that the blockade of PD-1 signaling enhanced CD4+ T helper 2 (Th2) cell responses and led to more severe liver immunopathology in mice with S. japonicum infection, without a reduction of egg production or deposition in the host liver. Conclusions/Significance Overall, our study suggests that PD-1 signaling is specifically induced to control Th2-associated inflammatory responses during schistosome infection and is beneficial to the development of PD-1-based control of liver immunopathology. PMID:27792733

Major role for CD8 T cells in the protection against Toxoplasma gondii following dendritic cell vaccination.

PubMed

Guiton, R; Zagani, R; Dimier-Poisson, I

2009-10-01

Toxoplasma gondii is the causative agent of toxoplasmosis, a worldwide zoonosis for which an effective vaccine is needed. Vaccination with pulsed dendritic cells is very efficient but their use in a vaccination protocol is unconceivable. Nevertheless, unravelling the induced effector mechanisms is crucial to design new vaccine strategies. We vaccinated CBA/J mice with parasite extract-pulsed dendritic cells, challenged them with T. gondii cysts and carried out in vivo depletion of CD4(+) or CD8(+) T lymphocytes to study the subsequent cellular immune response and protective mechanisms. CD4(+) lymphocytes were poorly implicated either in spleen and mesenteric lymph node (MLN) cytokine secretion or in mice protection. By contrast, the increasing number of intracerebral cysts and depletion of CD8(+) cells were strongly correlated, revealing a prominent role for CD8(+) lymphocytes in the protection of mice. Splenic CD8(+) lymphocytes induce a strong Th1 response controlled by a Th2 response whereas CD8(+) cells from MLNs inhibit both Th1 and Th2 responses. CD8(+) cells are the main effectors following dendritic cell vaccination and Toxoplasma infection while CD4(+) T cells only play a minor role. This contrasts with T. gondii infection which elicits the generation of CD4(+) and CD8(+) T cells that provide protective immunity.

Th1 and Th17 Immunocompetence in Humanized NOD/SCID/γC-KO mice

PubMed Central

Rajesh, Deepika; Zhou, Ying; Jankowska-Gan, Ewa; Ronneburg, Drew Allan; Dart, Melanie M; Torrealba, Jose; Burlingham, William J

2010-01-01

We evaluated the immunocompetence of human T cells in humanized NOD-scid IL2r-γ-null (Hu—NSG) mice bearing a human thymic organoid, after multilinegage reconstitution with isogeneic human leukocytes. Delayed type hypersensitivity (DTH) response was assessed by a direct footpad challenge of the immunized hu-NSG host, or by transfer of splenocytes from immunized hu-NSG, along with antigen, into footpads of CB17 SCID mice [trans-vivo (tv) DTH]. Both methods revealed cellular immunity to tetanus toxoid (TT) or collagen type V (ColV). Immunohistochemical analysis of the swollen footpads revealed infiltration of human CD45+ cells, including CD3+ T cells, CD68+ macrophages and murine Ly6G+ neutrophils. We observed a significant correlation between % circulating human CD4+ cells and the direct DTH swelling response to TT. The tvDTH response to TT was inhibited by anti-IFNγ, while the tvDTH response to collagen V was inhibited by anti IL-17 antibody, mimicking the cytokine bias of adult human T cells to these antigens. Hu-NSG mice were also capable of mounting a B cell response (primarily IgM) to TT antigen. The activation of either Th1- or Th17 - dependent cellular immune response supports the utility of Hu-NSG mice as a surrogate model of allograft rejection and autoimmunity. PMID:20298731

OGR1/GPR68 Modulates the Severity of Experimental Autoimmune Encephalomyelitis and Regulates Nitric Oxide Production by Macrophages

PubMed Central

D’Souza, Cheryl A.; Zhao, Fei Linda; Li, Xujian; Xu, Yan; Dunn, Shannon E.; Zhang, Li

2016-01-01

Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect decreases in extracellular pH that occur during inflammation. Although OGR1 has been shown to have pro-inflammatory functions in various diseases, its role in autoimmunity has not been examined. We therefore sought to determine whether OGR1 has a role in the development of T cell autoimmunity by contrasting the development of experimental autoimmune encephalomyelitis between wild type and OGR1-knockout mice. OGR1-knockout mice showed a drastically attenuated clinical course of disease that was associated with a profound reduction in the expansion of myelin oligodendrocyte glycoprotein 35-55-reactive T helper 1 (Th1) and Th17 cells in the periphery and a reduced accumulation of Th1 and Th17 effectors in the central nervous system. We determined that these impaired T cell responses in OGR1-knockout mice associated with a reduced frequency and number of dendritic cells in draining lymph nodes during EAE and a higher production of nitric oxide by macrophages. Our studies suggest that OGR1 plays a key role in regulating T cell responses during autoimmunity. PMID:26828924

Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17 differentiation.

PubMed

Wu, Xin; Tong, Bei; Yang, Yan; Luo, Jinque; Yuan, Xusheng; Wei, Zhifeng; Yue, Mengfan; Xia, Yufeng; Dai, Yue

2016-12-20

Arctigenin was previously proven to inhibit Th17 cell differentiation and thereby attenuate colitis in mice by down-regulating the activation of mechanistic target of rapamycin complex 1 (mTORC1). The present study was performed to address its underlying mechanism in view of estrogen receptor (ER). The specific antagonist PHTPP or siRNA of ERβ largely diminished the inhibitory effect of arctigenin on the mTORC1 activation in T cell lines and primary CD4+ T cells under Th17-polarization condition, suggesting that arctigenin functioned in an ERβ-dependent manner. Moreover, arctigenin was recognized to be an agonist of ERβ, which could bind to ERβ with a moderate affinity, promote dissociation of ERβ/HSP90 complex and nuclear translocation and phosphorylation of ERβ, and increase the transcription activity. Following activation of ERβ, arctigenin inhibited the activity of mTORC1 by disruption of ERβ-raptor-mTOR complex assembly. Deficiency of ERβ markedly abolished arctigenin-mediated inhibition of Th17 cell differentiation. In colitis mice, the activation of ERβ, inhibition of mTORC1 activation and Th17 response by arctigenin were abolished by PHTPP treatment. In conclusion, ERβ might be the target protein of arctigenin responsible for inhibition of mTORC1 activation and resultant prevention of Th17 cell differentiation and colitis development.

Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17 differentiation

PubMed Central

Wu, Xin; Tong, Bei; Yang, Yan; Luo, Jinque; Yuan, Xusheng; Wei, Zhifeng; Yue, Mengfan; Xia, Yufeng; Dai, Yue

2016-01-01

Arctigenin was previously proven to inhibit Th17 cell differentiation and thereby attenuate colitis in mice by down-regulating the activation of mechanistic target of rapamycin complex 1 (mTORC1). The present study was performed to address its underlying mechanism in view of estrogen receptor (ER). The specific antagonist PHTPP or siRNA of ERβ largely diminished the inhibitory effect of arctigenin on the mTORC1 activation in T cell lines and primary CD4+ T cells under Th17-polarization condition, suggesting that arctigenin functioned in an ERβ-dependent manner. Moreover, arctigenin was recognized to be an agonist of ERβ, which could bind to ERβ with a moderate affinity, promote dissociation of ERβ/HSP90 complex and nuclear translocation and phosphorylation of ERβ, and increase the transcription activity. Following activation of ERβ, arctigenin inhibited the activity of mTORC1 by disruption of ERβ-raptor-mTOR complex assembly. Deficiency of ERβ markedly abolished arctigenin-mediated inhibition of Th17 cell differentiation. In colitis mice, the activation of ERβ, inhibition of mTORC1 activation and Th17 response by arctigenin were abolished by PHTPP treatment. In conclusion, ERβ might be the target protein of arctigenin responsible for inhibition of mTORC1 activation and resultant prevention of Th17 cell differentiation and colitis development. PMID:27863380

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis.

PubMed

Silvestre, Marilene Chaves; Sato, Maria Notomi; Reis, Vitor Manoel Silva Dos

2018-03-01

Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis.

PubMed

Millet, Arnaud; Martin, Katherine R; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

2015-11-02

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology.

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis

PubMed Central

Millet, Arnaud; Martin, Katherine R.; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A.; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

2015-01-01

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology. PMID:26436651

Toxoplasma gondii infection inhibits Th17-mediated spontaneous development of arthritis in interleukin-1 receptor antagonist-deficient mice.

PubMed

Washino, Takuya; Moroda, Masataka; Iwakura, Yoichiro; Aosai, Fumie

2012-04-01

Interleukin 1 receptor antagonist (IL-1Ra)-deficient BALB/c mice develop spontaneous arthritis resembling human rheumatoid arthritis. We herein report that infection with Toxoplasma gondii, an intracellular protozoan, is capable of ameliorating the spontaneous development of arthritis in IL-1Ra-deficient mice. The onset of arthritis development was delayed and the severity score of arthritis was significantly suppressed in T. gondii-infected mice. Expression of IL-12p40 mRNA from CD11c(+) cells of mesenteric lymph nodes (mLN) and spleen markedly increased at 1 week after peroral infection. While CD11c(+) cells also produced IL-10, IL-1β, and IL-6, CD4(+) T cells from T. gondii-infected mice expressed significantly high levels of T-bet and gamma interferon (IFN-γ) mRNA in both mLN and spleen. Levels of GATA-3/IL-4 mRNA or RORγt/IL-17 mRNA decreased in the infected mice, indicating Th1 cell polarization and the reduction of Th2 and Th17 cell polarization. The severity of arthritis was related to Th1 cell polarization accompanied by Th17 cell reduction, demonstrating the protective role of the T. gondii-derived Th1 response against Th17 cell-mediated arthritis in IL-1Ra-deficient mice.

Cytokines and the regulation of fungus-specific CD4 T cell differentiation

PubMed Central

Espinosa, Vanessa; Rivera, Amariliz

2011-01-01

CD4 T cells play important and non-redundant roles in protection against infection with diverse fungi. Distinct CD4 T cell subsets can mediate protection against fungal disease where Th1 and Th17 CD4 T cell subsets have been found to promote fungal clearance and protective immunity against diverse fungal pathogens. The differentiation of naïve CD4 T cells into Th1 or Th17 cells is crucially controlled by their interaction with dendritic cells and instructed by cytokines. IL-12 and IFN-γ promote Th1 differentiation while TGF-β, IL-6, IL-1, IL-21 and IL-23 promote Th17 differentiation and maintenance. The production of these cytokines by DCs is in turn regulated by innate receptors triggered in response to fungal infection. In this review we will discuss the contributions of cytokines found to influence fungus-specific CD4 T cell differentiation and their role in defense against fungal disease. We will also highlight the contributions of innate receptors involved in recognition of fungi and how they shape cytokine secretion and CD4 T cell differentiation. PMID:22133343

MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

PubMed Central

Delano, Matthew J.; Scumpia, Philip O.; Weinstein, Jason S.; Coco, Dominique; Nagaraj, Srinivas; Kelly-Scumpia, Kindra M.; O'Malley, Kerri A.; Wynn, James L.; Antonenko, Svetlana; Al-Quran, Samer Z.; Swan, Ryan; Chung, Chun-Shiang; Atkinson, Mark A.; Ramphal, Reuben; Gabrilovich, Dmitry I.; Reeves, Wesley H.; Ayala, Alfred; Phillips, Joseph; LaFace, Drake; Heyworth, Paul G.; Clare-Salzler, Michael; Moldawer, Lyle L.

2007-01-01

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization. PMID:17548519

Role of T Cell TGF-β Signaling in Intestinal Cytokine Responses and Helminthic Immune Modulation

PubMed Central

Ince, M. Nedim; Elliott, David E.; Setiawan, Tommy; Metwali, Ahmed; Blum, Arthur; Chen, Hung-lin; Urban, Joseph F.; Flavell, Richard A.; Weinstock, Joel V.

2010-01-01

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-β that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell Th1 cytokine generation in an IL-10 dependent manner in wild-type mice. Helminths also stimulate mucosal TGF-β release. As TGF-β exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-β signaling in helminthic modulation of intestinal immunity. T cell TGF-β signaling is interrupted in TGF-βRII DN mice by T cell-specific over-expression of a dominant negative TGF-β receptor II. We studied lamina propria mononuclear cell responses in wild-type and TGF-βRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-β signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-β signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-βRII DN mice. Thus, T cell TGF-β signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal interferon-γ generation and H. polygyrus-mediated suppression of chronic colitis. PMID:19544487

TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity

PubMed Central

Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara; Dusi, Silvia; Pietronigro, Enrica; Zenaro, Elena; Della Bianca, Vittorina; Toffali, Lara; Piacentino, Gennj; Budui, Simona; Rennert, Paul; Xiao, Sheng; Laudanna, Carlo; Casasnovas, Jose M.; Kuchroo, Vijay K.; Constantin, Gabriela

2014-01-01

SUMMARY Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper-1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 IgV domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease. PMID:24703780

Iron oxide nanoparticles attenuate T helper 17 cell responses in vitro and in vivo.

PubMed

Hsiao, Yai-Ping; Shen, Chien-Chang; Huang, Chung-Hsiung; Lin, Yu-Chin; Jan, Tong-Rong

2018-05-01

Iron oxide nanoparticles (IONPs) have been shown to attenuate T helper (Th)1 and Th2 cell-mediated immunity in ovalbumin (OVA)-sensitized mice. The objective of this study is to investigate the effects of IONPs on the immune responses of Th17 cells, a subset of T cells involved in various inflammatory pathologies. For in vivo study, a murine model of delayed-type hypersensitivity (DTH) was employed. BALB/c mice received a single dose of IONPs (0.2-10 mg iron/kg) via the tail vein 1 h prior to ovalbumin (OVA) sensitization. Their footpads were subcutaneously challenged with OVA to induce DTH reactions. The expression of Th17 cell-related molecules in inflamed footpads were examined by immunohistochemistry. For in vitro study, OVA-primed splenocytes were directly exposed to IONPs (1-100 μg iron/mL), and then re-stimulated with OVA in culture. The expression of Th17 cell-related molecules were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. IONP administration attenuated the number of interleukin (IL)-6, IL-17, the transcription factor ROR-γ, and chemokine receptor 6 positive cells in OVA-challenged footpads, whereas the number of transforming growth factor-β, IL-23 and chemokine (C-C motif) ligand 20 positive cells was not altered. Direct exposure of OVA-primed splenocytes to IONPs suppressed the production of IL-6 and IL-17, and the mRNA expression of IL-17 and ROR-γt. These data indicate that exposure to IONPs attenuates Th17 cell responses in vivo and in vitro. Copyright © 2018. Published by Elsevier B.V.

Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

PubMed

Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

2015-08-15

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2.

PubMed

Koth, Laura L; Rodriguez, Madeleine W; Bernstein, Xin Liu; Chan, Salina; Huang, Xiaozhu; Charo, Israel F; Rollins, Barrett J; Erle, David J

2004-09-15

Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2

PubMed Central

Koth, Laura L; Rodriguez, Madeleine W; Bernstein, Xin Liu; Chan, Salina; Huang, Xiaozhu; Charo, Israel F; Rollins, Barrett J; Erle, David J

2004-01-01

Background Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. Methods To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. Results We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. Conclusion We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2. PMID:15377395

Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants.

PubMed

Garcia-Knight, Miguel A; Nduati, Eunice; Hassan, Amin S; Gambo, Faith; Odera, Dennis; Etyang, Timothy J; Hajj, Nassim J; Berkley, James Alexander; Urban, Britta C; Rowland-Jones, Sarah L

2015-01-01

Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.

A malaria protein factor induces IL-4 production by dendritic cells via PI3K-Akt-NF-κB signaling independent of MyD88/TRIF and promotes Th2 response.

PubMed

Wu, Xianzhu; Gowda, Nagaraj M; Kawasawa, Yuka I; Gowda, D Channe

2018-04-17

Dendritic cells (DC) and cytokines produced by DC play crucial roles in inducing and regulating pro-/anti-inflammatory and Th1/Th2 responses. DC are known to produce Th1-promoting cytokine, IL-12, in response to malaria and other pathogenic infections, but it is thought that DC do not produce Th2-promoting cytokine, IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11c hi MHCII hi CD3ε - CD49b - CD19 - FcεRI - DC via PI3K-Akt-NF-κB signaling independent of TLR-MyD88/TRIF. Malaria parasite-activated DC induced IL-4 responses by T cells both in vitro and in vivo , favoring Th2, and il-4 deficient DC were unable to induce IL-4 expression by T cell.  Interestingly, lethal parasites, Plasmodium falciparum and P. berghei ANKA, induced IL-4 response primarily by CD8a - DC, whereas nonlethal P. yoelii induced IL-4 by both CD8α + and CD8α - DC. In both P. berghei ANKA- and P. yoelii -infected mice, IL-4-expressing CD8α - DC did not express IL-12, but a distinct CD8α - DC subset expressed IL-12. In P. berghei ANKA infection, CD8α + DC expressed IL-12 but not IL-4, whereas in P. yoelii infection CD8α + DC expressed IL-4 but not IL-12. This differential IL-4 and IL-12 responses by DC subsets may contribute to different Th1/Th2 development and clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrate that a malaria protein factor induces IL-4 production by DC via PI3K-Akt-NF-κB signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4+ T-cell epitopes with other tree nuts

PubMed Central

Archila, Luis Diego; Chow, I-Ting; McGinty, John W.; Renand, Amedee; Jeong, David; Robinson, David; Farrington, Mary L.; Kwok, William.W.

2017-01-01

Background Allergies to cashew are increasing in prevalence, with clinical symptoms ranging from oral pruritus to fatal anaphylactic reaction. Yet, cashew-specific T-cell epitopes and T-cell cross-reactivity amongst cashew and other tree nut allergens in humans remain uncharacterized. Objectives In this study, we characterized cashew specific T-cell responses in cashew allergic subjects and examined cross-reactivity of these cashew specific cells toward other tree nut allergens. Methods CD154 up-regulation assay was used to determine immunodominance hierarchy among cashew major allergens at the T cell level. The phenotype, magnitude and functionality of cashew-specific T-cells was determined by utilizing ex vivo staining with MHC class II tetramers. Dual tetramer staining and proliferation experiments were used to determine cross-reactivity to other tree nuts. Results CD4+ T-cell responses were directed towards cashew allergens Ana o 1 and Ana o 2. Multiple Ana o 1 and Ana o 2 T-cell epitopes were then identified. These epitopes elicited either TH2 or TH2/TH17 responses in allergic subjects, which were either cashew unique epitope or cross-reactive epitopes. For clones that recognized the cross-reactive epitope, T-cell clones responded robustly to cashew, hazelnut and/or pistachio but not to walnut. Conclusions Phylogenetically diverse tree nut allergens can activate cashew reactive T-cells and elicit a TH2 type response at an epitope specific level. Clinical relevance Lack of cross-reactivity between walnut and cashew suggest that cashew peptide immunotherapy approach may not be most effective for walnut. PMID:27129138

Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4(+) T cell epitopes with other tree nuts.

PubMed

Archila, L D; Chow, I-T; McGinty, J W; Renand, A; Jeong, D; Robinson, D; Farrington, M L; Kwok, W W

2016-06-01

Allergies to cashew are increasing in prevalence, with clinical symptoms ranging from oral pruritus to fatal anaphylactic reaction. Yet, cashew-specific T cell epitopes and T cell cross-reactivity amongst cashew and other tree nut allergens in humans remain uncharacterized. In this study, we characterized cashew-specific T cell responses in cashew-allergic subjects and examined cross-reactivity of these cashew-specific cells towards other tree nut allergens. CD154 up-regulation assay was used to determine immunodominance hierarchy among cashew major allergens at the T cell level. The phenotype, magnitude and functionality of cashew-specific T cells were determined by utilizing ex vivo staining with MHC class II tetramers. Dual tetramer staining and proliferation experiments were used to determine cross-reactivity to other tree nuts. CD4(+) T cell responses were directed towards cashew allergens Ana o 1 and Ana o 2. Multiple Ana o 1 and Ana o 2 T cell epitopes were then identified. These epitopes elicited either TH 2 or TH 2/TH 17 responses in allergic subjects, which were either cashew unique epitope or cross-reactive epitopes. For clones that recognized the cross-reactive epitope, T cell clones responded robustly to cashew, hazelnut and/or pistachio but not to walnut. Phylogenetically diverse tree nut allergens can activate cashew-reactive T cells and elicit a TH 2-type response at an epitope-specific level. Lack of cross-reactivity between walnut and cashew suggests that cashew peptide immunotherapy approach may not be most effective for walnut. © 2016 John Wiley & Sons Ltd.

Tetanus Toxoid carrier protein induced T-helper cell responses upon vaccination of middle-aged adults.

PubMed

van der Heiden, Marieke; Duizendstra, Aafke; Berbers, Guy A M; Boots, Annemieke M H; Buisman, Anne-Marie

2017-10-09

Vaccines frequently induce suboptimal immune responses in the elderly, due to immunological ageing. Timely vaccination may be a strategy to overcome this problem, which classifies middle-aged adults asan interesting target group for future vaccine interventions. However, the immunological fitness of the middle-aged population is ill-defined. It is currently unknown whether effective T-cell help towards B-cells is initiated by conjugate-carrier vaccines at middle-age. We characterized systemic Tetanus Toxoid (TT) specific T-helper cell responses in the circulation of middle-aged adults (50-65years of age, n=31) having received the MenACWY-TT vaccination. Blood samples were taken pre- as well as 7days, 28days, and 1year post-vaccination. TT-specific T-cell responses were determined by IFNγ Elispot and by the secretion of IFNγ, IL13, IL10, IL17, and IL21 in cell culture supernatants. Circulating CD4+CXCR5+ICOS+IL21+ cells were analyzed by flow cytometry, and meningococcal and TT-specific IgG responses by bead-based immunoassays. The correlation between the T-cell help and humoral responses was evaluated. Vaccination with a TT-carrier protein induced a mixed TT-specific Th1 (IFNγ), Th2 (IL13, IL10), and Th17 (IL17) response in most participants. Additionally, circulating CD4+CXCR5+ICOS+IL21+ cells were significantly increased 7days post-vaccination. Pre-vaccination TT-specific cytokine production and post-vaccination Th2 responses correlated positively with the increase of CD4+CXCR5+ICOS+IL21+ cells. No correlation between T-cell help and antibody responses was found. The characteristics of the T-cell response upon a TT-carrier vaccination suggests effective T-cell help towards B-cells in response to meningococcal polysaccharides, although the absence of a correlation with the antibody responses warrants further clarification. However, the robust T-helper cell response in middle-aged adults, decades after previous TT vaccinations, strengthens the classification of this age group for future vaccine interventions in the context of population ageing. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.

PubMed

Sagiv-Barfi, Idit; Kohrt, Holbrook E K; Czerwinski, Debra K; Ng, Patrick P; Chang, Betty Y; Levy, Ronald

2015-03-03

Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.

An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis.

PubMed

Mikecz, Katalin; Glant, Tibor T; Markovics, Adrienn; Rosenthal, Kenneth S; Kurko, Julia; Carambula, Roy E; Cress, Steve; Steiner, Harold L; Zimmerman, Daniel H

2017-07-13

Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPS™) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70-treated mice demonstrated a shift from a pro-inflammatory to an anti-inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Breaking the asymptomatic phase of HIV-1 infection.

PubMed

Tomar, R H

1994-01-01

AIDS typically consists of three phases: (1) an acute, infectious mononucleosis-like syndrome followed by (2) a prolonged asymptomatic stage ending in (3) the appearance of frank AIDS. The asymptomatic phase may last for years and its presence suggests a persistent conflagration between the virus and the host's immune response. There is considerable evidence that an immune response develops but the response is ultimately inadequate. From the work of others as well as our own, we have constructed a hypothesis which attempts to explain some aspects of the immune response. We propose that HIV-1 preferentially infects a subset of CD4+ lymphocytes which are then either destroyed or altered in their biological functions. Further, we suggest that this subset represents the CD4+ TH1 lymphocyte population. By decreasing the quantity of IL-2 and interferon-gamma produced by TH1 lymphocytes, the production of cytokines by TH2 cells is increased. One of the cytokines produced by TH2 lymphocytes is IL-10, a polypeptide with significant inhibitory properties towards lymphocytes. Sera from patients with frank AIDS have significant lymphocyte inhibitory activities some of which operate through IL-10. Thus, a gradual shift to a TH2-type response and release of increasing amounts of inhibitors eventually prevents the host from replacing destroyed cells or mounting new and appropriate immune responses.

IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in lamina propria in mice

PubMed Central

Wang, Yuanyuan; Jiang, Xuefeng; Zhu, Junfeng; Dan Yue; Zhang, Xiaoqing; Wang, Xiao; You, Yong; Wang, Biao; Xu, Ying; Lu, Changlong; Sun, Xun; Yoshikai, Yasunobu

2016-01-01

Serum level of IL-21 is increased in patients with inflammatory bowel diseases (IBD), suggesting that IL-21/IL-21 receptor (IL-21R) signaling may be involved in the pathogenesis of IBD. However, the role of IL-21/IL-21 receptor signaling plays in the pathogenesis of IBD is not very clear. In this study, using IL-21R.KO mice, we tested the role of IL-21/IL-21R signaling in the regulation of T helper cell responses during intestinal inflammation. Here we found that IL-21R.KO mice were more susceptible to DSS-induced colitis as compared with C57BL/6 mice. The spontaneous inflammatory cytokines released by macrophages in LP of colon were significantly increased, and Th2, Th17 and Treg responses were down-regulated markedly. However, Th1 responses were significantly up-regulated in IL-21R.KO mice. Meanwhile, the population of CD8+CD44+IFN-γ+ T cells was markedly elevated in LP of inflammatory intestine of IL-21RKO mice. In vivo, after disease onset, DSS-induced intestinal inflammation was ameliorated in C57BL/6 mice treated with rIL-21. Our results demonstrate that IL-21/IL-21R signaling contributes to protection against DSS-induced acute colitis through suppression of Th1 and activation of Th2, Th17 and Treg responses in mice. Therefore, therapeutic manipulation of IL-21/IL-21R activity may allow improved immunotherapy for IBD and other inflammatory diseases associated with Th cell responses. PMID:27545302

T cell-intrinsic requirement for NF-kappa B induction in postdifferentiation IFN-gamma production and clonal expansion in a Th1 response.

PubMed

Corn, Radiah A; Aronica, Mark A; Zhang, Fuping; Tong, Yingkai; Stanley, Sarah A; Kim, Se Ryoung Agnes; Stephenson, Linda; Enerson, Ben; McCarthy, Susan; Mora, Ana; Boothby, Mark

2003-08-15

NF-kappaB/Rel transcription factors are linked to innate immune responses and APC activation. Whether and how the induction of NF-kappaB signaling in normal CD4(+) T cells regulates effector function are not well-understood. The liberation of NF-kappaB dimers from inhibitors of kappaB (IkappaBs) constitutes a central checkpoint for physiologic regulation of most forms of NF-kappaB. To investigate the role of NF-kappaB induction in effector T cell responses, we targeted inhibition of the NF-kappaB/Rel pathway specifically to T cells. The Th1 response in vivo is dramatically weakened when T cells defective in their NF-kappaB induction (referred to as IkappaBalpha(DeltaN) transgenic cells) are activated by a normal APC population. Analyses in vivo, and IL-12-supplemented T cell cultures in vitro, reveal that the mechanism underlying this T cell-intrinsic requirement for NF-kappaB involves activation of the IFN-gamma gene in addition to clonal expansion efficiency. The role of NF-kappaB in IFN-gamma gene expression includes a modest decrease in Stat4 activation, T box expressed in T cell levels, and differentiation efficiency along with a more prominent postdifferentiation step. Further, induced expression of Bcl-3, a trans-activating IkappaB-like protein, is decreased in T cells as a consequence of NF-kappaB inhibition. Together, these findings indicate that NF-kappaB induction in T cells regulates efficient clonal expansion, Th1 differentiation, and IFN-gamma production by Th1 lymphocytes at a control point downstream from differentiation.

Effects of ω-3 Polyunsaturated Fatty Acids on the Homeostasis of CD4+ T Cells and Lung Injury in Mice With Polymicrobial Sepsis.

PubMed

Chang, Yu-Fan; Hou, Yu-Chen; Pai, Man-Hui; Yeh, Sung-Ling; Liu, Jun-Jen

2017-07-01

Sepsis is a common cause of death in critically ill patients. An overwhelming inflammatory response and imbalance of helper T (Th) cells and regulatory T (Treg) cells are thought to be involved in the progression of sepsis. ω-3 Polyunsaturated fatty acids (PUFAs) were found to have anti-inflammatory and immunomodulatory properties. This study investigated the effects of ω-3 PUFAs on the balance of Th subsets, Treg cells, and the inflammatory response in septic mice. Mice were randomly assigned to soybean oil (SO) and fish oil (FO) groups. The 2 groups received an identical nutrient distribution except for the sources of the fat. The SO group was fed soybean oil, while part of the soybean oil was replaced by fish oil in the FO group. The FO group had an ω-6/ω-3 PUFA ratio of 2:1. After feeding the diets for 3 weeks, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed on days 0, 1, and 3. Compared with the SO group, the FO group had lower inflammatory mediator levels in the plasma and peritoneal lavage fluid after CLP. Also, the FO group had lower Th1, Th2, and Th17 percentages and a higher Th1/Th2 ratio in blood. In lung tissues, neutrophil infiltration was reduced, whereas peroxisome proliferator-activated receptor γ expression was upregulated. A fish oil diet with an ω-6/ω-3 PUFA ratio of 2:1 may elicit more balanced Th polarization, alleviate inflammatory responses, and attenuate lung injury in CLP-induced sepsis.

Immunomodulatory effects of HSV2 glycoprotein D in HSV1 infected mice: implications for immunotherapy of recurrent HSV infection.

PubMed

York, L J; Giorgio, D P; Mishkin, E M

1995-12-01

Immunological analyses in this laboratory and others have suggested that a nonrecurrent HSV seropositive immune status is more closely correlated with a type 1 T helper cell (Th1) response characterized by elevated levels of interferon-gamma and IL2 rather than high titers of virus-specific antibodies. Effective intervention with an immunotherapeutic vaccine may require modulation of the regulatory network of T helper cells such that there is selective restimulation and expansion of the Th1 response. We have established a murine model for assessing the immunomodulatory capacity of an HSV glycoprotein subunit vaccine in animals with pre-existing herpes immunity. Animals were infected with varying doses of HSV1 and then administered glycoprotein D (gD) vaccine adjuvanted with aluminum phosphate at 3-week intervals. Observed changes in serological and cellular responses indicated that administration of subunit vaccine adjuvanted with aluminum phosphate could shift a dominant Th1 response, induced by sensitization with live HSV, towards a Th2 profile of activity. These data suggest that use of aluminum based adjuvants will not selectively stimulate Th1-associated responses and alternative adjuvants may be required for effective use of subunit vaccine in an immunotherapeutic indication in humans.

Chlamydia trachomatis recombinant MOMP encapsulated in PLGA nanoparticles triggers primarily T helper 1 cellular and antibody immune responses in mice: a desirable candidate nanovaccine.

PubMed

Fairley, Stacie J; Singh, Shree R; Yilma, Abebayehu N; Waffo, Alain B; Subbarayan, Praseetha; Dixit, Saurabh; Taha, Murtada A; Cambridge, Chino D; Dennis, Vida A

2013-01-01

We recently demonstrated by in vitro experiments that PLGA (poly D, L-lactide-co-glycolide) potentiates T helper 1 (Th1) immune responses induced by a peptide derived from the recombinant major outer membrane protein (rMOMP) of Chlamydia trachomatis, and may be a promising vaccine delivery system. Herein we evaluated the immune-potentiating potential of PLGA by encapsulating the full-length rMOMP (PLGA-rMOMP), characterizing it in vitro, and investigating its immunogenicity in vivo. Our hypothesis was that PLGA-rMOMP triggers Th1 immune responses in mice, which are desirable prerequisites for a C. trachomatis candidate nanovaccine. Physical-structural characterizations of PLGA-rMOMP revealed its size (approximately 272 nm), zeta potential (-14.30 mV), apparent spherical smooth morphology, and continuous slow release pattern. PLGA potentiated the ability of encapsulated rMOMP to trigger production of cytokines and chemokines by mouse J774 macrophages. Flow cytometric analyses revealed that spleen cells from BALB/c mice immunized with PLGA-rMOMP had elevated numbers of CD4+ and CD8+ T cell subsets, and secreted more rMOMP-specific interferon-gamma (Th1) and interleukin (IL)-12p40 (Th1/Th17) than IL-4 and IL-10 (Th2) cytokines. PLGA-rMOMP-immunized mice produced higher serum immunoglobulin (Ig)G and IgG2a (Th1) than IgG1 (Th2) rMOMP-specific antibodies. Notably, sera from PLGA-rMOMP-immunized mice had a 64-fold higher Th1 than Th2 antibody titer, whereas mice immunized with rMOMP in Freund's adjuvant had only a four-fold higher Th1 than Th2 antibody titer, suggesting primarily induction of a Th1 antibody response in PLGA-rMOMP-immunized mice. Our data underscore PLGA as an effective delivery system for a C. trachomatis vaccine. The capacity of PLGA-rMOMP to trigger primarily Th1 immune responses in mice promotes it as a highly desirable candidate nanovaccine against C. trachomatis.

Immunochemoradiotherapy for Patients with Oral Squamous Cell Carcinoma: Augmentation of OK-432-Induced Helper T Cell 1 Response by 5-FU and X-ray Irradiation1

PubMed Central

Tano, Tomoyuki; Okamoto, Masato; Kan, Shin; Bando, Takashi; Goda, Hiroyuki; Nakashiro, Koh-ichi; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Fujita, Tomonobu; Sato, Mitsunobu; Yamashita, Naomi; Hamakawa, Hiroyuki; Kawakami, Yutaka

2013-01-01

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression. PMID:23814492

Deficiency in Th2 cytokine responses exacerbate orthopoxvirus infection.

PubMed

Sakala, Isaac G; Chaudhri, Geeta; Eldi, Preethi; Buller, R Mark; Karupiah, Gunasegaran

2015-01-01

Ectromelia virus (ECTV) causes mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related orthopoxviruses. Mousepox is an excellent small animal model to study the genetic and immunologic basis for resistance and susceptibility of humans to smallpox. Resistance to mousepox is dependent on a strong polarized type 1 immune response, associated with robust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) responses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, susceptible strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the combined absence of vIFN-γbp, and one or more host genes involved in Th2 response development, influence generation of protective immunity. Most mutant mouse strains infected with wild-type (WT) virus succumbed to disease more rapidly than WT animals. Conversely, the disease outcome was significantly improved in WT mice infected with ECTV-IFN-γbpΔ but absence of IL-4/IL-13/STAT-6 signaling pathways did not provide any added advantage. Deficiency in IL-13 or STAT-6 resulted in defective CTL responses, higher mortality rates and accelerated deaths. Deficiencies in IL-4/IL-13/STAT-6 signaling pathways significantly reduced the numbers of IFN-γ producing CD4 and CD8 T cells, indicating an absence of a switch to a Th1-like response. Factors contributing to susceptibility or resistance to mousepox are far more complex than a balance between Th1 and Th2 responses.

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

PubMed Central

Hasegawa, Hideaki; Mizoguchi, Izuru; Chiba, Yukino; Ohashi, Mio; Xu, Mingli; Yoshimoto, Takayuki

2016-01-01

The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules. PMID:27867385

Outer membrane protein A of Acinetobacter baumannii induces differentiation of CD4+ T cells toward a Th1 polarizing phenotype through the activation of dendritic cells.

PubMed

Lee, Jun Sik; Lee, Je Chul; Lee, Chang-Min; Jung, In Duk; Jeong, Young-Il; Seong, Eun-Young; Chung, Hae-Young; Park, Yeong-Min

2007-06-30

Acinetobacter baumannii is an increasing hospital-acquired pathogen that causes a various type of infections, but little is known about the protective immune response to this microorganism. Outer membrane protein A of A. baumannii (AbOmpA) is a major porin protein and plays an important role in pathogenesis. We analyzed interaction between AbOmpA and dendritic cells (DCs) to characterize the role of this protein in promoting innate and adaptive immune responses. AbOmpA functionally activates bone marrow-derived DCs by augmenting expression of the surface markers, CD40, CD54, B7 family (CD80 and CD86) and major histocompatibility complex class I and II. AbOmpA induces production of Th1-promoting interleukin-12 from DCs and augments the syngeneic and allogeneic immunostimulatory capacity of DCs. AbOmpA stimulates production of interferon-gamma from T cells in mixed lymphocyte reactions, which suggesting Th1-polarizing capacity. CD4(+) T cells stimulated by AbOmpA-stimulated DCs show a Th1-polarizing cytokine profile. The expression of surface markers on DCs is mediated by both mitogen-activated protein kinases and NF-kappaB pathways. Our findings suggest that AbOmpA induces maturation of DCs and drives Th1 polarization, which are important properties for determining the nature of immune response against A. baumannii.

Bone marrow transplantation alters lung antigen presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection

PubMed Central

Zhou, Xiaofeng; Loomis-King, Hillary; Gurczynski, Stephen J.; Wilke, Carol A.; Konopka, Kristine E.; Ptaschinski, Catherine; Coomes, Stephanie M; Iwakura, Yoichiro; van Dyk, Linda F.; Lukacs, Nicholas W.; Moore, Bethany B.

2015-01-01

Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplant (BMT) followed by infection with murine gamma herpesvirus (γHV-68) that results in pneumonitis and fibrosis and mimics human “non-infectious” HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection (dpi). CD4 T cells in BMT mice are skewed towards IL-17A rather than IFN-γ production. Transplantation of bone marrow from Il-17a−/− donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more TGF-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest “non-infectious” HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset. PMID:26376362

Immune Senescence Factors Associated with the Immunogenicity of a Live Attenuated Zoster Vaccine (ZV) in Older Adults

PubMed Central

Weinberg, Adriana; Schamder, Kenneth; Johnson, Michael; Popmihajlov, Zoran; Tovar-Salazar, Adriana; Caldas, Yupanqui; Pang, Lei; Cho, Alice; Levin, Myron

2017-01-01

Abstract Background ZV confers protection against herpes zoster by increasing the cell-mediated immunity (CMI) to varicella-zoster virus (VZV). ZV immunogenicity and protection decrease with increasing age. We investigated effects of age and immune senescence on ZV immunogenicity. Methods 399 adults ≥50 years had VZV T-cell helper 1 (Th1) CMI measured by ex vivo VZV-stimulated IL2/IFNg ELISPOT and blood T-cell nonspecific immune senescence by flow cytometric characterization of FOXP3, CD25, IL10, TGFb, PD1, CD28, CD57 and CD31 expression before and at 1, 6 and 52 weeks after ZV. In a subset of 95 vaccinees, VZV-stimulated T cell expression of CD107, Granzyme B, FOXP3, CD25, IL10, TGFb, CD39 and PD1 were also measured. Multivariate regression analysis was used to identify independent effects of age and immune senescence on VZV Th1 CMI (P < 0.025). Results IL2+ and IL2+IFNg+ Th1 memory VZV CMI peaked at 6 weeks after ZV and remained elevated at 1 year. Effectors, including VZV-specific IFNg+ Th1, and CD8+CD107+% and CD4+/CD8+Granzyme B+% cytotoxic T lymphocytes (CTL), peaked at 1 week, but only the IFNg+ Th1 effectors remained elevated at 1 year. There was also a transient increase in blood CD8+PD1+% exhausted T cells 1 week after ZV. Independent positive effects on peak memory Th1 VZV CMI included the baseline CMI and negative effects included blood CD4+FOXP3+% T regulatory (Treg) and CD8+PD1+% T exhausted cells. Independent positive effects on peak effector Th1 VZV CMI included baseline CMI and negative effects included blood CD8+CD25+FOXP3+% Treg. Age did not have an independent effect on peak CMI. Independent positive effects on persistent (1 year) memory Th1 included baseline CMI and negative effects included age, blood CD4+FOXP3+% Treg and CD8+PD1+% T exhausted cells. Persistent effector Th1 CMI was negatively affected by age only. Conclusion ZV generated VZV-specific Th1 and CTL responses. The early increase of CD8+ exhausted T cells in blood suggested that CTL responses to the vaccine virus may be compromised by immune senescence. The negative of age on VZV Th1 CMI was fully mediated by immune senescence at peak response, but age had a negative effect on CMI persistence that was independent from the markers of immune senescence included in this study. Disclosures A. Weinberg, merck: Grant Investigator, Research grant K. Schamder, merck: Grant Investigator, Research grant Z. Popmihajlov, Merck & Co., Inc.: Employee and Shareholder, Salary L. Pang, Merck: Employee and Shareholder, Salary M. Levin, merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant

The effect of in vivo exposure to zearalenone on cytokine secretion by Th1 and Th2 lymphocytes in porcine Peyer's patches after in vitro stimulation with LPS.

PubMed

Obremski, K

2014-01-01

Most research studies investigating the estrogenic effects of zearalenone (ZEN) focus on the mycotoxin's effect on the reproductive system. Since estrogen receptors are present on various types of immunocompetent cells, ZEN can also modify diverse immune functions. This study analyzed immunocompetent cells isolated from Peyer's patches in the ileum of pigs administered ZEN in the estimated daily dose of 8 μg kg(-1) BW (equivalent of 100 μg kg(-1) feed per day(-1)). The objective of the study was to determine whether long-term exposure to low ZEN doses below the NOEL threshold leads to changes in the percentages of lymphocyte subpopulations and cytokine secretion by Th1 (IL-2, IFN-γ) and Th2 (IL-4 and IL-10) lymphocytes in Peyer's patches of the ileum after in vitro stimulation with lipopolysaccharides (LPS). Immunocompetent cells isolated from Payer's patches on experimental days 0, 14, 28 and 42 were cultured in vitro and stimulated with LPS. The presence of IL-2, IFN-γ, IL-4 and IL-10 in culture media was determined by the ELISA method. The results of the study indicate that ZEN inhibits IL-2 and IFN-γ secretion and stimulates IL-4 and IL-10 produc- tion by Th1 and Th2 lymphocytes by shifting the Th1/Th2 balance towards the humoral immune response. The above can promote allergic responses, as demonstrated by the increase in the size of B1 cell populations producing more autoantibodies. ZEN can also lower resistance to viruses and tumors by inhibiting the proliferation of NK cells and IFN-γ secretion.

Dietary Fructo-Oligosaccharides Attenuate Early Activation of CD4+ T Cells Which Produce both Th1 and Th2 Cytokines in the Intestinal Lymphoid Tissues of a Murine Food Allergy Model.

PubMed

Tsuda, Masato; Arakawa, Haruka; Ishii, Narumi; Ubukata, Chihiro; Michimori, Mana; Noda, Masanari; Takahashi, Kyoko; Kaminogawa, Shuichi; Hosono, Akira

2017-01-01

Fructo-oligosaccharides (FOS) are prebiotic agents with immunomodulatory effects involving improvement of the intestinal microbiota and metabolome. In this study, we investigated the cellular mechanisms through which FOS modulate intestinal antigen-specific CD4+ T cell responses in food allergy, using OVA23-3 mice. OVA23-3 mice were fed an experimental diet containing either ovalbumin (OVA) or OVA and FOS for 1 week. Body weight and mucosal mast cell protease 1 in the serum were measured as the indicator of intestinal inflammation. Single-cell suspensions were prepared from intestinal and systemic lymphoid tissues for cellular analysis. Cytokine production was measured by ELISA. Activation markers and intracellular cytokines in CD4+ T cells were analyzed by flow cytometry. Activated CD4+ T cells were purified to examine cytokine production. Dietary intake of FOS provided moderate protection from the intestinal inflammation induced by the OVA-containing diet. FOS significantly reduced food allergy-induced Th2 cytokine responses in intestinal tissues but not in systemic tissues. FOS decreased OVA diet-induced IFN-γ+IL-4+ double-positive CD4+ T cells and early-activated CD45RBhighCD69+CD4+ T cells in the mesenteric lymph nodes. Furthermore, we confirmed that these CD45RBhighCD69+CD4+ T cells are able to produce high levels of IFN-γ and moderate level of IL-4, IL-10, and IL-13. Dietary intake of FOS during the development of food allergy attenuates the induction of intestinal Th2 cytokine responses by regulating early activation of naïve CD4+ T cells, which produce both Th1 and Th2 cytokines. Our results suggest FOS might be a potential food agent for the prevention of food allergy by modulating oral sensitization to food antigens. © 2017 S. Karger AG, Basel.

Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation.

PubMed

Tano, Tomoyuki; Okamoto, Masato; Kan, Shin; Bando, Takashi; Goda, Hiroyuki; Nakashiro, Koh-ichi; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Fujita, Tomonobu; Sato, Mitsunobu; Yamashita, Naomi; Hamakawa, Hiroyuki; Kawakami, Yutaka

2013-07-01

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses

NASA Astrophysics Data System (ADS)

Mittelbrunn, María; Molina, Ana; Escribese, María M.; Yáñez-Mó, María; Escudero, Ester; Ursa, Ángeles; Tejedor, Reyes; Mampaso, Francisco; Sánchez-Madrid, Francisco

2004-07-01

The integrin 41 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of 41 during the formation of the immune synapse is currently unknown. Here, we show that 41 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-4 antibodies, VLA-4 colocalizes with the CD3- chain at the center of the synapse. In addition, antibody engagement of 4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4+ T cell differentiation and naïve T cell priming by dendritic cells. The in vivo administration of anti-4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.

Neonatal innate TLR-mediated responses are distinct from those of adults.

PubMed

Kollmann, Tobias R; Crabtree, Juliet; Rein-Weston, Annie; Blimkie, Darren; Thommai, Francis; Wang, Xiu Yu; Lavoie, Pascal M; Furlong, Jeff; Fortuno, Edgardo S; Hajjar, Adeline M; Hawkins, Natalie R; Self, Steven G; Wilson, Christopher B

2009-12-01

The human neonate and infant are unduly susceptible to infection with a wide variety of microbes. This susceptibility is thought to reflect differences from adults in innate and adaptive immunity, but the nature of these differences is incompletely characterized. The innate immune response directs the subsequent adaptive immune response after integrating information from TLRs and other environmental sensors. We set out to provide a comprehensive analysis defining differences in response to TLR ligation between human neonates and adults. In response to most TLR ligands, neonatal innate immune cells, including monocytes and conventional and plasmacytoid dendritic cells produced less IL-12p70 and IFN-alpha (and consequently induced less IFN-gamma), moderately less TNF-alpha, but as much or even more IL-1beta, IL-6, IL-23, and IL-10 than adult cells. At the single-cell level, neonatal innate cells generally were less capable of producing multiple cytokines simultaneously, i.e., were less polyfunctional. Overall, our data suggest a robust if not enhanced capacity of the neonate vs the adult white-blood cell TLR-mediated response to support Th17- and Th2-type immunity, which promotes defense against extracellular pathogens, but a reduced capacity to support Th1-type responses, which promote defense against intracellular pathogens.

Distinct CD4+-T-cell responses to live and heat-inactivated Aspergillus fumigatus conidia.

PubMed

Rivera, Amariliz; Van Epps, Heather L; Hohl, Tobias M; Rizzuto, Gabrielle; Pamer, Eric G

2005-11-01

Aspergillus fumigatus is an important fungal pathogen that causes invasive pulmonary disease in immunocompromised hosts. Respiratory exposure to A. fumigatus spores also causes allergic bronchopulmonary aspergillosis, a Th2 CD4+-T-cell-mediated disease that accompanies asthma. The microbial factors that influence the differentiation of A. fumigatus-specific CD4+ T lymphocytes into Th1 versus Th2 cells remain incompletely defined. We therefore examined CD4+-T-cell responses of immunologically intact mice to intratracheal challenge with live or heat-inactivated A. fumigatus spores. Live but not heat-inactivated fungal spores resulted in recruitment of gamma interferon (IFN-gamma)-producing, fungus-specific CD4+ T cells to lung airways, achieving A. fumigatus-specific frequencies exceeding 5% of total CD4+ T cells. While heat-inactivated spores did not induce detectable levels of IFN-gamma-producing, A. fumigatus-specific CD4+ T cells in the airways, they did prime CD4+ T-cell responses in draining lymph nodes that produced greater amounts of interleukin 4 (IL-4) and IL-13 than T cells responding to live conidia. While immunization with live fungal spores induced antibody responses, we found a marked decrease in isotype-switched, A. fumigatus-specific antibodies in sera of mice following immunization with heat-inactivated spores. Our studies demonstrate that robust Th1 T-cell and humoral responses are restricted to challenge with fungal spores that have the potential to germinate and cause invasive infection. How the adaptive immune system distinguishes between metabolically active and inactive fungal spores remains an important question.

T CELLS LOCALIZED TO THE ANDROGEN-DEPRIVED PROSTATE ARE TH1 AND TH17 BIASED

PubMed Central

Morse, Matthew D.; McNeel, Douglas G.

2013-01-01

BACKGROUND T cells infiltrate the prostates of prostate cancer patients undergoing neoadjuvant androgen deprivation. These prostate-infiltrating T cells have an oligoclonal phenotype, suggesting the development of an antigen-specific T-cell response. We hypothesized that androgen deprivation might elicit a prostate tissue-specific T-cell response that could potentially be combined with other immune-active therapies, and consequently sought to investigate the nature and timing of this T-cell response following castration. METHODS We investigated the phenotype and cytokine expression of T cells at various time points in the prostates of Lewis rats following surgical castration, and used adoptive transfer of prostate-infiltrating lymphocytes to determine whether the infiltration by T cells was mediated by effects of castration on the prostate or lymphocytes. RESULTS Prostate T-cell infiltration shortly after castration was TH1 biased up to approximately 30 days, followed by a predominance of TH17-type cells, which persisted until at least 90 days post castration. Prostate-infiltrating lymphocytes from sham-treated or castrate rats localized to the prostates of castrate animals. CONCLUSIONS These observations suggest castration elicits a time-dependent prostate-specific T-cell infiltration, and this infiltration is likely mediated by effects of castration on prostate tissue rather than T cells. These findings have implications for the timing of immunotherapies combined with androgen deprivation as treatments for prostate cancer. PMID:22213030

Synergistically increased ILC2 and Th9 cells in lung tissue jointly promote the pathological process of asthma in mice.

PubMed

Ying, Xinyu; Su, Zhaoliang; Bie, Qingli; Zhang, Pan; Yang, Huijian; Wu, Yumin; Xu, Yunyun; Wu, Jing; Zhang, Mengying; Wang, Shengjun; Xu, Huaxi

2016-06-01

In recent years, T helper (Th) 9 cells have been demonstrated to be key mediators in immune responses in asthmatic lungs, and innate lymphoid cells 2 (ILC2s) have been described as a novel type of innate immunocyte with the ability to enhance immunoglobulin E (IgE) production. However, the interaction between ILC2s and Th9 cells in the pulmonary system of a mouse model of asthma remains to be elucidated. In the present study, the response state of lung tissue with regards to Th9 and ILC2s in a mouse model of asthma was investigated by detecting Th9‑ and ILC2‑associated cytokine receptors. The present study also investigated the association between the expression levels of the cytokine receptors in lung tissue samples and the IgE levels in sera samples from mouse models of asthma. Results from the present study demonstrated that the frequency of ILC2s and Th9 cells was significantly increased in the lung tissue samples, indicating that a Th2-type immune response had occurred. In addition, high mRNA expression levels of RAR‑related orphan receptor α, interleukin 1 receptor‑like 1, transcription factor PU.1 and interleukin (IL)‑9 were observed. Furthermore, IL‑5Rα, IL‑13Rα2 and high‑affinity IgE receptor were increased in mouse models of asthma, and a positive association was observed between the expression levels of ILC2‑ or Th9‑associated receptors in tissue samples and IgE levels in the sera. This indicated that ILC2s and Th9 were in a state of polarization and may promote each other in the lung tissue of mouse models of asthma, and that the lung tissue was responding to the two types of cells via increased expression of receptors.

Glycyrrhiza uralensis flavonoids present in anti-asthma formula, ASHMI™, inhibit memory Th2 responses in vitro and in vivo

PubMed Central

Yang, Nan; Patil, Sangita; Zhuge, Jian; Wen, Ming-Chun; Bolleddula, Jayaprakasam; Doddaga, Srinivasulu; Goldfarb, Joseph; Sampson, Hugh A.; Li, Xiu-Min

2012-01-01

Allergic asthma is associated with Th2-mediated inflammation. Several flavonoids were isolated from Glycyrrhiza uralensis, one of the herbs in the anti-asthma herbal medicine intervention, ASHMI. The aim of this investigation was to determine whether Glycyrrhiza uralensis flavonoids have inhibitory effects on memory Th2 responses in vitro, and antigen induced Th2 inflammation in vivo. The effects of three Glycyrrhiza uralensis flavonoids on effector memory Th2 cells, D10.G4.1 (D10 cells), were determined by measuring Th2 cytokine production. Isoliquiritigenin, 7, 4’-dihydroxyflavone (7, 4’-DHF) and liquiritigenin significantly suppressed IL-4 and IL-5 production in a dose dependent manner, 7, 4’-DHF being most potent. It was also evaluated for effects on D10 cell proliferation, GATA-3 expression and IL-4 mRNA expression, which were suppressed, with no loss of cell viability. Chronic treatment with 7, 4’-DHF in a murine model of allergic asthma not only significantly reduced eosinophilic pulmonary inflammation, serum IgE levels, IL-4 and IL-13 levels, but also increased IFN-γ production in lung cell cultures in response to antigen stimulation. PMID:23165939

Human Th17 Migration in Three-Dimensional Collagen Involves p38 MAPK.

PubMed

Kadiri, Maleck; El Azreq, Mohammed-Amine; Berrazouane, Sofiane; Boisvert, Marc; Aoudjit, Fawzi

2017-09-01

T cell migration across extracellular matrix (ECM) is an important step of the adaptive immune response but is also involved in the development of inflammatory autoimmune diseases. Currently, the molecular mechanisms regulating the motility of effector T cells in ECM are not fully understood. Activation of p38 MAPK has been implicated in T cell activation and is critical to the development of immune and inflammatory responses. In this study, we examined the implication of p38 MAPK in regulating the migration of human Th17 cells through collagen. Using specific inhibitor and siRNA, we found that p38 is necessary for human Th17 migration in three-dimensional (3D) collagen and that 3D collagen increases p38 phosphorylation. We also provide evidence that the collagen receptor, discoidin domain receptor 1 (DDR1), which promotes Th17 migration in 3D collagen, is involved in p38 activation. Together, our findings suggest that targeting DDR1/p38 MAPK pathway could be beneficial for the treatment of Th17-mediated inflammatory diseases. J. Cell. Biochem. 118: 2819-2827, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Generation of TCR-Expressing Innate Lymphoid-like Helper Cells that Induce Cytotoxic T Cell-Mediated Anti-leukemic Cell Response.

PubMed

Ueda, Norihiro; Uemura, Yasushi; Zhang, Rong; Kitayama, Shuichi; Iriguchi, Shoichi; Kawai, Yohei; Yasui, Yutaka; Tatsumi, Minako; Ueda, Tatsuki; Liu, Tian-Yi; Mizoro, Yasutaka; Okada, Chihiro; Watanabe, Akira; Nakanishi, Mahito; Senju, Satoru; Nishimura, Yasuharu; Kuzushima, Kiyotaka; Kiyoi, Hitoshi; Naoe, Tomoki; Kaneko, Shin

2018-06-05

CD4 + T helper (Th) cell activation is essential for inducing cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and re-differentiated the cells into original TCR-expressing T-lineage cells (iPS-T cells) with gene expression patterns resembling those of group 1 innate lymphoid cells. CD4 gene transduction into iPS-T cells enhanced b3a2 peptide-specific responses via b3a2 peptide-specific TCR. iPS-T cells upregulated CD40 ligand (CD40L) expression in response to interleukin-2 and interleukin-15. In the presence of Wilms tumor 1 (WT1) peptide, antigen-specific dendritic cells (DCs) conditioned by CD4-modified CD40L high iPS-T cells stimulated WT1-specific CTL priming, which eliminated WT1 peptide-expressing CML cells in vitro and in vivo. Thus, CD4 modification of CD40L high iPS-T cells generates innate lymphoid helper-like cells inducing bcr-abl-specific TCR signaling that mediates effectiveanti-leukemic CTL responses via DC maturation, showing potential for adjuvant immunotherapy against leukemia. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Emodin inhibits splenocyte proliferation and inflammation by modulating cytokine responses in a mouse model system.

PubMed

Sharma, Rahul; Tiku, Ashu Bhan

2016-01-01

Emodin, an anthraquinone derivative, was investigated for potential anti-inflammatory and anti-proliferative effects in vitro. The potential to induce these outcomes was assessed using concanavalin A (ConA)-stimulated mouse splenocytes. Dose-response studies showed that emodin at 100 µM was not cytotoxic to naive cells, and that the same dose caused proliferation to be significantly reduced in ConA-stimulated cells. In addition, emodin significantly reduced ConA-induced nitric oxide (NO) production and the formation/release of TH1 (IL-2, IFNγ, TNFα) and TH17 (IL-6 and IL-17) cell cytokines, but induced those of TH2 (IL-4) and Treg (IL-10) cells. From the results, it is concluded that earlier-reported immunomodulatory effects imparted by emodin may have been attributable, in part, to anti-proliferative effects on lymphocytes, as well as a shift within the TH1/TH2 and TH17/Treg balance (towards TH2 and Treg). These findings, while providing evidence of mechanisms of emodin immunomodulation, are also potentially important for sparking studies that ultimately may result in the potential use of this agent in preventive and/or corrective strategies against autoimmune and other inflammatory diseases.

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis*

PubMed Central

Silvestre, Marilene Chaves; Sato, Maria Notomi; dos Reis, Vitor Manoel Silva

2018-01-01

Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation. PMID:29723367

The Role of COX-2 in the Inflammatory and Fibrotic Response in the Lung Following Exposure to Multi-Walled Carbon Nanotubes

NASA Astrophysics Data System (ADS)

Sayers, Brian C.

Exposure to multiwalled carbon nanotubes (MWCNT) has been demonstrated to exacerbate airway inflammation and fibrosis in allergen-challenged mouse model. These data have led to concern that individuals with asthma could represent a susceptible population to adverse health effects following exposure to MWCNT, and possibly other engineered nanoparticles. Asthma pathogenesis is caused by the interaction of a complex genetic predisposition and environmental exposures. Because chronic airway inflammation is common to all asthma phenotypes, it is logical to investigate genes that are involved in inflammatory pathways in order to understand the genetic basis of asthma. The metabolism of arachidonic acid by cyclooxygenase (COX) enzymes is the rate-determining step in the synthesis of prostanoids, which are biologically active lipids that are important modulators of inflammation. Based on the role of COX enzymes in inflammatory pathways, we sought to investigate how COX enzymes are involved in the inflammatory response following MWCNT exposure in asthmatic airways. We report that MWCNT significantly exacerbated allergen-induced airway inflammation and mucus cell metaplasia in COX-2 deficient mice compared to wild type mice. In addition, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13, IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2 deficient mice but not in WT mice. We conclude that exacerbation of allergen-induced airway inflammation and mucus cell metaplasia by MWCNTs is enhanced by deficiency in COX-2 and associated with activation of a mixed Th1/Th2/Th17 immune response. Based on our observation that COX-2 deficient mice developed a mixed Th immune response following MWCNT exposure, we sought to evaluate how cytokines associated with different Th immune responses alter COX expression following MWCNT exposure. For this study, a mouse macrophage cell line (RAW264.7) was used because MWCNT were largely sequestered within alveolar macrophages with 24 hours after aspiration in mice. We report that the Th1 cytokine interferon gamma (IFNgamma) causes decreased COX-1 expression but increased prostaglandin E2 (PGE 2) production in mouse macrophages exposed to nickel nanoparticles (NiNP), a residual impurity found in MWCNT from the catalytic synthesis process. NiNP exposure alone increased COX-2 and decreased COX-1 in the absence of exogenous cytokines. IFNgamma further reduced COX-1 levels suppressed by NiNP. IL-4, IL-13, or IL-17 did not reduce COX-1 expression alone or in combination with NiNP. Exogenous PGE2 enhanced NiNP- or IFN-gamma-mediated COX-1 suppression. Pharmacologic inhibition of ERK1,2 or JAK/STAT-1 cell signaling pathways inhibited PGE2 production in all dose groups and restored COX-1 expression in cells treated with IFNgamma and NiNP. These data show that PGE2 production is induced in macrophages exposed to IFNgamma and NiNP and suggest that macrophages could be an important source of the anti-inflammatory mediator PGE2 following nanoparticle exposure in a Th1 immune microenvironment. In summary, these studies highlight an important role for COX enzymes in regulating inflammation in response to engineered nanoparticles and show that prostanoid production in response to nanoparticle exposure could be determined in part by the Th immune microenvironment.

Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses.

PubMed

Bishu, Shrinivas; Su, Ee Wern; Wilkerson, Erich R; Reckley, Kelly A; Jones, Donald M; McGeachy, Mandy J; Gaffen, Sarah L; Levesque, Marc C

2014-02-11

Accumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway. We analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva. Compared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70). RA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.

VIP modulates the pro-inflammatory maternal response, inducing tolerance to trophoblast cells

PubMed Central

Fraccaroli, Laura; Alfieri, Julio; Larocca, Luciana; Calafat, Mario; Roca, Valeria; Lombardi, Eduardo; Ramhorst, Rosanna; Leirós, Claudia Pérez

2009-01-01

Background and purpose Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions. Experimental approach We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses. Key results Swan 71 cells express VPAC1 receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor β expression. Also, during the trophoblast-maternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet. Conclusions and implications Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens. PMID:19133995

Multi-glycoside of Tripterygium wilfordii Hook. f. ameliorates imiquimod-induced skin lesions through a STAT3-dependent mechanism involving the inhibition of Th17-mediated inflammatory responses.

PubMed

Zhao, Jingxia; Di, Tingting; Wang, Yan; Liu, Xin; Liang, Daiying; Zhang, Guangzhong; Li, Ping

2016-09-01

Multi-glycoside of Tripterygium wilfordii Hook. f.(GTW) possesses anti-inflammatory and immunosuppressive properties, and has been used as a traditional treatment for psoriasis for many years, although the underlying immunological mechanisms remain poorly understood. The T helper (Th)17 cell response is considered to play a major role in the pathogenesis of psoriasis. Th17 cells are implicated in the mechanism of pathogenesis of imiquimod (IMQ)‑induced skin inflammation. Using a mouse model, we demonstrated that GTW protected mice from developing psoriasis-like lesions induced by topical IMQ administration. This protection was associated with significantly decreased mRNA levels of Th17 cytokines such as interleukin (IL)-17A, IL-17F and IL-22 in mouse skin samples as well as fewer IL-17-secreting splenic CD4+ lymphocytes in IMQ-exposed mice. There were no significant effects on the proportion of CD4+ interferon (IFN)-γ+ T cells, CD4+IL-4+ T cells and CD4+CD25+Foxp3+ Treg cells in the spleen cells. Taken together with the unchanged mRNA levels of Th1 cytokine IFN-γ, Th2 cytokine IL-4 and Treg cytokine IL-10 in IMQ-exposed mouse skin following GTW administration, our findings suggest that the immunosuppressive effect of GTW in psoriasis is exerted mainly on Th17 cells, rather than on Th1, Th2 or Treg cells. Furthermore, we showed that GTW suppressed Th17 function through the inhibition of STAT3 phosphorylation. These results have the potential to pave the way for the use of GTW as an agent for the treatment of psoriasis.

c-di-GMP enhances protective innate immunity in a murine model of pertussis.

PubMed

Elahi, Shokrollah; Van Kessel, Jill; Kiros, Tedele G; Strom, Stacy; Hayakawa, Yoshihiro; Hyodo, Mamoru; Babiuk, Lorne A; Gerdts, Volker

2014-01-01

Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required.

c-di-GMP Enhances Protective Innate Immunity in a Murine Model of Pertussis

PubMed Central

Elahi, Shokrollah; Van Kessel, Jill; Kiros, Tedele G.; Strom, Stacy; Hayakawa, Yoshihiro; Hyodo, Mamoru; Babiuk, Lorne A.; Gerdts, Volker

2014-01-01

Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required. PMID:25333720

Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus.

PubMed

Hwang, Hye Suk; Lee, Young-Tae; Kim, Ki-Hye; Ko, Eun-Ju; Lee, Youri; Kwon, Young-Man; Kang, Sang-Moo

2017-11-01

Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia. Copyright © 2017. Published by Elsevier Inc.

Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis.

PubMed

Mitosek-Szewczyk, Krystyna; Tabarkiewicz, Jacek; Wilczynska, Barbara; Lobejko, Katarzyna; Berbecki, Jerzy; Nastaj, Marcin; Dworzanska, Ewa; Kolodziejczyk, Beata; Stelmasiak, Zbigniew; Rolinski, Jacek

2013-09-15

Cladribine causes sustained reduction in peripheral T and B cell populations while sparing other immune cells. We determined two populations of dendritic cells (DCs): namely CD1c(+)/CD19(-) (myeloid DCs) and CD303(+)/CD123(+) (plasmacytoid DCs), CD19(+) B lymphocytes, CD3(+) T lymphocytes and CD4(+) or CD8(+) subpopulations in patients with multiple sclerosis after cladribine therapy. We examined 50 patients with secondary progressive multiple sclerosis (SP MS) according to McDonalds et al.'s criteria, 2001 [15]. Blood samples were collected before the initiation of cladribine therapy and after 1st, 2nd, 3th, 4th and 5th courses of treatment. DC subsets, T and B cells were analyzed by flow cytometry. During cladribine treatment the myeloid DCs CD1c(+)/CD19(-) did not change (p=0.73175), and the plasmacytoid DCs CD303(+)/CD123(+) significantly increased (p=0.00034) which resulted in significant changes in the ratio of myeloid DCs to plasmacytoid DCs (p=0.00273). During therapy, B lymphocyte CD19(+) significantly decreased (p=0.00005) and significant changes in CD4(+) cells (p=0.00191), changes in CD8(+) cells (p=0.05760) and significant changes in CD3(+) (p=0.01822) were found. We noticed significant trend to increase the CD303(+) circulating the dendritic cells. This population produces large amounts of IFN-alfa. We found significant and rapid decrease in B cells and CD4(+) Th cells. Our results suggest two possible ways of beneficial cladribine influence on immune system in MS. Induction of IFN-alfa producing cells and their predominance over BDCA-1(+) DCs, which are associated with cytotoxic response. Additionally, cladribine could influence two populations of lymphocytes: B cells and Th lymphocytes responsible for induction of immune response against myelin antigens. Copyright © 2013 Elsevier B.V. All rights reserved.

Obesity promotes prolonged ovalbumin-induced airway inflammation modulating T helper type 1 (Th1), Th2 and Th17 immune responses in BALB/c mice.

PubMed

Silva, F M C; Oliveira, E E; Gouveia, A C C; Brugiolo, A S S; Alves, C C; Correa, J O A; Gameiro, J; Mattes, J; Teixeira, H C; Ferreira, A P

2017-07-01

Clinical and epidemiological studies indicate that obesity affects the development and phenotype of asthma by inducing inflammatory mechanisms in addition to eosinophilic inflammation. The aim of this study was to assess the effect of obesity on allergic airway inflammation and T helper type 2 (Th2) immune responses using an experimental model of asthma in BALB/c mice. Mice fed a high-fat diet (HFD) for 10 weeks were sensitized and challenged with ovalbumin (OVA), and analyses were performed at 24 and 48 h after the last OVA challenge. Obesity induced an increase of inducible nitric oxide synthase (iNOS)-expressing macrophages and neutrophils which peaked at 48 h after the last OVA challenge, and was associated with higher levels of interleukin (IL)-4, IL-9, IL-17A, leptin and interferon (IFN)-γ in the lungs. Higher goblet cell hyperplasia was associated with elevated mast cell influx into the lungs and trachea in the obese allergic mice. In contrast, early eosinophil influx and lower levels of IL-25, thymic stromal lymphopoietin (TSLP), CCL11 and OVA-specific immunoglobulin (IgE) were observed in the obese allergic mice in comparison to non-obese allergic mice. Moreover, obese mice showed higher numbers of mast cells regardless of OVA challenge. These results indicate that obesity affects allergic airway inflammation through mechanisms involving mast cell influx and the release of TSLP and IL-25, which favoured a delayed immune response with an exacerbated Th1, Th2 and Th17 profile. In this scenario, an intense mixed inflammatory granulocyte influx, classically activated macrophage accumulation and intense mucus production may contribute to a refractory therapeutic response and exacerbate asthma severity. © 2017 British Society for Immunology.

Role of IL-22– and TNF-α–Producing Th22 Cells in Uveitis Patients with Behçet’s Disease

PubMed Central

Kawazoe, Yuko; Imai, Ayano; Kawaguchi, Tatsushi; Horie, Shintaro; Keino, Hiroshi; Takahashi, Masayo; Mochizuki, Manabu

2013-01-01

Behçet’s disease is a systemic inflammatory disorder with recurrent episodes of oral ulceration, skin lesions, genital ulceration, and intraocular inflammation (uveitis). The intraocular inflammation is strictly associated with Th effector cells. IL-22 is a member of the IL-10 cytokine family that is involved in inflammatory processes. Recently, Th22 cells were identified as a Th cell population that produces IL-22 and TNF-α and are distinct from Th1, Th2, and Th17 cells. In this study, we established Th22-type T cell clones from ocular samples taken from Behçet’s disease patients with active uveitis. These clones produced large amounts of IL-22 and TNF-α but not the Th1 cytokine IFN-γ and the Th17 cytokine IL-17. CD4+ T cells from the peripheral blood of Behçet’s disease patients differentiated into Th22 cells in the presence of IL-6 and TNF-α in vitro. The polarized Th22 cell lines produced large amounts of IL-22, and the polarized Th1 and Th17 cells also produced IL-22. In the presence of anti–TNF-α– and anti–IL-6–blocking Abs, Behçet’s disease Th22-type T cells failed to produce IL-22. In addition, infliximab-pretreated Th22 cells and Th22-type ocular T cells produced less IL-22 and TNF-α. Moreover, IL-22–producing T cells were isolated from mice with experimental autoimmune uveitis, an animal model of Behçet’s disease, and the intraocular T cells from uveitis models produced large amounts of IL-22 in the presence of retinal Ags. Our results suggest that inflammatory cytokines IL-22 and TNF-α may play a key role in the ocular immune response in Behçet’s disease. PMID:23630362

The relationship between atopy and neurological manifestations in HTLV-1 infection.

PubMed

Verde, Raquel Crisóstomo Lima; Carneiro Neto, José Abraão; Santos, Silvane Maria Braga; Carvalho, Edgar Marcelino; Lessa, Marcus Miranda

2018-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. Here, a cross-sectional study compared the prevalence of atopy in HTLV-1 carriers and HAM/TSP patients. It also compared the spontaneous cytokine production in HTLV-1-infected individuals. A retrospective cohort study evaluated the development of neurological manifestations in atopic and non-atopic carriers. Atopic HAM/TSP patients with high IFN-γ production exhibited higher IL-5 levels than non-atopic patients. Allergic rhinitis accelerated the development of Babinski signals and overactive bladders. Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.

Modeling Immune Response to Leishmania Species Indicates Adenosine As an Important Inhibitor of Th-Cell Activation

PubMed Central

Ribeiro, Henrique A. L.; Maioli, Tatiani U.; de Freitas, Leandro M.; Tieri, Paolo; Castiglione, Filippo

2017-01-01

Infection by Leishmania protozoan parasites can cause a variety of disease outcomes in humans and other mammals, from single self-healing cutaneous lesions to a visceral dissemination of the parasite. The correlation between chronic lesions and ecto-nucleotidase enzymes activity on the surface of the parasite is addressed here using damage caused in epithelial cells by nitric oxide. In order to explore the role of purinergic metabolism in lesion formation and the outcome of the infection, we implemented a cellular automata/lattice gas model involving major immune characters (Th1 and Th2 cells, IFN-γ, IL-4, IL-12, adenosine−Ado−, NO) and parasite players for the dynamic analysis of the disease progress. The model were analyzed using partial ranking correlation coefficient (PRCC) to indicate the components that most influence the disease progression. Results show that low Ado inhibition rate over Th-cells is shared by L. major and L. braziliensis, while in L. amazonensis infection the Ado inhibition rate over Th-cells reaches 30%. IL-4 inhibition rate over Th-cell priming to Th1 independent of IL-12 are exclusive of L. major. The lesion size and progression showed agreement with published biological data and the model was able to simulate cutaneous leishmaniasis outcomes. The sensitivity analysis suggested that Ado inhibition rate over Th-cells followed by Leishmania survival probability were the most important characteristics of the process, with PRCC of 0.89 and 0.77 respectively. The simulations also showed a non-linear relationship between Ado inhibition rate over Th-cells and lesion size measured as number of dead epithelial cells. In conclusion, this model can be a useful tool for the quantitative understanding of the immune response in leishmaniasis. PMID:28775959

Dendritic cells: importance in allergy.

PubMed

Aiba, Setsuya

2007-09-01

In this review we discuss the role of dendritic cells (DC) in the pathogenesis of allergic contact hypersensitivity (ACH) and atopic disorders, such as asthma and atopic eczema. In ACH patients, DC recognize the invasion of simple chemicals such as haptens, and trigger antigen-specific T cell responses leading to the characteristic histological and clinical changes such as spongiosis and papulovesicular eruptions. During atopic disorders, it is well known that the Th2-deviated immune response plays a crucial role in their pathogenesis. DC provide T cells with antigen and costimulatory signals (signals 1 and 2, respectively), as well as with a polarizing signal (signal 3). When studying ACH, it is important to understand how simple chemicals induce the activation of DC and their migration to the draining lymph nodes where they supply signals 1 and 2 to naive T cells. The mechanisms by which DC induce the Th2-deviated immune response, namely via the Th2-deviated signal 3, are central topics in the pathogenesis of atopic disorders.

Distinct Roles of Th17 and Th1 Cells in Inflammatory Responses Associated with the Presentation of Paucibacillary Leprosy and Leprosy Reactions.

PubMed

Santos, M B; de Oliveira, D T; Cazzaniga, R A; Varjão, C S; Dos Santos, P L; Santos, M L B; Correia, C B; Faria, D R; Simon, M do V; Silva, J S; Dutra, W O; Reed, S G; Duthie, M S; de Almeida, R P; de Jesus, A R

2017-07-01

It is well established that helper T cell responses influence resistance or susceptibility to Mycobacterium leprae infection, but the role of more recently described helper T cell subsets in determining severity is less clear. To investigate the involvement of Th17 cells in the pathogenesis of leprosy, we determined the immune profile with variant presentations of leprosy. Firstly, IL-17A, IFN-γ and IL-10 were evaluated in conjunction with CD4 + T cell staining by confocal microscopy of lesion biopsies from tuberculoid (TT) and lepromatous leprosy (LL) patients. Secondly, inflammatory cytokines were measured by multiplex assay of serum samples from Multibacillary (MB, n = 28) and Paucibacillary (PB, n = 23) patients and household contacts (HHC, n = 23). Patients with leprosy were also evaluated for leprosy reaction occurrence: LR+ (n = 8) and LR- (n = 20). Finally, peripheral blood mononuclear cells were analysed by flow cytometry used to determine the phenotype of cytokine-producing cells. Lesions from TT patients were found to have more CD4 + IL-17A + cells than those from LL patients. Higher concentrations of IL-17A and IL-1β were observed in serum from PB than MB patients. The highest serum IFN-γ concentrations were, however, detected in sera from MB patients that developed leprosy reactions (MB LR + ). Together, these results indicate that Th1 cells were associated with both the PB presentation and also with leprosy reactions. In contrast, Th17 cells were associated with an effective inflammatory response that is present in the PB forms but were not predictive of leprosy reactions in MB patients. © 2017 The Foundation for the Scandinavian Journal of Immunology.

T cell subsets in cord blood are influenced by maternal allergy and associated with atopic dermatitis.

PubMed

Fu, Yujing; Lou, Hongfei; Wang, Chengshuo; Lou, Wei; Wang, Yang; Zheng, Tao; Zhang, Luo

2013-03-01

This study aimed to investigate the influence of maternal allergy on cord blood regulatory and effector T cells and to evaluate their role as a predictor of atopic dermatitis (AD) during the first 2 yr of life. Seventy mother-infant pairs were recruited in this prospective birth cohort study (21 allergic and 49 non-allergic mothers). Cord blood samples were collected and assayed for the percentage of regulatory T cells (Treg), interferon-γ (IFN-γ), and interleukin-4 (IL-4) producing T cells (Th1 and Th2, respectively) using flow cytometry. Experiments were undertaken to assess the function of cord blood CD4(+) CD25(+) CD127(-) Treg cells by cell proliferation and cytokine responses. Their offspring at the age of 2 yr old were evaluated by dermatologists to determine whether they had AD. During the first 2 yr of life, 15.7% of the children developed a physician-diagnosed AD. A significantly increased percentage of Th2 cell was observed in cord blood of newborns with maternal allergy. Treg/Th2 ratio significantly decreased among the offspring of allergic mothers. Treg cell-associated suppression of Th2 response was attenuated in Der p1-stimulated CD4(+) CD25(-) T cells from the offspring of allergic mothers. Children with reduced Th1/Th2 (p = 0.001, OR = 0.37) and Treg/Th2 (p = 0.001, OR = 0.47) ratio in cord blood had a higher risk of developing AD. Maternal allergic status is associated with increased percentage of IL-4(+) CD4(+) T cells and a reduced Treg/Th2 ratio in cord blood at their children's birth, which may predispose to an increased risk for developing AD. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Acquisition of Pneumococci Specific Effector and Regulatory Cd4+ T Cells Localising within Human Upper Respiratory-Tract Mucosal Lymphoid Tissue

PubMed Central

Pido-Lopez, Jeffrey; Kwok, William W.; Mitchell, Timothy J.; Heyderman, Robert S.; Williams, Neil A.

2011-01-01

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4+ T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4+ T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25hi T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4+ T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines. PMID:22144893

Naive helper T cells from BCG-vaccinated volunteers produce IFN-gamma and IL-5 to mycobacterial antigen-pulsed dendritic cells.

PubMed

Kowalewicz-Kulbat, Magdalena; Kaźmierczak, Dominik; Donevski, Stefan; Biet, Franck; Pestel, Joël; Rudnicka, Wiesława

2008-01-01

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a live vaccine that has been used in routine vaccination against tuberculosis for nearly 80 years. However, its efficacy is controversial. The failure of BCG vaccination may be at least partially explained by the induction of poor or inappropriate host responses. Dendritic cells (DCs) are likely to play a key role in the induction of immune response to mycobacteria by polarizing the reactivity of T lymphocytes toward a Th1 profile, contributing to the generation of protective cellular immunity against mycobacteria. In this study we aimed to investigate the production of Th1 and Th2 cytokines by naive CD4+ T cells to mycobacterial antigen-pulsed DCs in the group of young, healthy BCG vaccinated volunteers. The response of naive helper T cells was compared with the response of total blood lymphocytes. Our present results clearly showed that circulating naive CD45RA+CD4+ lymphocytes from BCG-vaccinated subjects can become effector helper cells producing IFN-gamma and IL-5 under the stimulation by autologous dendritic cells presenting mycobacterial protein antigen-PPD or infected with live M. bovis BCG bacilli.

Chemokine receptors CCR6 and CXCR3 are necessary for CD4(+) T cell mediated ocular surface disease in experimental dry eye disease.

PubMed

Coursey, Terry G; Gandhi, Niral B; Volpe, Eugene A; Pflugfelder, Stephen C; de Paiva, Cintia S

2013-01-01

CD4(+) T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4(+) T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4(+) T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4(+) T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease.

Chemokine Receptors CCR6 and CXCR3 Are Necessary for CD4+ T Cell Mediated Ocular Surface Disease in Experimental Dry Eye Disease

PubMed Central

Coursey, Terry G.; Gandhi, Niral B.; Volpe, Eugene A.; Pflugfelder, Stephen C.; de Paiva, Cintia S.

2013-01-01

CD4+ T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4+ T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4+ T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4+ T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease. PMID:24223818

Regulation of expression of the ligand for CD40 on T helper lymphocytes.

PubMed

Castle, B E; Kishimoto, K; Stearns, C; Brown, M L; Kehry, M R

1993-08-15

Activated Th cells deliver contact-dependent signals to resting B lymphocytes that initiate and drive B cell proliferation. Recently, a ligand for the B lymphocyte membrane protein, CD40, has been identified that delivers contact-dependent Th cell signals to B cells. A dimeric soluble form of CD40 was produced and used to further characterize the regulation of expression of the CD40 ligand. Expression of the CD40 ligand was rapidly induced after Th lymphocyte activation, and its stability depended upon whether Th cells were activated with soluble or plastic-bound stimuli. Th cells activated with soluble stimuli rapidly turned over cell-surface CD40 ligand whereas Th cells activated with plastic-bound stimuli exhibited more stable CD40 ligand expression for up to 48 h. Removal of activated Th cells from the plastic-bound stimulus resulted in a rapid turnover of CD40 ligand, suggesting that continuous stimulation could maintain CD40 ligand expression. Ligation by soluble CD40 could also stabilize expression of CD40 ligand on the Th cell surface. Both CD40 ligand and IL-2 were transiently synthesized from 1 to 12 h after Th cell activation and had similar kinetics of synthesis. In Con A-activated Th cells newly synthesized CD40 ligand exhibited an initial high turnover (1.5 h t1/2) and after 5 h of Th cell activation became more stable (10-h t1/2). In Th cells activated with plastic-bound anti-CD3, CD40 ligand exhibited a similar biphasic turnover except that the rapid turnover phase began significantly later. This delay could allow more time for newly synthesized CD40 ligand to assemble or associate with other molecules and thus become stabilized on the cell surface. Newly synthesized CD40 ligand in Con A-activated Th cells appeared to not be efficient in delivering Th cell-dependent contact signals to resting B cells, implying the need for assembly or accessory proteins. Regulation of CD40 ligand expression was consistent with all the characteristics of Th cell-delivered contact signals to B cells and may contribute to the high degree of specificity in B cell responses.

Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections.

PubMed

Conti, Heather R; Peterson, Alanna C; Brane, Lucas; Huppler, Anna R; Hernández-Santos, Nydiaris; Whibley, Natasha; Garg, Abhishek V; Simpson-Abelson, Michelle R; Gibson, Gregory A; Mamo, Anna J; Osborne, Lisa C; Bishu, Shrinivas; Ghilardi, Nico; Siebenlist, Ulrich; Watkins, Simon C; Artis, David; McGeachy, Mandy J; Gaffen, Sarah L

2014-09-22

Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα(-/-), and Rag1(-/-) mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of γδ T cells and CD3(+)CD4(+)CD44(hi)TCRβ(+)CCR6(+) natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-β(-/-) and TCR-δ(-/-) mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-β clonal diversity, and was absent in Rag1(-/-), IL-7Rα(-/-), and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens. © 2014 Conti et al.

T helper cell 2 immune skewing in pregnancy/early life: chemical exposure and the development of atopic disease and allergy.

PubMed

McFadden, J P; Thyssen, J P; Basketter, D A; Puangpet, P; Kimber, I

2015-03-01

During the last 50 years there has been a significant increase in Western societies of atopic disease and associated allergy. The balance between functional subpopulations of T helper cells (Th) determines the quality of the immune response provoked by antigen. One such subpopulation - Th2 cells - is associated with the production of IgE antibody and atopic allergy, whereas, Th1 cells antagonize IgE responses and the development of allergic disease. In seeking to provide a mechanistic basis for this increased prevalence of allergic disease, one proposal has been the 'hygiene hypothesis', which argues that in Westernized societies reduced exposure during early childhood to pathogenic microorganisms favours the development of atopic allergy. Pregnancy is normally associated with Th2 skewing, which persists for some months in the neonate before Th1/Th2 realignment occurs. In this review, we consider the immunophysiology of Th2 immune skewing during pregnancy. In particular, we explore the possibility that altered and increased patterns of exposure to certain chemicals have served to accentuate this normal Th2 skewing and therefore further promote the persistence of a Th2 bias in neonates. Furthermore, we propose that the more marked Th2 skewing observed in first pregnancy may, at least in part, explain the higher prevalence of atopic disease and allergy in the first born. © 2014 British Association of Dermatologists.

Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses.

PubMed

Gonzalez-Rey, Elena; Chorny, Alejo; Del Moral, Raimundo G; Varela, Nieves; Delgado, Mario

2007-05-01

Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease-that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor beta1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.

Developmental control of integrin expression regulates Th2 effector homing

USDA-ARS?s Scientific Manuscript database

Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T ...

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease.

PubMed

Brüggen, Marie-Charlotte; Klein, Irene; Greinix, Hildegard; Bauer, Wolfgang; Kuzmina, Zoya; Rabitsch, Werner; Kalhs, Peter; Petzelbauer, Peter; Knobler, Robert; Stingl, Georg; Stary, Georg

2014-01-09

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n = 25), clGVHD (n = 17), and csGVHD (n = 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n = 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4(+) T cells. Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-γ- and IL-17-producing CD8(+) T cells. Our findings shed new light on the T-cell responses involved in the different manifestations of cutaneous GVHD and identify molecular signatures indicating the development of the disease.

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function.

PubMed

Layman, Awo A K; Oliver, Paula M

2016-05-15

The human body is exposed to potentially pathogenic microorganisms at barrier sites such as the skin, lungs, and gastrointestinal tract. To mount an effective response against these pathogens, the immune system must recruit the right cells with effector responses that are appropriate for the task at hand. Several types of CD4(+) T cells can be recruited, including Th cells (Th1, Th2, and Th17), T follicular helper cells, and regulatory T cells. These cells help to maintain normal immune homeostasis in the face of constantly changing microbes in the environment. Because these cells differentiate from a common progenitor, the composition of their intracellular milieu of proteins changes to appropriately guide their effector function. One underappreciated process that impacts the levels and functions of effector fate-determining factors is ubiquitylation. This review details our current understanding of how ubiquitylation regulates CD4(+) T cell effector identity and function. Copyright © 2016 by The American Association of Immunologists, Inc.

Interleukin-1 and Interferon-γ Orchestrate β-Glucan-Activated Human Dendritic Cell Programming via IκB-ζ Modulation

PubMed Central

Cardone, Marco; Dzutsev, Amiran K.; Li, Hongchuan; Riteau, Nicolas; Gerosa, Franca; Shenderov, Kevin; Winkler-Pickett, Robin; Provezza, Lisa; Riboldi, Elena; Leighty, Robert M.; Orr, Selinda J.; Steinhagen, Folkert; Wewers, Mark D.; Sher, Alan; Anderson, Stephen K.; Goldszmid, Romina; McVicar, Daniel W.

2014-01-01

Recognition of microbial components via innate receptors including the C-type lectin receptor Dectin-1, together with the inflammatory environment, programs dendritic cells (DCs) to orchestrate the magnitude and type of adaptive immune responses. The exposure to β-glucan, a known Dectin-1 agonist and component of fungi, yeasts, and certain immune support supplements, activates DCs to induce T helper (Th)17 cells that are essential against fungal pathogens and extracellular bacteria but may trigger inflammatory pathology or autoimmune diseases. However, the exact mechanisms of DC programming by β-glucan have not yet been fully elucidated. Using a gene expression/perturbation approach, we demonstrate that in human DCs β-glucan transcriptionally activates via an interleukin (IL)-1- and inflammasome-mediated positive feedback late-induced genes that bridge innate and adaptive immunity. We report that in addition to its known ability to directly prime T cells toward the Th17 lineage, IL-1 by promoting the transcriptional cofactor inhibitor of κB-ζ (IκB-ζ) also programs β-glucan-exposed DCs to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors. Interferon (IFN)-γ interferes with the IL-1/IκB-ζ axis in β-glucan-activated DCs and promotes T cell-mediated immune responses with increased release of IFN-γ and IL-22, and diminished production of IL-17. Thus, our results identify IL-1 and IFN-γ as regulators of DC programming by β-glucan. These molecular networks provide new insights into the regulation of the Th17 response as well as new targets for the modulation of immune responses to β-glucan-containing microorganisms. PMID:25474109

Dendritic Cells, New Tools for Vaccination

DTIC Science & Technology

2003-01-01

stimulating a protective Th1 response, but secreting the Th2 cytokine IL-4 in response to hyphae , which was not protec- tive. However, suppression of IL...4 production by hyphae - pulsed DCs allowed for a protective response to occur. The success of this approach is based on two factors. (i) Pathogens can

Silencing of Endogenous IL-10 in Human Dendritic Cells Leads to the Generation of an Improved CTL Response Against Human Melanoma Associated Antigenic Epitope, MART-127−35

PubMed Central

Chhabra, Arvind; Chakraborty, Nityo G.; Mukherji, Bijay

2008-01-01

Dendritic cells (DC) present antigenic epitopes to and activate T cells. They also polarize the ensuing T cell response to Th1 or Th2 type response, depending on their cytokine production profile. For example, IL-12 producing DC generate Th1 type T cell response whereas IL-10 producing DC is usually tolerogenic. Different strategies -- such as the use of cytokines and anti-cytokine antibodies, dominant negative forms of protein, anti-sense RNA etc. -- have been employed to influence the cytokine synthetic profile of DC as well as to make DC more immunogenic. Utilizing GFP expressing recombinant adenoviruses in association with lipid-mediated transfection of siRNA, we have silenced the endogenous IL-10 gene in DC. We show that IL-10 gene silenced DC produce more IL-12 and also generates a better cytolytic T cell response against the human melanoma associated epitope, MART-127−35, in-vitro. We also show that the GFP expressing adenoviral vector can be used to optimize the parameters for siRNA delivery in primary cells and show that RNA interference methodology can efficiently knock-down virus encoded genes transcribed at very high multiplicity of infection in DC. PMID:18249038

CpG Oligodeoxynucleotides Enhance the Efficacy of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes by Modifying the Th1 Polarization and Local Infiltration of Th17 Cells

PubMed Central

Xu, Lin; Wang, Chunhong; Wen, Zhenke; Zhou, Ya; Liu, Zhongmin; Liang, Yongjie; Xu, Zengguang; Ren, Tao

2010-01-01

Adoptive cell transfer immunotherapy using tumor infiltrating lymphocytes (TILs) was an important therapeutic strategy against tumors. But the efficacy remains limited and development of new strategies is urgent. Recent evidence suggested that CpG-ODNs might be a potent candidate for tumor immunotherapy. Here we firstly reported that CpG-ODNs could significantly enhance the antitumor efficacy of adoptively transferred TILs in vivo accompanied by enhanced activity capacity and proliferation of CD8+ T cells and CD8+ T cells, as well as a Th1 polarization immune response. Most importantly, we found that CpG-ODNs could significantly elevate the infiltration of Th17 cells in tumor mass, which contributed to anti-tumor efficacy of TILs in vivo. Our findings suggested that CpG ODNs could enhance the anti-tumor efficacy of adoptively transferred TILs through modifying Th1 polarization and local infiltration of Th17 cells, which might provide a clue for developing a new strategy for ACT based on TILs. PMID:20981279

Pertussis Circulation Has Increased T-Cell Immunity during Childhood More than a Second Acellular Booster Vaccination in Dutch Children 9 Years of Age

PubMed Central

Schure, Rose-Minke; de Rond, Lia; Öztürk, Kemal; Hendrikx, Lotte; Sanders, Elisabeth; Berbers, Guy; Buisman, Anne-Marie

2012-01-01

Here we report the first evaluation of T-cell responses upon a second acellular pertussis booster vaccination in Dutch children at 9 years of age, 5 years after a preschool booster vaccination. Blood samples of children 9 years of age were studied longitudinally until 1 year after the second aP booster and compared with those after the first aP booster in children 4 and 6 years of age from a cross-sectional study. After stimulation with pertussis-vaccine antigens, Th1, Th2 and Th17 cytokine responses were measured and effector memory cells (CCR7-CD45RA-) were characterized by 8-colour FACS analysis. The second aP booster vaccination at pre-adolescent age in wP primed individuals did increase pertussis-specific Th1 and Th2 cytokine responses. Noticeably, almost all T-cell responses had increased with age and were already high before the booster vaccination at 9 years of age. The enhancement of T-cell immunity during the 5 year following the booster at 4 years of age is probably caused by natural boosting due to the a high circulation of pertussis. However, the incidence of pertussis is high in adolescents and adults who have only received the Dutch wP vaccine during infancy and no booster at 4 years of age. Therefore, an aP booster vaccination at adolescence or later in these populations might improve long-term immunity against pertussis and reduce the transmission to the vulnerable newborns. Trial Registration Controlled-Trials.com ISRCTN64117538 PMID:22860033

Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+ T-Cell Activation by Inducing IL-10-Producing Th1 Cells

PubMed Central

Selleri, Silvia; Dieng, Mame Massar; Nicoletti, Simon; Louis, Isabelle; Beausejour, Christian; Le Deist, Françoise

2013-01-01

The mechanisms by which mesenchymal stromal cells (MSCs) induce immunomodulation are still poorly understood. In the current work, we show by a combination of polymerase chain reaction (PCR) array, flow cytometry, and multiplex cytokine data analysis that during the inhibition of an alloantigen-driven CD4+ T-cell response, MSCs induce a fraction of CD4+ T-cells to coexpress interferon-γ (IFNγ) and interleukin-10 (IL-10). This CD4+ IFNγ+ IL-10+ cell population shares properties with recently described T-cells originating from switched Th1 cells that start producing IL-10 and acquire a regulatory function. Here we report that IL-10-producing Th1 cells accumulated with time during T-cell stimulation in the presence of MSCs. Moreover, MSCs caused stimulated T-cells to downregulate the IFNγ receptor (IFNγR) without affecting IL-10 receptor expression. Further, the inhibitory effect of MSCs could be reversed by an anti-IFNγR-blocking antibody, indicating that IFNγ is one of the major players in MSC-induced T-cell suppression. Stimulated (and, to a lesser extent, resting) CD4+ T-cells treated with MSCs were able to inhibit the proliferation of autologous CD4+ T-cells, demonstrating their acquired regulatory properties. Altogether, our results suggest that the generation of IL-10-producing Th1 cells is one of the mechanisms by which MSCs can downmodulate an immune response. PMID:23167734

Fate vs choice: the immune system reloaded.

PubMed

Murphy, Kenneth M

2005-01-01

Development can occur by either instructive or stochastic processes. My colleagues and I have studied the contributions of these processes to differentiation of naïve CD4+ T-cells to either a Th1 or Th2 phenotype. Our initial discovery that pathogens in our in vitro priming system led to the development of Th1 cells through the action of interleukin-12 was important evidence of a link between innate and adaptive immunity. Subsequent studies in our laboratory revealed an important role for GATA-3 autoactivation in Th2 development. Other interesting projects that have emerged as a result of our Th cell differentiation studies include understanding the role of the inhibitory immunoreceptor B- and T-lymphocyte attenuator in the immune response, as well as the role of the transcription factor ERM in both T-cells and spermatogenesis. We currently maintain our interests in the Th differentiation field by trying to understand the role of type 1 interferons in Th1 development and the role of alternate promoters for the GATA-3 gene, among other things, but are also actively embarking on studies related to the choice between divergent cell types during embryonic stem cell differentiation.

Simultaneous Subcutaneous and Intranasal Administration of a CAF01-Adjuvanted Chlamydia Vaccine Elicits Elevated IgA and Protective Th1/Th17 Responses in the Genital Tract

PubMed Central

Wern, Jeanette Erbo; Sorensen, Maria Rathmann; Olsen, Anja Weinreich; Andersen, Peter; Follmann, Frank

2017-01-01

The selection of any specific immunization route is critical when defining future vaccine strategies against a genital infection like Chlamydia trachomatis (C.t.). An optimal Chlamydia vaccine needs to elicit mucosal immunity comprising both neutralizing IgA/IgG antibodies and strong Th1/Th17 responses. A strategic tool to modulate this immune profile and mucosal localization of vaccine responses is to combine parenteral and mucosal immunizations routes. In this study, we investigate whether this strategy can be adapted into a two-visit strategy by simultaneous subcutaneous (SC) and nasal immunization. Using a subunit vaccine composed of C.t. antigens (Ags) adjuvanted with CAF01, a Th1/Th17 promoting adjuvant, we comparatively evaluated Ag-specific B and T cell responses and efficacy in mice following SC and simultaneous SC and nasal immunization (SIM). We found similar peripheral responses with regard to interferon gamma and IL-17 producing Ag-specific splenocytes and IgG serum levels in both vaccine strategies but in addition, the SIM protocol also led to Ag-specific IgA responses and increased B and CD4+ T cells in the lung parenchyma, and in lower numbers also in the genital tract (GT). Following vaginal infection with C.t., we observed that SIM immunization gave rise to an early IgA response and IgA-secreting plasma cells in the GT in contrast to SC immunization, but we were not able to detect more rapid recruitment of mucosal T cells. Interestingly, although SIM vaccination in general improved mucosal immunity we observed no improved efficacy against genital infection compared to SC, a finding that warrants for further investigation. In conclusion, we demonstrate a novel vaccination strategy that combines systemic and mucosal immunity in a two-visit strategy. PMID:28567043

Distinct pathways of humoral and cellular immunity induced with the mucosal administration of a nanoemulsion adjuvant.

PubMed

Bielinska, Anna U; Makidon, Paul E; Janczak, Katarzyna W; Blanco, Luz P; Swanson, Benjamin; Smith, Douglas M; Pham, Tiffany; Szabo, Zsuzsanna; Kukowska-Latallo, Jolanta F; Baker, James R

2014-03-15

Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1- and Th-17-balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell-mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.

Effects of intestinal bacteria-derived p-cresyl sulfate on Th1-type immune response in vivo and in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shiba, Takahiro, E-mail: takahiro-shiba@yakult.co.jp; Kawakami, Koji; Sasaki, Takashi

2014-01-15

Protein fermentation by intestinal bacteria generates various compounds that are not synthesized by their hosts. An example is p-cresol, which is produced from tyrosine. Patients with chronic kidney disease (CKD) accumulate high concentrations of intestinal bacteria-derived p-cresyl sulfate (pCS), which is the major metabolite of p-cresol, in their blood, and this accumulation contributes to certain CKD-associated disorders. Immune dysfunction is a CKD-associated disorder that frequently contributes to infectious diseases among CKD patients. Although some studies imply pCS as an etiological factor, the relation between pCS and immune systems is poorly understood. In the present study, we investigated the immunological effectsmore » of pCS derived from intestinal bacteria in mice. For this purpose, we fed mice a tyrosine-rich diet that causes the accumulation of pCS in their blood. The mice were shown to exhibit decreased Th1-driven 2, 4-dinitrofluorobenzene-induced contact hypersensitivity response. The concentration of pCS in blood was negatively correlated with the degree of the contact hypersensitivity response. In contrast, the T cell-dependent antibody response was not influenced by the accumulated pCS. We also examined the in vitro cytokine responses by T cells in the presence of pCS. The production of IFN-γ was suppressed by pCS. Further, pCS decreased the percentage of IFN-γ-producing Th1 cells. Our results suggest that intestinal bacteria-derived pCS suppressesTh1-type cellular immune responses. - Highlights: • Mice fed a tyrosine-rich diet accumulated p-cresyl sulfate in their blood. • p-Cresyl sulfate negatively correlated with contact hypersensitivity response. • The in vitro production of IFN-γ was suppressed by p-cresyl sulfate. • p-Cresyl sulfate decreased the percentage of IFN-γ-producing Th1 cells in vitro.« less

Encapsulating Immunostimulatory CpG Oligonucleotides in Listeriolysin O-Liposomes Promotes a Th1-Type Response and CTL Activity

PubMed Central

Andrews, Chasity D.; Huh, Myung-Sook; Patton, Kathryn; Higgins, Debbie; Van Nest, Gary; Ott, Gary; Lee, Kyung-Dall

2013-01-01

Immunostimulatory sequences (ISS) are short DNA sequences containing unmethylated CpG dimers that have multiple effects on the host immune system, including the ability to stimulate antigen-specific cytotoxic T lymphocytes (CTLs) and drive Th1-type immune responses. Listeriolysin O (LLO)-containing pH-sensitive liposomes have been shown to efficiently deliver macromolecules to the cytosol of APCs and efficiently stimulate CTLs. We hypothesized that encapsulating ISS-oligodeoxyribonucleotides (ODNs) in this delivery system would enhance the cell-mediated immune response and skew Th1-type responses in protein antigen-based vaccination utilizing LLO-liposomes. In vitro studies indicated that co-encapsulation of ISS in LLO-liposomes engendered activation of the NF-κB pathway while maintaining the efficient cytosolic delivery of antigen mediated by the co-encapsulated LLO. Antigen-specific CTL responses monitored by using the model antigen ovalbumin (OVA) in mice were enhanced when mice were immunized with OVA and ISS-ODN-containing LLO-liposomes compared with those immunized with either OVA-containing LLO-liposomes or OVA-ISS conjugates. The enhanced immune responses were of the Th1-type as monitored by the robust OVA-specific IgG2a induction and the OVA CD8 peptide-stimulated IFN-γ secretion. Our study suggests that including ISS-ODN in LLO-containing pH-sensitive liposomes yields a vaccine delivery system that enhances the cell-mediated immune response and skews this response toward the Th1-type. PMID:22376145

Relationships between Th1 or Th2 iNKT Cell Activity and Structures of CD1d-Antigen Complexes: Meta-analysis of CD1d-Glycolipids Dynamics Simulations

PubMed Central

Laurent, Xavier; Renault, Nicolas; Farce, Amaury; Chavatte, Philippe; Hénon, Eric

2014-01-01

A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1. PMID:25376021

Insights into the role of Bcl6 in follicular Th cells using a new conditional mutant mouse model.

PubMed

Hollister, Kristin; Kusam, Saritha; Wu, Hao; Clegg, Ninah; Mondal, Arpita; Sawant, Deepali V; Dent, Alexander L

2013-10-01

The transcriptional repressor Bcl6 controls development of the follicular Th cell (T(FH)) lineage, but the precise mechanisms by which Bcl6 regulates this process are unclear. A model has been proposed whereby Bcl6 represses the differentiation of T cells into alternative effector lineages, thus favoring T(FH) cell differentiation. Analysis of T cell differentiation using Bcl6-deficient mice has been complicated by the strong proinflammatory phenotype of Bcl6-deficient myeloid cells. In this study, we report data from a novel mouse model where Bcl6 is conditionally deleted in T cells (Bcl6(fl/fl)Cre(CD4) mice). After immunization, programmed death -1 (PD-1)(high) T(FH) cells in Bcl6(fl/fl)Cre(CD4) mice are decreased >90% compared with control mice, and Ag-specific IgG is sharply reduced. Residual PD-1(high)CXCR5(+) T(FH) cells in Bcl6(fl/fl)Cre(CD4) mice show a significantly higher rate of apoptosis than do PD-1(high)CXCR5(+) T(FH) cells in control mice. Immunization of Bcl6(fl/fl)Cre(CD4) mice did not reveal enhanced differentiation into Th1, Th2, or Th17 lineages, although IL-10 expression by CD4 T cells was markedly elevated. Thus, T cell-extrinsic factors appear to promote the increased Th1, Th2, and Th17 responses in germline Bcl6-deficient mice. Furthermore, IL-10 may be a key target gene for Bcl6 in CD4 T cells, which enables Bcl6 to promote the T(FH) cell phenotype. Finally, our data reveal a novel mechanism for the role of Bcl6 in promoting T(FH) cell survival.

Alternatively activated macrophages in helminth infections

PubMed Central

Kreider, Timothy; Anthony, Robert M.; Urban, Joseph F.; Gause, William C.

2007-01-01

Summary Helminthic parasites can trigger highly polarized immune responses typically associated with increased numbers of CD4+ Th2 cells, eosinophils, mast cells, and basophils. These cell populations are thought to coordinate an effective response ultimately leading to parasite expulsion, but they also play a role in the regulation of associated pathologic inflammation. Recent studies suggest that macrophages, conventionally associated with IFNγ-dominant Th1-type responses to many bacteria and viruses, also play an essential role in the Th2-type inflammatory response. These macrophages are referred to as alternatively activated macrophages (AAMΦs) as they express a characteristic pattern of cell surface and secreted molecules distinct from that of classically activated macrophages (CAMΦs) associated with microbe infections. In this review, we will discuss recent findings regarding the role of AAMΦs in the development of disease and host protection following helminth infection. PMID:17702561

Immunological modes of pregnancy loss: inflammation, immune effectors, and stress.

PubMed

Kwak-Kim, Joanne; Bao, Shihua; Lee, Sung Ki; Kim, Joon Woo; Gilman-Sachs, Alice

2014-08-01

Inflammatory immune response plays a key role in reproductive failures such as multiple implantation failures (MIF), early pregnancy loss, and recurrent pregnancy losses (RPL). Cellular immune responses particularly mediated by natural killer (NK), and T cells are often dysregulated in these conditions. Excessive or inappropriate recruitment of peripheral blood NK cells to the uterus may lead to cytotoxic environment in utero, in which proliferation and differentiation of trophoblast is hampered. In addition, inadequate angiogenesis by uterine NK cells often leads to abnormal vascular development and blood flow patterns, which, in turn, leads to increased oxidative stress or ischemic changes in the invading trophoblast. T-cell abnormalities with increased Th1 and Th17 immunity, and decreased Th2 and T regulatory immune responses may play important roles in RPL and MIF. A possible role of stress in inflammatory immune response is also reviewed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epitope analysis of HLA-DR-restricted helper T-cell responses to Der p II, a major allergen molecule of Dermatophagoides pteronyssinus.

PubMed

Okano, M; Nagano, T; Nakada, M; Masuda, Y; Kino, K; Yasueda, H; Nose, Y; Nishimura, Y; Ohta, N

1996-01-01

T-cell epitopes of Der p II, a major allergen of Dermatophagoides pteronyssinus, were analyzed by using human T-cell clones. We tested 38 cloned T cells from two Japanese patients with allergic rhinitis, and identified at least two peptides (K33-T47 and I58-C73) as helper T-cell epitopes. The former epitope was shown to be restricted by HLA-DRB1*1502, and the latter by HLA-DRB1*0405, both of which are typical Japanese HLA-DR alleles, suggesting that those T-cell epitopes might be important for the onset of house-dust mite allergy in the Japanese population. We prepared 15 analog peptides of the HLA- DRB1*1502-restricted 15-mer peptide. Of those 15 residues, five (F35, L37, A39, F41, and E42) were critical for the epitope activity, and three residues (F35, A39, and E42) seemed to be included in anchor motifs for HLA-DRB1*1502. The epitope peptide was also recognized by HLA-DRB1*1502-positive healthy donors; however, only allergic T cells showed Th2 functions. Antigen-presenting cells of nonallergic donors were able to activate allergic T cells to express Th2 function. This seemed to suggest that antigen recognition of T cells, as well as additional unknown factors which promote Th2, rather than Th1, responses, might be important for the onset of house-dust mite allergy.

Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma.

PubMed

Laouar, Yasmina; Sutterwala, Fayyaz S; Gorelik, Leonid; Flavell, Richard A

2005-06-01

Interferon-gamma and interleukin 12 produced by the innate arm of the immune system are important regulators of T helper type 1 (T(H)1) cell development, but signals that negatively regulate their expression remain controversial. Here we show that transforming growth factor-beta (TGF-beta) controlled T(H)1 differentiation through the regulation of interferon-gamma produced by natural killer (NK) cells. Blockade of TGF-beta signaling in NK cells caused the accumulation of a large pool of NK cells secreting copious interferon-gamma, responsible for T(H)1 differentiation and protection from leishmania infection. In contrast, blockade of TGF-beta signaling in dendritic cells did not affect dendritic cell homeostasis or interleukin 12 production, thus indicating a previously undescribed demarcation of the function of TGF-beta in NK cells versus dendritic cells.

M2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis.

PubMed

de Carli, Marina Lara; Miyazawa, Marta; Nonogaki, Suely; Shirata, Neuza Kasumi; Oliveira, Denise Tostes; Pereira, Alessandro Antônio Costa; Hanemann, João Adolfo Costa

2016-02-01

Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by Paracoccidioides brasiliensis (Pb) and associated with deficient cellular immune response, which is modulated by inflammatory cells, mainly macrophages, and cytokines. Recently, the comprehension of the macrophage polarization mediated by Th1 and Th2 cytokines has contributed to elucidate the immune response that takes part in some diseases. Thus, the aim of this study was to assess the presence of Th1- and Th2-immune response and also Pb counting in oral lesions of chronic PCM. Forty-eight cases of chronic PCM oral lesions were included. All cases were classified as loose or dense granulomas. S100 protein, IL-1β, IL-6, TNF-α, CD163 and CD68 immunoexpressions, and Pb localization were evaluated. The fungi present in the tissue were quantified by anti-Pb antibody. Most patients were white men with mean age of 47 years old and showed higher incidence of multiple lesions. Loose granulomas were predominant and exhibited a great amount of M2 macrophages, which were visualized with anti-CD163 antibody. The expression for CD163 and CD68 was similar (P = 0.05), highlighting the predominance of M2 macrophages in PCM. IL-1β, IL-6, and TNF-α immunoexpression did not significantly change with CD163, CD68, and S100 protein. The number of fungi was significantly higher in cases with intense IL-1β immunoexpression (P = 0.003). M2-activated macrophages were the majority among inflammatory cells in chronic PCM, characterizing the action of a Th2-immune response. Nevertheless, Th1 cytokines were also found; mainly IL-1β, which was associated with fungi counting in oral lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ambient particulate matter activates the aryl hydrocarbon receptor in dendritic cells and enhances Th17 polarization.

PubMed

Castañeda, Alejandro R; Pinkerton, Kent E; Bein, Keith J; Magaña-Méndez, Alfonso; Yang, Houa T; Ashwood, Paul; Vogel, Christoph F A

2018-08-01

The objective of this study was to explore the role of the aryl hydrocarbon receptor (AhR) in ambient particulate matter (PM)-mediated activation of dendritic cells (DCs) and Th17-immune responses in vitro. To assess the potential role of the AhR in PM-mediated activation of DCs, co-stimulation, and cytokine expression, bone marrow (BM)-derived macrophages and DCs from C57BL/6 wildtype or AhR knockout (AhR -/- ) mice were treated with PM. Th17 differentiation was assessed via co-cultures of wildtype or AhR -/- BMDCs with autologous naive T cells. PM 2.5 significantly induced AhR DNA binding activity to dioxin responsive elements (DRE) and expression of the AhR repressor (AhRR), cytochrome P450 (CYP) 1A1, and CYP1B1, indicating activation of the AhR. In activated (OVA sensitized) BMDCs, PM 2.5 induced interleukin (IL)-1β, CD80, CD86, and MHC class II, suggesting enhanced DC activation, co-stimulation, and antigen presentation; responses that were abolished in AhR deficient DCs. DC-T cell co-cultures treated with PM and lipopolysaccharide (LPS) led to elevated IL-17A and IL-22 expression at the mRNA level, which is mediated by the AhR. PM-treated DCs were essential in endowing T cells with a Th17-phenotype, which was associated with enhanced expression of MHC class II and cyclooxygenase (COX)-2. In conclusion, PM enhances DC activation that primes naive T cell differentiation towards a Th17-like phenotype in an AhR-dependent manner. Copyright © 2018 Elsevier B.V. All rights reserved.

Recombinant ESAT-6-CFP10 Fusion Protein Induction of Th1/Th2 Cytokines and FoxP3 Expressing Treg Cells in Pulmonary TB.

PubMed

Jackson-Sillah, Dolly; Cliff, Jacqueline M; Mensah, Gloria Ivy; Dickson, Emmanuel; Sowah, Sandra; Tetteh, John K A; Addo, Kwasi K; Ottenhoff, Tom H M; Bothamley, Graham; Dockrell, Hazel M

2013-01-01

Early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are Mycobacterium tuberculosis (Mtb)-specific antigens that are secreted by actively metabolising bacteria and contribute to the virulence of the bacteria. Their ability to induce Treg and Th2 responses, particularly during the first two weeks of treatment, has not been comprehensively examined to date. The purpose of this work was to characterise Th1, Th2 and Treg responses to rESAT-6-CFP10 fusion protein in TB patients before and during the intensive phase of treatment and in healthy M.bovis BCG vaccinated donors. Forty-six newly diagnosed, HIV-negative, smear-positive pulmonary TB patients and 20 healthy donors were recruited in the UK and Ghana. Their peripheral blood mononuclear cells (PBMC) were used in ex vivo ELISPOT and in vitro cultures to identify immunological parameters of interest. The study confirmed that protective immune responses to rESAT-6-CFP10 are impaired in active TB but improved during treatment: circulating antigen-specific IL-4-producing T-cells were increased in untreated TB but declined by two weeks of treatment while the circulating antigen-specific IFN-γ producing T cells which showed a transient rise at one week of treatment, persisted at baseline levels at two months of treatment. In vitro T cell proliferation and IFN-γ production were reduced, while IL-4 and CD4(+)FoxP3(+)CD25(hi) cell expression were increased in response to rESAT-6-CFP10 fusion protein in untreated TB. These responses were reversed during early treatment of TB. These observations support further investigations into the possible utility of these parameters as markers of active disease and favourable treatment outcomes.

Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma.

PubMed

Ehrentraut, Stefan; Schneider, Björn; Nagel, Stefan; Pommerenke, Claudia; Quentmeier, Hilmar; Geffers, Robert; Feist, Maren; Kaufmann, Maren; Meyer, Corinna; Kadin, Marshall E; Drexler, Hans G; MacLeod, Roderick A F

2016-06-07

We propose that deregulated T-helper-cell (Th) signaling underlies evolving Th17 cytokine expression seen during progression of cutaneous T-cell lymphoma (CTCL). Accordingly, we developed a lymphoma progression model comprising cell lines established at indolent (MAC-1) and aggressive (MAC-2A) CTCL stages. We discovered activating JAK3 (V722I) mutations present at indolent disease, reinforced in aggressive disease by novel compound heterozygous SOCS1 (G78R/D105N) JAK-binding domain inactivating mutations. Though isogenic, indolent and aggressive-stage cell lines had diverged phenotypically, the latter expressing multiple Th17 related cytokines, the former a narrower profile. Importantly, indolent stage cells remained poised for Th17 cytokine expression, readily inducible by treatment with IL-2 - a cytokine which mitigates Th17 differentiation in mice. In indolent stage cells JAK3 expression was boosted by IL-2 treatment. Th17 conversion of MAC-1 cells by IL-2 was blocked by pharmacological inhibition of JAK3 or STAT5, implicating IL2RG - JAK3 - STAT5 signaling in plasticity responses. Like IL-2 treatment, SOCS1 knockdown drove indolent stage cells to mimic key aggressive stage properties, notably IL17F upregulation. Co-immunoprecipitation experiments showed that SOCS1 mutations abolished JAK3 binding, revealing a key role for SOCS1 in regulating JAK3/STAT5 signaling. Collectively, our results show how JAK/STAT pathway mutations contribute to disease progression in CTCL cells by potentiating inflammatory cytokine signaling, widening the potential therapeutic target range for this intractable entity. MAC-1/2A cells also provide a candidate human Th17 laboratory model for identifying potentally actionable CTCL markers or targets and testing their druggability in vitro.

Extracellular vesicles are key intercellular mediators in the development of immune dysfunction to allergens in the airways.

PubMed

Shin, T-S; Kim, J H; Kim, Y-S; Jeon, S G; Zhu, Z; Gho, Yong Song; Kim, Yoon-Keun

2010-10-01

Previous evidence indicates that inhalation of lipopolysaccharide (LPS)-containing with allergens induced mixed Th1 and Th17 cell responses in the airways. Extracellular vesicles (EVs) are nanometer-sized spherical, lipid-bilayered structures and are recently in the public eye as an intercellular communicator in immune responses. To evaluate the role of EVs secreted by LPS inhalation in the development of airway immune dysfunction in response to allergens. Extracellular vesicles in bronchoalveolar lavage fluids of BALB/c mice were isolated and characterized 24 h after applications to the airway of 10 μg of LPS for 3 days. To evaluate the role of LPS-induced EVs on the development of airway immune dysfunction, in vivo and in vitro experiments were performed using the isolated LPS-induced EVs. The inhalation of LPS enhanced EVs release into the BAL fluid, when compared to the application of PBS. Airway sensitization with allergens and LPS-induced EVs resulted in a mixed Th1 and Th17 cell responses, although that with allergens and PBS-induced EVs induced immune tolerance. In addition, LPS-induced EVs enhanced the production of Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) by lung dendritic cells. Moreover, the immune responses induced by the LPS-induced EVs were blocked by denaturation of the EV-bearing proteins. These data suggest that EVs (especially, the protein components) secreted by LPS inhalation are a key intercellular communicator in the development of airway immune dysfunction to inhaled LPS-containing allergens.

Extracellular vesicles are key intercellular mediators in the development of immune dysfunction to allergens in the airways

PubMed Central

Shin, T-S; Kim, J H; Kim, Y-S; Jeon, S G; Zhu, Z; Gho, Y S; Kim, Y-K

2010-01-01

Background Previous evidence indicates that inhalation of lipopolysaccharide (LPS)-containing with allergens induced mixed Th1 and Th17 cell responses in the airways. Extracellular vesicles (EVs) are nanometer-sized spherical, lipid-bilayered structures and are recently in the public eye as an intercellular communicator in immune responses. Objective To evaluate the role of EVs secreted by LPS inhalation in the development of airway immune dysfunction in response to allergens. Methods Extracellular vesicles in bronchoalveolar lavage fluids of BALB/c mice were isolated and characterized 24 h after applications to the airway of 10 μg of LPS for 3 days. To evaluate the role of LPS-induced EVs on the development of airway immune dysfunction, in vivo and in vitro experiments were performed using the isolated LPS-induced EVs. Results The inhalation of LPS enhanced EVs release into the BAL fluid, when compared to the application of PBS. Airway sensitization with allergens and LPS-induced EVs resulted in a mixed Th1 and Th17 cell responses, although that with allergens and PBS-induced EVs induced immune tolerance. In addition, LPS-induced EVs enhanced the production of Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) by lung dendritic cells. Moreover, the immune responses induced by the LPS-induced EVs were blocked by denaturation of the EV-bearing proteins. Conclusion These data suggest that EVs (especially, the protein components) secreted by LPS inhalation are a key intercellular communicator in the development of airway immune dysfunction to inhaled LPS-containing allergens. PMID:20337607

Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes

PubMed Central

Tang, Chun-Lian; Liu, Zhi-Ming; Gao, Yan Ru; Xiong, Fei

2018-01-01

Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed—Schistosoma infection and Schistosoma-derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma-derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D. PMID:29387059

Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes.

PubMed

Tang, Chun-Lian; Liu, Zhi-Ming; Gao, Yan Ru; Xiong, Fei

2017-01-01

Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed- Schistosoma infection and Schistosoma -derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma -derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D.

Immune Checkpoints in Leprosy: Immunotherapy As a Feasible Approach to Control Disease Progression.

PubMed

Lima, Hayana Ramos; Gasparoto, Thaís Helena; de Souza Malaspina, Tatiana Salles; Marques, Vinícius Rizzo; Vicente, Marina Jurado; Marcos, Elaine Camarinha; Souza, Fabiana Corvolo; Nogueira, Maria Renata Sales; Barreto, Jaison Antônio; Garlet, Gustavo Pompermaier; da Silva, João Santana; Brito-de-Souza, Vânia Nieto; Campanelli, Ana Paula

2017-01-01

Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae . Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae , are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.

Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences.

PubMed

Roved, Jacob; Westerdahl, Helena; Hasselquist, Dennis

2017-02-01

Males and females differ in both parasite load and the strength of immune responses and these effects have been verified in humans and other vertebrates. Sex hormones act as important modulators of immune responses; the male sex hormone testosterone is generally immunosuppressive while the female sex hormone estrogen tends to be immunoenhancing. Different sets of T-helper cells (Th) have important roles in adaptive immunity, e.g. Th1 cells trigger type 1 responses which are primarily cell-mediated, and Th2 cells trigger type 2 responses which are primarily humoral responses. In our review of the literature, we find that estrogen and progesterone enhance type 2 and suppress type 1 responses in females, whereas testosterone suppresses type 2 responses and shows an inconsistent pattern for type 1 responses in males. When we combine these patterns of generally immunosuppressive and immunoenhancing effects of the sex hormones, our results imply that the sex differences in immune responses should be particularly strong in immune functions associated with type 2 responses, and less pronounced with type 1 responses. In general the hormone-mediated sex differences in immune responses may lead to genetic sexual conflicts on immunity. Thus, we propose the novel hypothesis that sexually antagonistic selection may act on immune genes shared by the sexes, and that the strength of this sexually antagonistic selection should be stronger for type 2- as compared with type 1-associated immune genes. Finally, we put the consequences of sex hormone-induced effects on immune responses into behavioral and ecological contexts, considering social mating system, sexual selection, geographical distribution of hosts, and parasite abundance. Copyright © 2016 Elsevier Inc. All rights reserved.

Targeting allergen to FcgammaRI reveals a novel T(H)2 regulatory pathway linked to thymic stromal lymphopoietin receptor.

PubMed

Hulse, Kathryn E; Reefer, Amanda J; Engelhard, Victor H; Patrie, James T; Ziegler, Steven F; Chapman, Martin D; Woodfolk, Judith A

2010-01-01

The molecule H22-Fel d 1, which targets cat allergen to FcgammaRI on dendritic cells (DCs), has the potential to treat cat allergy because of its T-cell modulatory properties. We sought to investigate whether the T-cell response induced by H22-Fel d 1 is altered in the presence of the T(H)2-promoting cytokine thymic stromal lymphopoietin (TSLP). Studies were performed in subjects with cat allergy with and without atopic dermatitis. Monocyte-derived DCs were primed with H22-Fel d 1 in the presence or absence of TSLP, and the resulting T-cell cytokine repertoire was analyzed by flow cytometry. The capacity for H22-Fel d 1 to modulate TSLP receptor expression on DCs was examined by flow cytometry in the presence or absence of inhibitors of Fc receptor signaling molecules. Surprisingly, TSLP alone was a weak inducer of T(H)2 responses irrespective of atopic status; however, DCs coprimed with TSLP and H22-Fel d 1 selectively and synergistically amplified T(H)2 responses in highly atopic subjects. This effect was OX40 ligand independent, pointing to an unconventional TSLP-mediated pathway. Expression of TSLP receptor was upregulated on atopic DCs primed with H22-Fel d 1 through a pathway regulated by FcgammaRI-associated signaling components, including src-related tyrosine kinases and Syk, as well as the downstream molecule phosphoinositide 3-kinase. Inhibition of TSLP receptor upregulation triggered by H22-Fel d 1 blocked TSLP-mediated T(H)2 responses. Discovery of a novel T(H)2 regulatory pathway linking FcgammaRI signaling to TSLP receptor upregulation and consequent TSLP-mediated effects questions the validity of receptor-targeted allergen vaccines. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Changes in immunological profile as a function of urbanization and lifestyle

PubMed Central

Mbow, Moustapha; de Jong, Sanne E; Meurs, Lynn; Mboup, Souleymane; Dieye, Tandakha Ndiaye; Polman, Katja; Yazdanbakhsh, Maria

2014-01-01

Differences in lifestyle and break with natural environment appear to be associated with changes in the immune system resulting in various adverse health effects. Although genetics can have a major impact on the immune system and disease susceptibility, the contribution of environmental factors is thought to be substantial. Here, we investigated the immunological profile of healthy volunteers living in a rural and an urban area of a developing African country (Senegal), and in a European country (the Netherlands). Using flow cytometry, we investigated T helper type 1 (Th1), Th2, Th17, Th22 and regulatory T cells, as well as CD4+ T-cell and B-cell activation markers, and subsets of memory T and B cells in the peripheral blood. Rural Senegalese had significantly higher frequencies of Th1, Th2 and Th22 cells, memory CD4+ T and B cells, as well as activated CD4+ T and B cells compared with urban Senegalese and urban Dutch people. Within the Senegalese population, rural paritcipants displayed significantly higher frequencies of Th2 and Th22 cells, as well as higher pro-inflammatory and T-cell activation and memory profiles compared with the urban population. The greater magnitude of immune activation and the enlarged memory pool, together with Th2 polarization, seen in rural participants from Africa, followed by urban Africans and Europeans suggest that environmental changes may define immunological footprints, which could have consequences for disease patterns in general and vaccine responses in particular. PMID:24924958

Polarization of T-helper lymphocytes toward the Th2 phenotype in uremic patients.

PubMed

Libetta, C; Rampino, T; Dal Canton, A

2001-08-01

T-helper (Th) lymphocytes consist of Th1 and Th2 subsets. Th1 cells are effectors of cell-mediated immunity and secrete interferon-gamma (IFN-gamma), which recruits new Th1 cells in cooperation with interleukin-12 (IL-12; produced by monocytes) and inhibits Th2 differentiation. Th2 cells produce IL-4 and IL-10, which inhibit IFN-gamma secretion and cell immunity. We investigated whether the impaired immune response in uremia is associated with an altered balance of Th1/Th2. Peripheral-blood mononuclear cells (PBMCs) were collected from patients with chronic renal failure (CRF) on conservative treatment (CRF patients), patients with end-stage renal disease (ESRD) on regular hemodialysis therapy (ESRD-HD patients), and healthy controls (CON). CD4(+) cells were isolated from PBMCs by negative selection using a magnetic labeling system. PBMCs and purified CD4(+) cells were cultured in Iscove's medium and Iscove's medium plus mitogens (phytohemagglutinin and lipopolysaccharide). IFN-gamma, IL-12, IL-4, and IL-10 were measured in supernatant. The constitutive release of IL-4 and IL-10 by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was increased by five to eight times in comparison with CON (P < 0.001). Constitutive IFN-gamma release by PBMCs of ESRD-HD patients was undetectable, although they secreted an increased amount of IL-12. Mitogen-stimulated release of IFN-gamma by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was blunted (average PBMCs: CON, 115.8 pg/2 x10(6) cells; CRF, 81.8 pg/2 x10(6) cells; ESRD-HD, 9.3 pg/2 x10(6) cells; CD4(+) cells: CON, 358.0 pg/5 x 10(5) cells; CRF, 165.4 pg/5 x 10(5) cells; ESRD-HD, 43.5 pg/5 x 10(5) cells). The ability of PBMCs of ESRD-HD patients to secrete IFN-gamma was recovered after IL-4 and IL-10 neutralization. Uremia is associated with a prevalence of Th1 over Th2 cells and a configuration of cytokine network that depresses cell-mediated immunity.

Asymptomatic Borrelia-seropositive individuals display the same incidence of Borrelia-specific interferon-gamma (IFN-γ)-secreting cells in blood as patients with clinical Borrelia infection

PubMed Central

Ekerfelt, C; Forsberg, P; Svenvik, M; Roberg, M; Bergström, S; Ernerudh, J

1999-01-01

Lyme disease is a complex disorder that sometimes becomes chronic. There are contradictory reports of experimental Borrelia infections regarding which type of T cell cytokine responses, i.e. Th1 or Th2, are needed to eradicate the Borrelia spirochaetes. In human borreliosis a predominance of Borrelia-specific Th1-like responses has been shown. In this study, spontaneous, as well as Borrelia-specific, secretion of IFN-γ (Th1) and IL-4 (Th2) in Borrelia-seropositive healthy asymptomatic individuals (n = 17) was investigated in peripheral blood by a sensitive ELISPOT assay, and compared with previously reported responses in patients with clinical Borrelia infection (n = 25). The seropositive asymptomatic individuals displayed the same predominance of Borrelia-specific IFN-γ-secreting cells as the patients with clinical Borrelia infection. Interestingly, the proportion of spontaneously IL-4-secreting cells, reflecting the unstimulated in vivo secretion, was lower in the seropositive asymptomatic individuals compared with patients with chronic Borrelia infections (n = 13, P = 0.02), whereas no such difference was found compared with subacute Borrelia infections (n = 12). These findings indicate that IFN-γ secretion alone is not sufficient to eliminate Borrelia spirochaetes in humans, although IFN-γ may still have a beneficial role in borreliosis acting in concert with other mechanisms. PMID:10193424

Age-related T cell responses to allergens in childhood.

PubMed

Smart, J M; Suphioglu, C; Kemp, A S

2003-03-01

T cell priming, as determined by allergen-induced proliferative responses, is believed to occur principally in early childhood in both atopic and non-atopic infants under the influence of multiple factors including environmental allergen exposure. It is considered that T cell priming with expansion of Th2 cells is a crucial factor in the development of atopic disease. To examine T cell priming to commonly encountered allergens in childhood in relation to age. In a cross-sectional study T cell proliferation in relation to age was examined for three common allergens, ovalbumin (OVA), house dust mite (HDM) and rye grass pollen (RYE), in atopic and non-atopic children. The effect of age on Th1 (IFN-gamma) and Th2 (IL-5 and IL-13) cytokine production in response to these allergens was investigated to examine the possibility of immune deviation with time. A significant increase in T cell proliferation with age was observed with RYE among atopic children only. However, the same was not observed with the two other allergens studied (i.e. OVA and HDM). In addition, RYE-induced (but not HDM or OVA) cytokine production showed an increased Th2 deviation with age as reflected in the increasing IL-5/IFN-gamma and IL-13/IFN-gamma ratios only among the atopic subjects with rye grass pollen sensitivity. These findings suggest that grass pollen sensitivity in childhood is accompanied by a progressive accumulation of allergen-primed T cells and progressive deviation of the allergen-induced cytokine response towards a Th2 response in atopic subjects throughout childhood.

Profiling MHC II immunopeptidome of blood-stage malaria reveals that cDC1 control the functionality of parasite-specific CD4 T cells.

PubMed

Draheim, Marion; Wlodarczyk, Myriam F; Crozat, Karine; Saliou, Jean-Michel; Alayi, Tchilabalo Dilezitoko; Tomavo, Stanislas; Hassan, Ali; Salvioni, Anna; Demarta-Gatsi, Claudia; Sidney, John; Sette, Alessandro; Dalod, Marc; Berry, Antoine; Silvie, Olivier; Blanchard, Nicolas

2017-11-01

In malaria, CD4 Th1 and T follicular helper (T FH ) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T-cell subsets are critical to hamper pathology. Yet the antigen-presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood-stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently whether blood stage is preceded or not by liver stage, but the same ETRAMP-specific dominant response develops in both contexts. In naïve mice and at the onset of cerebral malaria, CD8α + dendritic cells (cDC1) are superior to other DC subsets for MHC II presentation of the ETRAMP epitope. Using in vivo depletion of cDC1, we show that cDC1 promote parasite-specific Th1 cells and inhibit the development of IL-10 + CD4 T cells. This work profiles the P. berghei blood-stage MHC II immunopeptidome, highlights the potency of cDC1 to present malaria antigens on MHC II, and reveals a major role for cDC1 in regulating malaria-specific CD4 T-cell responses. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

The Translational Repressor T-cell Intracellular Antigen-1 (TIA-1) is a Key Modulator of Th2 and Th17 Responses Driving Pulmonary Inflammation Induced by Exposure to House Dust Mite

PubMed Central

Simarro, Maria; Giannattasio, Giorgio; Xing, Wei; Lundequist, Emma-Maria; Stewart, Samantha; Stevens, Richard L.; Orduña, Antonio; Boyce, Joshua A.; Anderson, Paul J.

2012-01-01

T-cell Intracellular Antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1−/−) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates. Tia-1−/− mice also had higher levels of Df-specific IgE and IgG1 in serum and ex vivo restimulated Tia-1−/− lymph node cells and splenocytes transcribed and released more Th2/Th17 cytokines. To evaluate the site of action of TIA-1, we studied the response to Df in bone marrow chimeras. These experiments revealed that TIA-1 acts on both hematopoietic and non-hematopoietic cells to dampen pulmonary inflammation. Our results identify TIA-1 as a negative regulator of allergen-mediated pulmonary inflammation in vivo. Thus, TIA-1 might be an important player in the pathogenesis of bronchial asthma. PMID:22525013

The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of Th2 and Th17 responses driving pulmonary inflammation induced by exposure to house dust mite.

PubMed

Simarro, Maria; Giannattasio, Giorgio; Xing, Wei; Lundequist, Emma-Maria; Stewart, Samantha; Stevens, Richard L; Orduña, Antonio; Boyce, Joshua A; Anderson, Paul J

2012-08-30

T-cell intracellular antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1(-/-)) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates. Tia-1(-/-) mice also had higher levels of Df-specific IgE and IgG(1) in serum and ex vivo restimulated Tia-1(-/-) lymph node cells and splenocytes transcribed and released more Th2/Th17 cytokines. To evaluate the site of action of TIA-1, we studied the response to Df in bone marrow chimeras. These experiments revealed that TIA-1 acts on both hematopoietic and non-hematopoietic cells to dampen pulmonary inflammation. Our results identify TIA-1 as a negative regulator of allergen-mediated pulmonary inflammation in vivo. Thus, TIA-1 might be an important player in the pathogenesis of bronchial asthma. Copyright © 2012 Elsevier B.V. All rights reserved.

The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.

PubMed

Claudio, Estefania; Sønder, Søren Ulrik; Saret, Sun; Carvalho, Gabrielle; Ramalingam, Thirumalai R; Wynn, Thomas A; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Chen, Amy; Ren, Nina Y; Wang, Hongshan; Siebenlist, Ulrich

2009-02-01

IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c(+) macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.

Hemin controls T cell polarization in sickle cell alloimmunization.

PubMed

Zhong, Hui; Bao, Weili; Friedman, David; Yazdanbakhsh, Karina

2014-07-01

Patients with sickle cell disease (SCD) often require transfusions to treat and prevent worsening anemia and other SCD complications. However, transfusions can trigger alloimmunization against transfused RBCs with serious clinical sequelae. Risk factors for alloimmunization in SCD remain poorly understood. We recently reported altered regulatory T cell (Treg) and Th responses with higher circulating Th1 (IFN-γ(+)) cytokines in chronically transfused SCD patients with alloantibodies as compared with those without alloantibodies. Because monocytes play a critical role in polarization of T cell subsets and participate in clearance of transfused RBCs, we tested the hypothesis that in response to the RBC breakdown product hemin, monocyte control of T cell polarization will differ between alloimmunized and non-alloimmunized SCD patients. Exogenous hemin induced Treg polarization in purified T cell/monocyte cocultures from healthy volunteers through the monocyte anti-inflammatory heme-degrading enzyme heme oxygenase-1. Importantly, hemin primarily through its effect on CD16+ monocytes induced an anti-inflammatory (higher Treg/lower Th1) polarization state in the non-alloimmunized SCD group, whereas it had little effect in the alloimmunized group. Non-alloimmunized SCD CD16+ monocytes expressed higher basal levels of heme oxygenase-1. Furthermore, IL-12, which contributed to a proinflammatory polarization state (low Treg/high Th1) in SCD, was dampened in hemin-treated stimulated monocytes from non-alloimmunized SCD patients, but not in the alloimmunized group. These data suggest that unlike alloimmunized patients, non-alloimmunized SCD CD16+ monocytes in response to transfused RBC breakdown products promote an anti-inflammatory state that is less conducive to alloimmunization. Copyright © 2014 by The American Association of Immunologists, Inc.

Acinetobacter baumannii Infection Inhibits Airway Eosinophilia and Lung Pathology in a Mouse Model of Allergic Asthma

PubMed Central

Qiu, Hongyu; KuoLee, Rhonda; Harris, Greg; Zhou, Hongyan; Miller, Harvey; Patel, Girishchandra B.; Chen, Wangxue

2011-01-01

Allergic asthma is a dysregulation of the immune system which leads to the development of Th2 responses to innocuous antigens (allergens). Some infections and microbial components can re-direct the immune response toward the Th1 response, or induce regulatory T cells to suppress the Th2 response, thereby inhibiting the development of allergic asthma. Since Acinetobacter baumannii infection can modulate lung cellular and cytokine responses, we studied the effect of A. baumannii in modulating airway eosinophilia in a mouse model of allergic asthma. Ovalbumin (OVA)-sensitized mice were treated with live A. baumannii or phosphate buffered saline (PBS), then intranasally challenged with OVA. Compared to PBS, A. baumannii treatment significantly reduced pulmonary Th2 cytokine and chemokine responses to OVA challenge. More importantly, the airway inflammation in A. baumannii-treated mice was strongly suppressed, as seen by the significant reduction of the proportion and the total number of eosinophils in the bronchoalveolar lavage fluid. In addition, A. baumannii-treated mice diminished lung mucus overproduction and pathology. However, A. baumannii treatment did not significantly alter systemic immune responses to OVA. Serum OVA-specific IgE, IgG1 and IgG2a levels were comparable between A. baumannii- and PBS-treated mice, and tracheobronchial lymph node cells from both treatment groups produced similar levels of Th1 and Th2 cytokines in response to in vitro OVA stimulation. Moreover, it appears that TLR-4 and IFN-γ were not directly involved in the A. baumannii-induced suppression of airway eosinophilia. Our results suggest that A. baumannii inhibits allergic airway inflammation by direct suppression of local pulmonary Th2 cytokine responses to the allergen. PMID:21789200

Deoxynivalenol as a New Factor in the Persistence of Intestinal Inflammatory Diseases: An Emerging Hypothesis through Possible Modulation of Th17-Mediated Response

PubMed Central

Meurens, François; Cognie, Juliette; Abrami, Roberta; Oswald, Isabelle P.; Guzylack-Piriou, Laurence

2013-01-01

Background/Aims Deoxynivalenol (DON) is a mycotoxin produced by Fusarium species which is commonly found in temperate regions worldwide as a natural contaminant of cereals. It is of great concern not only in terms of economic losses but also in terms of animal and public health. The digestive tract is the first and main target of this food contaminant and it represents a major site of immune tolerance. A finely tuned cross-talk between the innate and the adaptive immune systems ensures the homeostatic equilibrium between the mucosal immune system and commensal microorganisms. The aim of this study was to analyze the impact of DON on the intestinal immune response. Methodology Non-transformed intestinal porcine epithelial cells IPEC-1 and porcine jejunal explants were used to investigate the effect of DON on the intestinal immune response and the modulation of naive T cells differentiation. Transcriptomic proteomic and flow cytometry analysis were performed. Results DON induced a pro-inflammatory response with a significant increase of expression of mRNA encoding for IL-8, IL-1α and IL-1β, TNF-α in all used models. Additionally, DON significantly induced the expression of genes involved in the differentiation of Th17 cells (STAT3, IL–17A, IL-6, IL-1β) at the expenses of the pathway of regulatory T cells (Treg) (FoxP3, RALDH1). DON also induced genes related to the pathogenic Th17 cells subset such as IL–23A, IL-22 and IL-21 and not genes related to the regulatory Th17 cells (rTh17) such as TGF-β and IL-10. Conclusion DON triggered multiple immune modulatory effects which could be associated with an increased susceptibility to intestinal inflammatory diseases. PMID:23326479

Single-Cell RNA Sequencing Reveals T Helper Cells Synthesizing Steroids De Novo to Contribute to Immune Homeostasis

PubMed Central

Mahata, Bidesh; Zhang, Xiuwei; Kolodziejczyk, Aleksandra A.; Proserpio, Valentina; Haim-Vilmovsky, Liora; Taylor, Angela E.; Hebenstreit, Daniel; Dingler, Felix A.; Moignard, Victoria; Göttgens, Berthold; Arlt, Wiebke; McKenzie, Andrew N.J.; Teichmann, Sarah A.

2014-01-01

Summary T helper 2 (Th2) cells regulate helminth infections, allergic disorders, tumor immunity, and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2 signaling molecules. Although steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterized. Here, we demonstrate production of the steroid pregnenolone by Th2 cells in vitro and in vivo in a helminth infection model. Single-cell RNA sequencing and quantitative PCR analysis suggest that pregnenolone synthesis in Th2 cells is related to immunosuppression. In support of this, we show that pregnenolone inhibits Th cell proliferation and B cell immunoglobulin class switching. We also show that steroidogenic Th2 cells inhibit Th cell proliferation in a Cyp11a1 enzyme-dependent manner. We propose pregnenolone as a “lymphosteroid,” a steroid produced by lymphocytes. We speculate that this de novo steroid production may be an intrinsic phenomenon of Th2-mediated immune responses to actively restore immune homeostasis. PMID:24813893

Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101.

PubMed

Sredni, B; Tichler, T; Shani, A; Catane, R; Kaufman, B; Strassmann, G; Albeck, M; Kalechman, Y

1996-09-18

Several studies have recently suggested that the immune response to malignant growths is regulated by distinct patterns of type 2 cytokine production. These cytokines, regulating the cytotoxic T-lymphocyte response in patients with advanced cancers, may be associated with disease progression. Evidence suggests that the T Helper 1 (TH1) and T Helper 2 (TH2) types of reaction are reciprocally regulated in vivo. The immunomodulator AS101 (ammonium trichloro[dioxoethylene-O,O']tellurate) was found to stimulate mouse and human cells to proliferate and secrete a variety of cytokines. Clinical trials using AS101 on cancer patients are now in progress. The aim of this study was to evaluate the ability of AS101 to modulate TH1 and TH2 responses in tumor-bearing mice and in patients with advanced cancer. In addition, we investigated the association between the predominance of each type of response with the antitumoral effects of AS101. Mice into which Lewis lung carcinoma (3LL) had been transplanted (n = 221) and cancer patients (n = 13) were treated with AS101 on alternate days, at 10 micrograms/mouse intraperitoneally, or for the patients, at 3 mg/m2 intravenously. The types were sarcoma, melanoma, and colon, lung, ovarian, and renal cancers. Cytokine levels were determined by immunoassay kits and compared with the paired Student's t test: in mice, they were tested in spleen cell supernatants; in humans, in sera and mononuclear cell supernatants. The chi-squared test was used to compare tumor volumes. All P values represent two-sided tests of statistical significance. Our results show that treatment of mice and patients with AS101 results in a clear predominance in TH1 responses, with a concomitant decrease in the TH2-type response. This was reflected by a significant enhancement in interleukin 2 (IL-2) and interferon gamma (IFN gamma) levels (P < .01) paralleled by a substantial decrease in IL-4 and IL-10 (P < .01). Moreover, the concentration of IL-12 was significantly increased (P < .01) in AS101-treated patients who also showed enhanced levels of natural and lymphokine-activated killer cell-mediated cytotoxicity. The statistically significant increases in IL-2 and IFN gamma levels, paralleled by the pronounced decrease in IL-4 and IL-10 in the AS101-treated mice, were associated with its antitumoral effects. In addition, systemic cotreatment of 3LL-transplanted mice with AS101 and anti-IL-12 antibodies partly abrogated the antitumoral effect of AS101. Immunotherapy with AS101 enhances TH1 function while interfering with the TH2 response. This TH1 trend may be related to the antitumor effects of AS101. Isolation and characterization of a distinct cytokine pattern in patients with advanced cancer treated with AS101 may contribute to the development of intervention strategies using this compound.

The immune response induced by DNA vaccine expressing nfa1 gene against Naegleria fowleri.

PubMed

Kim, Jong-Hyun; Lee, Sang-Hee; Sohn, Hae-Jin; Lee, Jinyoung; Chwae, Yong-Joon; Park, Sun; Kim, Kyongmin; Shin, Ho-Joon

2012-12-01

The pathogenic free-living amoeba, Naegleria fowleri, causes fatal primary amoebic meningoencephalitis in experimental animals and in humans. The nfa1 gene that was cloned from N. fowleri is located on pseudopodia, especially amoebic food cups and plays an important role in the pathogenesis of N. fowleri. In this study, we constructed and characterized retroviral vector and lentiviral vector systems for nfa1 DNA vaccination in mice. We constructed the retroviral vector (pQCXIN) and the lentiviral vector (pCDH) cloned with the egfp-nfa1 gene. The expression of nfa1 gene in Chinese hamster ovary cell and human primary nasal epithelial cell transfected with the pQCXIN/egfp-nfa1 vector or pCDH/egfp-nfa1 vector was observed by fluorescent microscopy and Western blotting analysis. Our viral vector systems effectively delivered the nfa1 gene to the target cells and expressed the Nfa1 protein within the target cells. To evaluate immune responses of nfa1-vaccinated mice, BALB/c mice were intranasally vaccinated with viral particles of each retro- or lentiviral vector expressing nfa1 gene. DNA vaccination using viral vectors expressing nfa1 significantly stimulated the production of Nfa1-specific IgG subclass, as well as IgG levels. In particular, both levels of IgG2a (Th1) and IgG1 (Th2) were significantly increased in mice vaccinated with viral vectors. These results show the nfa1-vaccination induce efficiently Th1 type, as well as Th2 type immune responses. This is the first report to construct viral vector systems and to evaluate immune responses as DNA vaccination in N. fowleri infection. Furthermore, these results suggest that nfal vaccination may be an effective method for treatment of N. fowleri infection.

A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.

PubMed

Chen, Q; Muramoto, K; Masaaki, N; Ding, Y; Yang, H; Mackey, M; Li, W; Inoue, Y; Ackermann, K; Shirota, H; Matsumoto, I; Spyvee, M; Schiller, S; Sumida, T; Gusovsky, F; Lamphier, M

2010-05-01

Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

The Interactive Roles of Lipopolysaccharides and dsRNA/Viruses on Respiratory Epithelial Cells and Dendritic Cells in Allergic Respiratory Disorders: The Hygiene Hypothesis.

PubMed

Lin, Tsang-Hsiung; Su, Hsing-Hao; Kang, Hong-Yo; Chang, Tsung-Hsien

2017-10-23

The original hygiene hypothesis declares "more infections in early childhood protect against later atopy". According to the hygiene hypothesis, the increased incidence of allergic disorders in developed countries is explained by the decrease of infections. Epithelial cells and dendritic cells play key roles in bridging the innate and adaptive immune systems. Among the various pattern-recognition receptor systems of epithelial cells and dendritic cells, including toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and others, TLRs are the key systems of immune response regulation. In humans, TLRs consist of TLR1 to TLR10. They regulate cellular responses through engagement with TLR ligands, e.g., lipopolysaccharides (LPS) acts through TLR4 and dsRNA acts through TLR3, but there are certain common components between these two TLR pathways. dsRNA activates epithelial cells and dendritic cells in different directions, resulting in allergy-related Th2-skewing tendency in epithelial cells, and Th1-skewing tendency in dendritic cells. The Th2-skewing effect by stimulation of dsRNA on epithelial cells could be suppressed by the presence of LPS above some threshold. When LPS level decreases, the Th2-skewing effect increases. It may be via these interrelated networks and related factors that LPS modifies the allergic responses and provides a plausible mechanism of the hygiene hypothesis. Several hygiene hypothesis-related phenomena, seemingly conflicting, are also discussed in this review, along with their proposed mechanisms.

The Role of Th1/Th2 Cytokine Balance in Gulf War-Related Illness

DTIC Science & Technology

2001-02-01

Ramirez et al, 1996). Finally, although natural infection with Bordetella pertussis and its whole cell-derived vaccine promote a strong Thl response...the stress of deployment with additional effects of the T helper 2 (Th2) adjuvant pertussis could skew the immune response towards a Th2 profile. The...paradoxically the acellular vaccine component pertussis toxin used as adjuvant in GW vaccinations causes Th2 deviation (Munoz et al, 1990; Mu et al, 1993

A role for B cells in the development of T cell helper function in a malaria infection in mice

PubMed Central

Langhorne, Jean; Cross, Caroline; Seixas, Elsa; Li, Ching; von der Weid, Thierry

1998-01-01

B cell knockout mice are unable to clear a primary erythrocytic infection of Plasmodium chabaudi chabaudi. However, the early acute infection is controlled to some extent, giving rise to a chronic relapsing parasitemia that can be reduced either by drug treatment or by adoptive transfer of B cells. Similar to mice rendered B-cell deficient by lifelong treatment with anti-μ antibodies, B cell knockout mice (μMT) retain a predominant CD4+ Th1-like response to malarial antigens throughout a primary infection. This contrasts with the response seen in control C57BL/6 mice in which the CD4+ T-cell response has switched to that characteristic of Th2 cells at the later stages of infection, manifesting efficient help for specific antibodies in vitro and interleukin 4 production. Both chloroquine and adoptive transfer of immune B cells reduced parasite load. However, the adoptive transfer of B cells resulted in a Th2 response in recipient μMT mice, as indicated by a relative increase in the precursor frequency of helper cells for antibody production. These data support the idea that B cells play a role in the regulation of CD4+ T subset responses. PMID:9465085

Myocardial Gene Expression of T-bet, GATA-3, Ror-γt, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

PubMed Central

Nogueira, Luciana Gabriel; Santos, Ronaldo Honorato Barros; Fiorelli, Alfredo Inácio; Mairena, Eliane Conti; Benvenuti, Luiz Alberto; Bocchi, Edimar Alcides; Stolf, Noedir Antonio; Kalil, Jorge; Cunha-Neto, Edecio

2014-01-01

Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg) in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by TH2 cells (IL-4, IL-5, and IL-13) or associated with Treg (TGF-β and IL-10) were not upregulated in CCC myocardium. Expression of TH1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local TH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation. PMID:25152568

Fecal bacteria from treatment-naive Crohn's disease patients can skew helper T cell responses.

PubMed

Ma, Fei; Zhang, Yi; Xing, Junjie; Song, Xiaoling; Huang, Ling; Weng, Hao; Wu, Xiangsong; Walker, Emma; Wang, Zhongchuan

2017-12-01

Many studies have demonstrated that the inflamed mucosa of Crohn's disease (CD) patients presented a disturbed gut commensal community, and the shift in microbial composition and species variety is associated with disease severity. To establish a link between changes in the intestinal bacterial composition and the alteration of inflammation, we obtained fecal bacteria from CD patients and non-CD controls. The bacteria were then used to stimulate the peripheral blood mononuclear cells (PBMCs) from one non-CD individual. We found that the frequency of IFN-γ- and IL-17-expressing CD4 T cells was significantly higher after stimulation with CD bacteria than with non-CD bacteria, while the frequency of IL-4- and IL-10-expressing CD4 T cells was significantly decreased after stimulation with CD bacteria. A similar trend was observed in the level of cytokine expression and transcription expression. However, this difference was not clear-cut, as overlapping regions were observed between the two groups. With longer stimulation using CD bacteria, the skewing toward Th1/Th17 responses were further increased. This increase depended on the presence of monocytes/macrophages. Interestingly, we also found that B cells presented an inhibitory effect in CD bacteria-mediated skewing toward Th1/Th17 cells and promoted IL-10 secretion in CD bacteria-stimulated PBMCs. Together, our results demonstrated that CD bacteria could promote Th1/Th17 inflammation in a host factor-independent fashion. Copyright © 2017 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morita, Daisuke; Miyamoto, Ayumi; Hattori, Yuki

Highlights: •Glucose monomycolate (GMM) is a marker glycolipid for active tuberculosis. •Tissue responses to GMM involved up-regulation of Th1-attracting chemokines. •Th1-skewed local responses were mounted at the GMM-injected tissue. -- Abstract: Trehalose 6,6′-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cellmore » responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette–Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.« less

The in Vitro Inhibitory Effect of Ectromelia Virus Infection on Innate and Adaptive Immune Properties of GM-CSF-Derived Bone Marrow Cells Is Mouse Strain-Independent.

PubMed

Szulc-Dąbrowska, Lidia; Struzik, Justyna; Cymerys, Joanna; Winnicka, Anna; Nowak, Zuzanna; Toka, Felix N; Gieryńska, Małgorzata

2017-01-01

Ectromelia virus (ECTV) belongs to the Orthopoxvirus genus of the Poxviridae family and is a natural pathogen of mice. Certain strains of mice are highly susceptible to ECTV infection and develop mousepox, a lethal disease similar to smallpox of humans caused by variola virus. Currently, the mousepox model is one of the available small animal models for investigating pathogenesis of generalized viral infections. Resistance and susceptibility to ECTV infection in mice are controlled by many genetic factors and are associated with multiple mechanisms of immune response, including preferential polarization of T helper (Th) immune response toward Th1 (protective) or Th2 (non-protective) profile. We hypothesized that viral-induced inhibitory effects on immune properties of conventional dendritic cells (cDCs) are more pronounced in ECTV-susceptible than in resistant mouse strains. To this extent, we confronted the cDCs from resistant (C57BL/6) and susceptible (BALB/c) mice with ECTV, regarding their reactivity and potential to drive T cell responses following infection. Our results showed that in vitro infection of granulocyte-macrophage colony-stimulating factor-derived bone marrow cells (GM-BM-comprised of cDCs and macrophages) from C57BL/6 and BALB/c mice similarly down-regulated multiple genes engaged in DC innate and adaptive immune functions, including antigen uptake, processing and presentation, chemokines and cytokines synthesis, and signal transduction. On the contrary, ECTV infection up-regulated Il10 in GM-BM derived from both strains of mice. Moreover, ECTV similarly inhibited surface expression of major histocompatibility complex and costimulatory molecules on GM-BM, explaining the inability of the cells to attain full maturation after Toll-like receptor (TLR)4 agonist treatment. Additionally, cells from both strains of mice failed to produce cytokines and chemokines engaged in T cell priming and Th1/Th2 polarization after TLR4 stimulation. These data strongly suggest that in vitro modulation of GM-BM innate and adaptive immune functions by ECTV occurs irrespective of whether the mouse strain is susceptible or resistant to infection. Moreover, ECTV limits the GM-BM (including cDCs) capacity to stimulate protective Th1 immune response. We cannot exclude that this may be an important factor in the generation of non-protective Th2 immune response in susceptible BALB/c mice in vivo .

Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections

PubMed Central

Conti, Heather R.; Peterson, Alanna C.; Brane, Lucas; Huppler, Anna R.; Hernández-Santos, Nydiaris; Whibley, Natasha; Garg, Abhishek V.; Simpson-Abelson, Michelle R.; Gibson, Gregory A.; Mamo, Anna J.; Osborne, Lisa C.; Bishu, Shrinivas; Ghilardi, Nico; Siebenlist, Ulrich; Watkins, Simon C.; Artis, David; McGeachy, Mandy J.

2014-01-01

Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα−/−, and Rag1−/− mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1–2 d by tongue-resident populations of γδ T cells and CD3+CD4+CD44hiTCRβ+CCR6+ natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-β−/− and TCR-δ−/− mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-β clonal diversity, and was absent in Rag1−/−, IL-7Rα−/−, and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens. PMID:25200028

Cellular and Molecular Dynamics of Th17 Differentiation and its Developmental Plasticity in the Intestinal Immune Response

PubMed Central

Bhaumik, Suniti; Basu, Rajatava

2017-01-01

After emerging from the thymus, naive CD4 T cells circulate through secondary lymphoid tissues, including gut-associated lymphoid tissue of the intestine. The activation of naïve CD4 T cells by antigen-presenting cells offering cognate antigen initiate differentiation programs that lead to the development of highly specialized T helper (Th) cell lineages. Although initially believed that developmental programing of effector T cells such as T helper 1 (Th1) or T helper 2 (Th2) resulted in irreversible commitment to a fixed fate, subsequent studies have demonstrated greater flexibility, or plasticity, in effector T cell stability than originally conceived. This is particularly so for the Th17 subset, differentiation of which is a highly dynamic process with overlapping developmental axes with inducible regulatory T (iTreg), T helper 22 (Th22), and Th1 cells. Accordingly, intermediary stages of Th17 cells are found in various tissues, which co-express lineage-specific transcription factor(s) or cytokine(s) of developmentally related CD4 T cell subsets. A highly specialized tissue like that of the intestine, which harbors the largest immune compartment of the body, adds several layers of complexity to the intricate process of Th differentiation. Due to constant exposure to millions of commensal microbes and periodic exposure to pathogens, the intestinal mucosa maintains a delicate balance between regulatory and effector T cells. It is becoming increasingly clear that equilibrium between tolerogenic and inflammatory axes is maintained in the intestine by shuttling the flexible genetic programming of a developing CD4 T cell along the developmental axis of iTreg, Th17, Th22, and Th1 subsets. Currently, Th17 plasticity remains an unresolved concern in the field of clinical research as targeting Th17 cells to cure immune-mediated disease might also target its related subsets. In this review, we discuss the expanding sphere of Th17 plasticity through its shared developmental axes with related cellular subsets such as Th22, Th1, and iTreg in the context of intestinal inflammation and also examine the molecular and epigenetic features of Th17 cells that mediate these overlapping developmental programs. PMID:28408906

Immunostimulatory activities of dendritic cells loaded with adenovirus vector carrying HBcAg/HBsAg

PubMed Central

Jia, Hongyu; Li, Chunling; Zhang, Yimin; Yu, Liang; Xiang, Dairong; Liu, Jun; Chen, Fengzhe; Han, Xiaochun

2015-01-01

Objective: This study is to investigate the immunostimulatory activities of dendritic cells (DCs) transfected with HBcAg and/or HBsAg recombinant adenovirus (rAd). Methods: DCs were transfected with rAd (DC/Ad-C+Ad-S, DC/Ad-C, and DC/Ad-S), or pulsed with HBcAg antigen (DC/HBcAg). Flow cytometry was used to detect the phenotype of DCs and the cytokine production of T lymphocytes. Mice were vaccinated with DCs transfected with rAd or pulsed with antigen, and DNA vaccine. Mixed lymphocyte reaction (MLR) was used to evaluate the T-cell stimulatory capacity, and HBcAg-specific cytotoxic T lymphocyte (CTL) activity was assessed. Results: Phenotypic analysis showed that DCs transfected with rAd or pulsed with HBcAg antigen exhibited mature phenotypes. MLR indicated no significant differences in stimulating T-cell proliferation between the DC/rAd and DC/HBcAg groups. When mixed with DCs, Th and Tc cells mainly secreted IFN-γ, indicating type I immune responses. In vaccinated mice, DCs transduced with rAd and pulsed with HBcAg induced significantly more IFN-γ secretion from Th cells, compared with DNA vaccine, indicating stronger Th1 response. Moreover, DCs transduced with rAd stimulated Tc cells to produce more IFN-γ, indicating stronger Tc1 response. In vaccinated mice, HBcAg-specific CTL activities were decreased in the following order: the DC/Ad-C+Ad-S, DC/Ad-C, DC/Ad-S, DC/HBcAg, and DNA vaccine groups. Conclusion: DCs transfected with rAd induce stronger Th1/Tc1 (type I) cell immune responses and specific CTL response than HBcAg-pulsed DCs or DNA vaccine. Our findings suggest that DCs transfected with rAd-C/rAd-S might provide an effective approach in the treatment of persistent hepatitis B virus infection. PMID:26064236

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells.

PubMed

Cao, Qi; Wang, Li; Du, Fang; Sheng, Huiming; Zhang, Yan; Wu, Juanjuan; Shen, Baihua; Shen, Tianwei; Zhang, Jingwu; Li, Dangsheng; Li, Ningli

2007-07-01

Regulatory T cells (Treg) play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Th1 responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4+CD25+ T cells from the immunized mice. Moreover, CD4+CD25+Foxp3+ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naïve mice. Further analysis showed that the serum of immunized mice contains a high level of anti-CD25 antibody (about 30 ng/ml, p<0.01 vs controls). Consistent with a role of anti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naïve mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4+CD25+Foxp3+ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Th1 response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.

Follicular helper T cells in immunity and systemic autoimmunity.

PubMed

Craft, Joseph E

2012-05-01

Follicular helper T (T(FH)) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of T(FH) cells have been less clearly defined than classic CD4(+) effector T-cell subsets, including T-helper-1 (T(H)1), T(H)2 and T(H)17 cells. As such, our understanding of the genesis of T(FH) cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of T(FH)-cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of T(FH) cells as therapeutic targets in these diseases.

Mycobacterium bovis BCG mycobacteria--new application.

PubMed

Kowalewicz-Kulbat, Magdalena; Pestel, Joël; Biet, Franck; Locht, Camille; Tonnel, André-Bernard; Druszczyńska, Magdalena; Rudnicka, Wiesława

2006-01-01

The polarized response of T helper-2 (Th2) lymphocytes to an allergen is considered to be the main cause of the pathogenesis of asthma. In this study, we asked a question whether M. bovis BCG mycobacteria which are known for the preferential stimulation of T helper-1 (Th1) immunity, diminish the effector functions of Th2 cells from allergic patients upon stimulation with a common house dust mite Der p-1 allergen. Our results allow a positive answer to this question. We demonstrate that BCG modulates the dendritic cell-dependent allergen presentation process and switches naive T lymphocytes towards an anti-allergic Th1 profile.

Induction of multispecific Th-1 type immune response against HCV in mice by protein immunization using CpG and Montanide ISA 720 as adjuvants

PubMed Central

Qiu, Qi; Wang, Richard Yuan-Hu; Jiao, Xuanmao; Jin, Bo; Sugauchi, Fuminaka; Grandinetti, Teresa; Alter, Harvey J.; Shih, J. Wai-Kuo

2017-01-01

Recent studies demonstrate that Th1-type immune responses against a broad spectrum of hepatitis C virus (HCV) gene products are crucial to the resolution of acute HCV infection. We investigated new vaccine approaches to augment the strength of HCV-specific Th1-type immune responses. ELISPOT assay revealed that single or multiple protein immunization using both CpG ODN and Montanide ISA 720 as adjuvants induced much stronger IFN-γ-producing Th1 responses against core, NS3 and NS5b targets than did the formulation without these adjuvants. Protein vaccination using CpG ODN and Montanide ISA 720 as adjuvants also greatly enhanced humoral responses to HCV core, E1/E2 and NS3. When specific IgG isotypes were assayed, protein immunization using CpG ODN and Montanide ISA 720 as adjuvants produced higher titers of IgG2a dominant antibodies than did protein immunization alone, indicating a more Th1-biasedpathway. This increase in IgG2a is consistent with the induction of Th1 cells secreting IFN-γ demonstrated by ELISPOT assay. In conclusion, protein immunization using CpG ODN and Montanide ISA 720 as adjuvants greatly enhanced cellular (Th1 type) as well as humoral immune responses against HCV in Balb/c mice. The use of adjuvants appears critical to the induction of Th1 immune responses during HCV vaccination with recombinant proteins. PMID:18675871

Induction of multispecific Th-1 type immune response against HCV in mice by protein immunization using CpG and Montanide ISA 720 as adjuvants.

PubMed

Qiu, Qi; Wang, Richard Yuan-Hu; Jiao, Xuanmao; Jin, Bo; Sugauchi, Fuminaka; Grandinetti, Teresa; Alter, Harvey J; Shih, J Wai-Kuo

2008-10-09

Recent studies demonstrate that Th1-type immune responses against a broad spectrum of hepatitis C virus (HCV) gene products are crucial to the resolution of acute HCV infection. We investigated new vaccine approaches to augment the strength of HCV-specific Th1-type immune responses. ELISPOT assay revealed that single or multiple protein immunization using both CpG ODN and Montanide ISA 720 as adjuvants induced much stronger IFN-gamma-producing Th1 responses against core, NS3 and NS5b targets than did the formulation without these adjuvants. Protein vaccination using CpG ODN and Montanide ISA 720 as adjuvants also greatly enhanced humoral responses to HCV core, E1/E2 and NS3. When specific IgG isotypes were assayed, protein immunization using CpG ODN and Montanide ISA 720 as adjuvants produced higher titers of IgG2a dominant antibodies than did protein immunization alone, indicating a more Th1-biased pathway. This increase in IgG2a is consistent with the induction of Th1 cells secreting IFN-gamma demonstrated by ELISPOT assay. In conclusion, protein immunization using CpG ODN and Montanide ISA 720 as adjuvants greatly enhanced cellular (Th1 type) as well as humoral immune responses against HCV in Balb/c mice. The use of adjuvants appears critical to the induction of Th1 immune responses during HCV vaccination with recombinant proteins.

Bystanders not so innocent after all.

PubMed

Batten, Marcel; Ghilardi, Nico

2012-06-29

Interleukin 27 (IL-27) regulates immune responses, including T helper 17 (Th17) cell activity. In this issue of Immunity, Hirahara et al. (2012) demonstrate that IL-27 suppresses Th17 cells in trans through induction of the inhibitory ligand PD-L1 on bystander T cells. Copyright © 2012 Elsevier Inc. All rights reserved.

T Follicular Helper Cell Plasticity Shapes Pathogenic T Helper 2 Cell-Mediated Immunity to Inhaled House Dust Mite.

PubMed

Ballesteros-Tato, André; Randall, Troy D; Lund, Frances E; Spolski, Rosanne; Leonard, Warren J; León, Beatriz

2016-02-16

Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper 2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. We found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of interleukin-4 (IL-4)-committed T follicular helper (Tfh) cells. Following challenge exposure to HDM, Tfh cells differentiated into IL-4 and IL-13 double-producing Th2 cells that accumulated in the lung and recruited eosinophils. B cells were required to expand IL-4-committed Tfh cells during the sensitization phase, but did not directly contribute to disease. Impairment of Tfh cell responses during the sensitization phase or Tfh cell depletion prevented Th2 cell-mediated responses following challenge. Thus, our data demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma. Copyright © 2016 Elsevier Inc. All rights reserved.

ERK1 is important for Th2 differentiation and development of experimental asthma

PubMed Central

Goplen, Nicholas; Karim, Zunayet; Guo, Lei; Zhuang, Yonghua; Huang, Hua; Gorska, Magdalena M.; Gelfand, Erwin; Pagés, Gilles; Pouysségur, Jacques; Alam, Rafeul

2012-01-01

The ERK1/2 signaling pathway regulates a variety of T-cell functions. We observed dynamic changes in the expression of ERK1/2 during T-helper cell differentiation. Specifically, the expression of ERK1/2 was decreased and increased by IL-12 and IL-4, respectively. To address this subject further, we examined the specific role of ERK1 in Th2 differentiation and development of experimental asthma using ERK1−/− mice. ERK1−/− mice were unable to mount airway inflammation and hyperreactivity in two different models of asthma, acute and chronic. ERK1−/− mice had reduced expression of Th2 cytokines IL-4 and IL-5 but not IL-17A or IFN-γ. They had reduced levels of allergen-specific IgE and blood eosinophils. T cells from immunized ERK1−/− mice manifested reduced proliferation in response to the sensitizing allergen. ERK1−/− T cells had reduced and short-lived expression of JunB following TCR stimulation, which likely contributed to their impaired Th2 differentiation. Immunized ERK1−/− mice showed reduced numbers of CD44high CD4 T cells in the spleen. In vitro studies demonstrated that Th2 but not Th1 cells from ERK1−/− mice had reduced numbers of CD44high cells. Finally, CD4 T cells form ERK1−/− mice expressed higher levels of BIM under growth factor-deprived conditions and reduced Mcl-1 on stimulation. As a result, the survival of CD4 T cells, especially CD44high Th2 cells, was much reduced in ERK1−/− mice. We conclude that ERK1 plays a nonredundant role in Th2 differentiation and development of experimental asthma. ERK1 controls Th2 differentiation and survival through its effect on JunB and BIM, respectively.—Goplen, N., Karim, Z., Guo, L., Zhuang, Y., Huang, H., Gorska, M. M., Gelfand, E., Pagés, G., Pouysségur, J., Alam, R. ERK1 is important for Th2 differentiation and development of experimental asthma. PMID:22262639

Obaculactone suppresses Th1 effector cell function through down-regulation of T-bet and prolongs skin graft survival in mice.

PubMed

Gong, Fangyuan; Shen, Yan; Zhang, Qi; Sun, Yang; Tang, Jiayu; Tao, Feifei; Xu, Qiang

2010-07-15

Allograft rejection is a predominantly Th1 immune response. In this study, we showed that obaculactone, a natural compound derived from citrus fruit, prolonged skin graft survival in mice when treated after but not before transplantation. Furthermore, obaculactone inhibited alloantigen-specific production of Th1 cytokine IFN-gamma as well as proinflammatory cytokine IL-2, TNFalpha and IL-6. In parallel, IL-10 production was markedly up-regulated. Obaculactone significantly enhanced the percentage of CD4(+)CD25(+)Foxp3(+) Treg cells in the CD4(+) splenocytes without any effect on their inhibitory function. In vitro and in vivo tests showed obaculactone down-regulated T-bet expression in Th1 effector cells. Taken together, the unique immunomodulatory properties might qualify obaculactone as a putative, therapeutic compound for the treatment of Th1-driven diseases, including transplant rejection. 2010 Elsevier Inc. All rights reserved.

Animal models of allergen-induced tolerance in asthma: are T-regulatory-1 cells (Tr-1) the solution for T-helper-2 cells (Th-2) in asthma?

PubMed

Tournoy, K G; Hove, C; Grooten, J; Moerloose, K; Brusselle, G G; Joos, G F

2006-01-01

Non-specific anti-inflammatory medication is actually the treatment of choice for controlling the T-helper type 2 (Th-2) cell-driven airway inflammation in asthma. The induction of counterbalancing Th-1 cell clones, long considered a promising approach for immunotherapy, has failed to fulfil its promise because of potentially detrimental side-effects. This is therefore probably not a valid option for the treatment of asthma. With the increasing awareness that active immune mechanisms exist to control inflammatory responses, interest rises to investigate whether these can be exploited to control allergen-induced airway disease. The induction of antigen-specific T cells with suppressive characteristics (regulatory T cells) is therefore a potentially interesting approach. These regulatory T cells mediate tolerance in healthy, non-atopic individuals and have the potential of becoming an effective means of preventing allergen-induced airway inflammation and possibly of suppressing ongoing allergic immune responses. Here we review the available knowledge about allergen-induced suppressive immunity obtained from animal models taking into account the different developmental stages of allergic airway disease.

Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection.

PubMed

Demiri, M; Müller-Luda, K; Agace, W W; Svensson-Frej, M

2017-10-01

Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low- and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses. Mice lacking IRF4-dependent cDC failed to clear a high-dose infection and displayed impaired Th2 responses. Conversely, mice lacking IRF8-dependent cDC cleared a low-dose infection and displayed an impaired Th1 response while increased production of Th2 cytokines. Finally, mice lacking both IRF4- and IRF8-dependent cDC were able to generate a Th2 response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC. © 2017 John Wiley & Sons Ltd.

IL-17 is not essential for inflammation and chronic pelvic pain development in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Motrich, Ruben D; Breser, María L; Sánchez, Leonardo R; Godoy, Gloria J; Prinz, Immo; Rivero, Virginia E

2016-03-01

Pain and inflammation in the absence of infection are hallmarks in chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) patients. The etiology of CP/CPPS is unclear, and autoimmunity has been proposed as a cause. Experimental autoimmune prostatitis (EAP) models have long been used for studying CP/CPPS. Herein, we studied prostate inflammation induction and chronic pelvic pain development in EAP using IL-12p40-KO, IL-4-KO, IL-17-KO, and wild-type (C57BL/6) mice. Prostate antigen (PAg) immunization in C57BL/6 mice induced specific Th1 and Th17 immune responses and severe prostate inflammation and cell infiltration, mainly composed of CD4 T cells and macrophages. Moreover, chronic pelvic pain was evidenced by increased allodynia responses. In immunized IL-17-KO mice, the presence of a prominent PAg-specific Th1 immune response caused similar prostate inflammation and chronic pelvic pain. Furthermore, markedly high PAg-specific Th1 immune responses, exacerbated prostate inflammation, and chronic pelvic pain were detected in immunized IL-4-KO mice. Conversely, immunized IL-12p40-KO mice developed PAg-specific Th2 immune responses, characterized by high IL-4 secretion and neither infiltration nor damage in the prostate. As observed in wild-type control animals, IL12p40-KO mice did not evidence tactile allodynia responses. Our results suggest that, as in patients, chronic pelvic pain is a consequence of prostate inflammation. After PAg immunization, a Th1-associated immune response develops and induces prostate inflammation and chronic pelvic pain. The absence of Th1 or Th2 cytokines, respectively, diminishes or enhances EAP susceptibility. In addition, IL-17 showed not to be essential for pathology induction and chronic pelvic pain development.

The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation1

PubMed Central

Claudio, Estefania; Sønder, Søren Ulrik; Saret, Sun; Carvalho, Gabrielle; Ramalingam, Thirumalai R; Wynn, Thomas A; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Chen, Amy; Ren, Nina Y.; Wang, Hongshan; Siebenlist, Ulrich

2008-01-01

IL-17 is the signature cytokine of recently discovered T helper type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (a.k.a. Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses these two cytokines elicit. We identify CD11c+ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo. PMID:19155511

Changes in the immune response after treatment with benznidazole versus no treatment in patients with chronic indeterminate Chagas disease.

PubMed

Vallejo, Alejandro; Monge-Maillo, Begoña; Gutiérrez, Carolina; Norman, Francesca F; López-Vélez, Rogelio; Pérez-Molina, José A

2016-12-01

Symptomatic chronic Chagas disease affects up to 40% of patients infected with Trypanosoma cruzi. The lack of reliable early markers of cure after therapy hinders disease management and clinical trials with new drugs. We performed a study with 18 months of follow-up to compare changes in immune parameters and T. cruzi-specific immune responses as surrogate markers of response to therapy between patients treated with benznidazole and untreated patients. This was a pilot, open-label, randomised clinical trial of treatment with benznidazole versus no treatment in patients with indeterminate chronic T. cruzi infection. In both groups we investigated changes in T-cell activation, T-cell subpopulations, regulatory T-cell counts, IL6, and sCD14 levels, and T. cruzi-specific immune responses (Th1, Th2, and Th17 responses). Fourteen patients were included in the study (seven in each group). Median age was 35 years (P 25-75 31-43), 57% were female, and 93% were Bolivian. Benznidazole was administered at 5mg/kg/day for 60days. Three patients discontinued benznidazole owing to adverse reactions and were not evaluated. At the end of the follow-up period, treated patients showed significantly less immune activation and lower regulatory T-cell counts, with an increased Th17 and Th1 response. This randomised pilot clinical trial administering benznidazole to patients with indeterminate chronic Chagas disease brings about changes in the adaptive immunity, leading to a general decrease in inflammatory status. This apparently beneficial response could act as the basis for monitoring new antiparasitic drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Cytokine responses in acute and persistent human parvovirus B19 infection

PubMed Central

Isa, A; Lundqvist, A; Lindblom, A; Tolfvenstam, T; Broliden, K

2007-01-01

The aim of this study was to characterize the proinflammatory and T helper (Th)1/Th2 cytokine responses during acute parvovirus B19 (B19) infection and determine whether an imbalance of the Th1/Th2 cytokine pattern is related to persistent B19 infection. Cytokines were quantified by multiplex beads immunoassay in serum from B19-infected patients and controls. The cytokine responses were correlated with B19 serology, quantitative B19 DNA levels and clinical symptoms. In addition to a proinflammatory response, elevated levels of the Th1 type of cytokines interleukin (IL)-2, IL-12 and IL-15 were evident at time of the initial peak of B19 viral load in a few patients during acute infection. This pattern was seen in the absence of an interferon (IFN)-γ response. During follow-up (20–130 weeks post-acute infection) some of these patients had a sustained Th1 cytokine response. The Th1 cytokine response correlated with the previously identified sustained CD8+ T cell response and viraemia. A cross-sectional study on patients with persistent B19 infection showed no apparent imbalance of their cytokine pattern, except for an elevated level of IFN-γ response. No general immunodeficiency was diagnosed as an explanation for the viral persistence in this later group. Neither the acutely infected nor the persistently infected patients demonstrated a Th2 cytokine response. In conclusion, the acutely infected patients demonstrated a sustained Th1 cytokine response whereas the persistently infected patients did not exhibit an apparent imbalance of their cytokine pattern except for an elevated IFN-γ response. PMID:17302890

Differentiation of Effector CD4 T Cell Populations*

PubMed Central

Zhu, Jinfang; Yamane, Hidehiro; Paul, William E.

2012-01-01

CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation. PMID:20192806

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis.

PubMed

Muñoz-Carrillo, José Luis; Muñoz-López, José Luis; Muñoz-Escobedo, José Jesús; Maldonado-Tapia, Claudia; Gutiérrez-Coronado, Oscar; Contreras-Cordero, Juan Francisco; Moreno-García, María Alejandra

2017-12-01

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response.

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis

PubMed Central

Muñoz-Carrillo, José Luis; Muñoz-López, José Luis; Muñoz-Escobedo, José Jesús; Maldonado-Tapia, Claudia; Gutiérrez-Coronado, Oscar; Contreras-Cordero, Juan Francisco; Moreno-García, María Alejandra

2017-01-01

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response. PMID:29320813

Excessive expression of miR-27 impairs Treg-mediated immunological tolerance

PubMed Central

Cruz, Leilani O.; Hashemifar, Somaye Sadat; Wu, Cheng-Jang; Cho, Sunglim; Nguyen, Duc T.; Lin, Ling-Li; Khan, Aly Azeem

2017-01-01

MicroRNAs (miRs) are tightly regulated in the immune system, and aberrant expression of miRs often results in hematopoietic malignancies and autoimmune diseases. Previously, it was suggested that elevated levels of miR-27 in T cells isolated from patients with multiple sclerosis facilitate disease progression by inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we have demonstrated that, although mice with T cell–specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner. Rather, dysregulation of Th1 responses and autoimmunity resulted from a perturbed Treg compartment. Excessive miR-27 expression in murine T cells severely impaired Treg differentiation. Moreover, Tregs with exaggerated miR-27–mediated gene regulation exhibited diminished homeostasis and suppressor function in vivo. Mechanistically, we determined that miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg biology. Collectively, our data show that miR-27 functions as a key regulator in Treg development and function and suggest that proper regulation of miR-27 is pivotal to safeguarding Treg-mediated immunological tolerance. PMID:28067667

The Adaptor CARD9 Is Required for Adaptive but Not Innate Immunity to Oral Mucosal Candida albicans Infections

PubMed Central

Bishu, Shrinivas; Hernández-Santos, Nydiaris; Simpson-Abelson, Michelle R.; Huppler, Anna R.; Conti, Heather R.; Ghilardi, Nico; Mamo, Anna J.

2014-01-01

Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate “type 17” cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9−/− mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9−/− mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses. PMID:24379290

Th2 polarization by Der p 1--pulsed monocyte-derived dendritic cells is due to the allergic status of the donors.

PubMed

Hammad, H; Charbonnier, A S; Duez, C; Jacquet, A; Stewart, G A; Tonnel, A B; Pestel, J

2001-08-15

The polarization of the immune response toward a Th2 or a Th1 profile can be mediated by dendritic cells (DCs) following antigen presentation and interaction with T cells. Costimulatory molecules such as CD80 and CD86 expressed by DCs, the polarizing cytokine environment during DC--T-cell interaction, and also the nature of the antigen are critical in the orientation of the immune response. In this study, the effect of the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, on these different parameters was evaluated comparatively on monocyte-derived DCs obtained from healthy donors, from pollen-sensitive patients, or from patients sensitive to Dermatophagoides pteronyssinus. Results showed that Der p 1 induced an increase in CD86 expression only on DCs from house dust mite--sensitive patients. This was also associated with a higher capacity to induce T-cell proliferation, a rapid increase in the production of proinflammatory cytokines, tumor necrosis factor--alpha and interleukin (IL)-1 beta, and the type 2 cytokine IL-10. No changes in the release of IL-12 p70 were induced by Der p 1. Finally, purified T cells from house dust mite-sensitive patients stimulated by autologous Der p 1--pulsed DCs preferentially produced IL-4 rather than interferon-gamma. These effects were abolished in the presence of the inactive precursor of Der p 1 (ProDer p 1). Taken together, these data suggest that DCs from house dust mite--sensitive patients, in contrast to DCs from healthy donors and from pollen-sensitive patients, exposed to Der p 1 play a pivotal role in the enhancement of the Th2 response associated with the allergic reaction developed in response to house dust mite exposure. (Blood. 2001;98:1135-1141)

Immunological response induced by cryoablation against murine H22 hepatoma cell line in vivo.

PubMed

Yang, Xueling; Li, Xiaoli; Guo, Zhi; Si, Tongguo; Yu, Haipeng; Xing, Wenge

2018-02-01

To describe immunological consequences induced by cryoablation against H22 cells in vivo. Adult BALB/c mice underwent subcutaneous implantation of H22 cells. All of them were assigned into three groups randomly: group A (false surgery), group B (cryoablation) and group C (cryoablation plus Freund's adjuvant). Animals were sacrificed 1, 2 and 3 weeks after treatment. Serum IFN-γ and IL-4, Th1/Th2 in spleens and cytotoxicity were detected. Compared with that of group A, (1) INF-γ of group B was higher, but IL-4 was lower; cryoablation plus Freund's adjuvant enhanced these effects. (2) Th1/Th2 rose significantly in both group B and group C. (3) Strong cytolytic activity against H22 cells of group B and group C was found on day 7, 14 and 21. Our study showed a marked shift toward Th1 and IFN-γ expression after cryoablation, with an immuno-stimulatory effect against murine H22 hepatoma Cell. Copyright © 2017. Published by Elsevier Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bass, H.; Mosmann, T.; Strober, S.

Purified CD4+ BALB/c spleen T cells obtained 4-6 wk after total lymphoid irradiation (TLI) helped normal syngeneic B cells to produce a vigorous antibody response to TNP keyhole limpet hemocyanin in adoptive cell transfer experiments. However, the same cells failed to transfer delayed-type hypersensitivity to the adoptive hosts as measured by a foot pad swelling assay. In addition, purified CD4+ cells from TLI-treated mice were unable to induce graft vs. host disease in lethally irradiated allogeneic C57BL/Ka recipient mice. In response to mitogen stimulation, unfractionated spleen cells obtained from TLI mice secreted normal levels of IL-4 and IL-5, but markedlymore » reduced levels of IL-2 and INF-gamma. A total of 229 CD4+ clones from spleen cells of both normal and TLI-treated mice were established, and the cytokine secretion pattern from each clone was analyzed. The results demonstrate that the ratio of Th1- and Th2-like clones in the spleens of normal BALB/c mice is 1:0.6, whereas the ratio in TLI mice is approximately 1:7. These results suggest that Th2-like cells recover rapidly (at approximately 4-6 wk) after TLI treatment and account for the early return of antibody helper activity and secretion of IL-4 and IL-5, but Th1-like cells recover more slowly (in approximately 3 mo) after irradiation, and this accounts for the deficit in cell-mediated immunity and the reduced amount of IL-2 and IFN-gamma secretion.« less

Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation

PubMed Central

Marks, Benjamin R.; Nowyhed, Heba N.; Choi, Jin-Young; Poholek, Amanda C.; Odegard, Jared M.; Flavell, Richard A.; Craft, Joe

2009-01-01

Interleukin 17 (IL-17)-producing CD4+ T (TH-17) cells share a developmental relationship with FoxP3+ regulatory T (Treg) cells. Here we show that a TH-17 population differentiates within the thymus in a manner influenced by self-antigen recognition, and by the cytokines IL-6 and transforming growth factor (TGF)-β. Like previously described TH-17 cells, TH-17 cells that develop in the thymus expressed the orphan nuclear receptor RORγt and the IL-23 receptor. These cells also expressed α4β1 integrins and the chemokine receptor CCR6, and were recruited to the lung, gut, and liver. In the liver these cells secreted IL-22 in response to self-antigen and mediated host protection during inflammation. Thus, TH-17 cells, like Treg cells, can be selected by self-antigens in the thymus. PMID:19734905

Immunization with Leishmania donovani protein disulfide isomerase DNA construct induces Th1 and Th17 dependent immune response and protection against experimental visceral leishmaniasis in Balb/c mice.

PubMed

Amit, Ajay; Vijayamahantesh; Dikhit, Manas R; Singh, Ashish Kumar; Kumar, Vikash; Suman, Shashi S; Singh, Ashu; Kumar, Akhilesh; Thakur, Ajit Kumar; Das, Vidyanand Ravi; Das, Pradeep; Bimal, Sanjiva

2017-02-01

In the present study, the efficacy of Leishmania donovani protein disulfide isomerase (LdPDI) as a DNA vaccine was evaluated in BALB/C mice. Mice immunized with the LdPDI-DNA construct were found to be the most immuno-reactive, as the construct induced higher T-cell proliferation. The increased T-cell proliferation was associated with a substantial rise in Th1 and Th17+ CD4 cell response and triggered a higher proportion of CD8+ T cells for the release of interferon-gamma along with a reduced splenic parasite load on Days20 and 60 post challenge (PC). Furthermore, the vaccine construct triggered increased interferon (IFN)-γ, interleukin(IL)-17A, and IL-22 release accompanied by decreased extracellular signal-regulated kinases (ERK) 1/2 signaling and increased mitogen-activated protein kinase (MAPK) signaling coinciding with an increase in the amount of nitrite and reactive oxygen species (ROS)in vaccinating the splenocyts. We summarize from our data that the PDI-DNA construct of Leishmania donovani has the potential to elicit protective immunity through the pro-inflammatory cytokines of CD8+ and CD4+(Th1 and Th17) following an intervention in the downstream signaling event of ERK1/2 (probably through p38MAPK signaling). Therefore, the study suggests a new control against visceral leishmaniasis in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis.

PubMed

Zhuang, Yuan; Cheng, Ping; Liu, Xiao-fei; Peng, Liu-sheng; Li, Bo-sheng; Wang, Ting-ting; Chen, Na; Li, Wen-hua; Shi, Yun; Chen, Weisan; Pang, Ken C; Zeng, Ming; Mao, Xu-hu; Yang, Shi-ming; Guo, Hong; Guo, Gang; Liu, Tao; Zuo, Qian-fei; Yang, Hui-jie; Yang, Liu-yang; Mao, Fang-yuan; Lv, Yi-pin; Zou, Quan-ming

2015-09-01

Helper T (Th) cell responses are critical for the pathogenesis of Helicobacter pylori-induced gastritis. Th22 cells represent a newly discovered Th cell subset, but their relevance to H. pylori-induced gastritis is unknown. Flow cytometry, real-time PCR and ELISA analyses were performed to examine cell, protein and transcript levels in gastric samples from patients and mice infected with H. pylori. Gastric tissues from interleukin (IL)-22-deficient and wild-type (control) mice were also examined. Tissue inflammation was determined for pro-inflammatory cell infiltration and pro-inflammatory protein production. Gastric epithelial cells and myeloid-derived suppressor cells (MDSC) were isolated, stimulated and/or cultured for Th22 cell function assays. Th22 cells accumulated in gastric mucosa of both patients and mice infected with H. pylori. Th22 cell polarisation was promoted via the production of IL-23 by dendritic cells (DC) during H. pylori infection, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterised by the CXCR2-dependent influx of MDSCs, whose migration was induced via the IL-22-dependent production of CXCL2 by gastric epithelial cells. Under the influence of IL-22, MDSCs, in turn, produced pro-inflammatory proteins, such as S100A8 and S100A9, and suppressed Th1 cell responses, thereby contributing to the development of H. pylori-associated gastritis. This study, therefore, identifies a novel regulatory network involving H. pylori, DCs, Th22 cells, gastric epithelial cells and MDSCs, which collectively exert a pro-inflammatory effect within the gastric microenvironment. Efforts to inhibit this Th22-dependent pathway may therefore prove a valuable strategy in the therapy of H. pylori-associated gastritis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The Female Lower Genital Tract Is a Privileged Compartment with IL-10 Producing Dendritic Cells and Poor Th1 Immunity following Chlamydia trachomatis Infection

PubMed Central

Marks, Ellen; Tam, Miguel A.; Lycke, Nils Y.

2010-01-01

While a primary genital tract infection with C. trachomatis stimulates partial-protection against re-infection, it may also result in severe inflammation and tissue destruction. Here we have dissected whether functional compartments exist in the genital tract that restrict Th1-mediated protective immunity. Apart from the Th1-subset, little is known about the role of other CD4+ T cell subsets in response to a genital tract chlamydial infection. Therefore, we investigated CD4+ T cell subset differentiation in the genital tract using RT-PCR for expression of critical transcription factors and cytokines in the upper (UGT) and lower genital tract (LGT) of female C57BL/6 mice in response to C. trachomatis serovar D infection. We found that the Th1 subset dominated the UGT, as IFN-γ and T-bet mRNA expression were high, while GATA-3 was low following genital infection with C. trachomatis serovar D. By contrast, IL-10 and GATA-3 mRNA dominated the LGT, suggesting the presence of Th2 cells. These functional compartments also attracted regulatory T cells (Tregs) differently as increased FoxP3 mRNA expression was seen primarily in the UGT. Although IL-17A mRNA was somewhat up-regulated in the LGT, no significant change in RORγ-t mRNA expression was observed, suggesting no involvement of Th17 cells. The dichotomy between the LGT and UGT was maintained during infection by IL-10 because in IL-10-deficient mice the distinction between the two compartments was completely lost and a dramatic shift to the predominance of Th1 cells in the LGT occurred. Unexpectedly, the major source of IL-10 was CD11c+ CD11b+ DC, probably creating an anti-inflammatory privileged site in the LGT. PMID:21079691

Effects of interferon-alpha subtypes on the TH1/TH2 balance in peripheral blood mononuclear cells from patients with hepatitis virus infection-associated liver disorders.

PubMed

Ariyasu, Toshio; Tanaka, Takeshi; Fujioka, Noboru; Yanai, Yoshiaki; Yamamoto, Shigeto; Yamauchi, Hiroshi; Ikegami, Hakuo; Ikeda, Masao; Kurimoto, Masashi

2005-01-01

Interferon-alpha (IFN-alpha) has recently been shown to modulate in vitro T helper (Th) 1-driven responses in the peripheral blood mononuclear cells (PBMC) of patients with hepatitis B virus or C virus infection. In this study, we examined the in vitro effects of IFN-alpha subtypes (IFN-alpha1, -alpha2, -alpha5, -alpha8, and -alpha10) on the Th1/Th2 balance in PBMC obtained from patients with hepatitis virus infection-associated liver disorders and chronic hepatitis (CH), in comparison with the effect on healthy control volunteer PBMC. The Th1-type cell percentages and Th1/Th2 ratios were significantly higher in the PBMC of patients when compared with controls both before and after cultivation in vitro, with the IFN-alpha subtypes. The IFNalpha-5 induced an increase in the Th2-type cell percentages in both control and patient PBMC, resulting in that IFN-alpha5 lowered the Th1/Th2 ratio in patients with CH. Furthermore, statistical analysis revealed that IFN-alpha8 significantly promoted an increase in the Th1/Th2 ratios of PBMC from patients with CH and liver cirrhosis (LC) but not that of PBMC from patients with LC-hepatocellular carcinoma (HCC) and HCC. These findings imply that hepatitis virus infection and its disease status modify the effects of IFN-alpha subtypes on Th1 and Th2 immune balance in patients. Our findings should help to elucidate the mechanisms underlying successful IFN therapy for hepatitis virus infection and prevention of hepatocellular carcinogenesis.

Flagellin is a Th1 polarizing factor for human CD4+ T cells and induces protection in a murine neonatal vaccination model of rotavirus infection.

PubMed

Labastida-Conde, Rosario Guadalupe; Ramírez-Pliego, Oscar; Peleteiro-Olmedo, Mercedes; Lopez-Guerrero, Delia Vanessa; Badillo-Godinez, Oscar Daniel; Gutiérrez-Xicoténcatl, María de Lourdes; Rosas-Salgado, Gabriela; González-Fernández, África; Esquivel-Guadarrama, Fernando R; Santana, M Angélica

2018-07-05

Neonates have an increased susceptibility to infections, particularly those caused by intracellular pathogens, leading to high morbidity and mortality rates. This is partly because of a poor response of neonatal CD4 + T cells, leading to deficient antibody production and a low production of IFN-γ, resulting in deficient elimination of intracellular pathogens. The poor memory response of human neonates has underpinned the need for improving vaccine formulations. Molecular adjuvants that improve the response of neonatal lymphocytes, such as the ligands of toll-like receptors (TLRs), are attractive candidates. Among them, flagellin, the TLR5 ligand, is effective at very low doses; prior immunity to flagellin does not impair its adjuvant activity. Human CD4 + and CD8 + T cells express TLR5. We found that flagellin induces the expression of IFN-γ, IL-1β and IL-12 in mononuclear cells from human neonate and adult donors. When human naïve CD4 + T cells were activated in the presence of flagellin, there was high level of expression of IFN-γ in both neonates and adults. Furthermore, flagellin induced IFN-γ production in Th1 cells obtained from adult donors; in the Th2 population, it inhibited IL-4 cytokine production. Flagellin also promoted expression of the IFN-γ receptor in naive CD4 + T cells from neonates and adults. To test the adjuvant capacity of flagellin in vivo, we used a murine neonate vaccination model for infection with rotavirus, a pathogen responsible for severe diarrhea in young infants. Using the conserved VP6 antigen, we observed an 80% protection against rotavirus infection in the presence of flagellin, but only in those mice previously primed in the neonatal period. Our data suggest that flagellin could be an attractive adjuvant for achieving a Th1 response. Copyright © 2018 Elsevier Ltd. All rights reserved.

Heme oxygenase-1 restores impaired GARPCD4⁺CD25⁺ regulatory T cells from patients with acute coronary syndrome by upregulating LAP and GARP expression on activated T lymphocytes.

PubMed

Liu, Yuzhou; Zhao, Xiaoqi; Zhong, Yucheng; Meng, Kai; Yu, Kunwu; Shi, Huairui; Wu, Bangwei; Tony, Hasahya; Zhu, Jianghao; Zhu, Ruirui; Peng, Yudong; Mao, Yi; Cheng, Peng; Mao, Xiaobo; Zeng, Qiutang

2015-01-01

Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4(+)CD25(+)regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP) (+) CD4(+) CD25(+) activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP(+) CD4(+) CD25(+)Tregs in patients with ACS and thus regulate immune imbalance. T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) (+)CD4(+) T cells and the expression of Foxp3 and GARP by CD4(+)CD25(+)T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-β1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction. Patients with ACS exhibited an impaired number and suppressive function of GARP(+) CD4(+) CD25(+)Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP(+) CD4(+) CD25(+)Tregs and resulted in increased expression of LAP and GARP by activated T cells. The reduced number and impaired suppressive function of GARP(+) CD4(+) CD25(+)Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP(+) CD4(+) CD25(+)Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells. © 2015 S. Karger AG, Basel.

Reciprocal modulation of helper Th1 and Th17 cells by the β2-adrenergic receptor agonist drug terbutaline.

PubMed

Carvajal Gonczi, Catalina M; Tabatabaei Shafiei, Mahdieh; East, Ashley; Martire, Erika; Maurice-Ventouris, Meagane H I; Darlington, Peter J

2017-09-01

Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (β2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a β2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4 + CXCR3 - CCR6 + ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the β2AR. © 2017 Federation of European Biochemical Societies.

Toll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function.

PubMed

Karim, Ahmad Faisal; Reba, Scott M; Li, Qing; Boom, W Henry; Rojas, Roxana E

2017-09-01

We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on CD4 + T cells and up-regulate T-cell receptor (TCR) triggered Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4 + T-cell differentiation and function, we conducted a gene expression analysis of murine naïve CD4 + T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naïve CD4 + T-cells co-stimulated via TLR2 showed a significant up-regulation of Il9 mRNA compared to cells co-stimulated via CD28. Under TH9 differentiation, we observed up-regulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants in the presence of TLR2 agonist both in polyclonal and Ag85B cognate peptide specific stimulations. Under non-polarizing conditions, TLR2 engagement on CD4 + T-cells had minimal effect on IL-9 secretion and TH9 differentiation, likely due to a prominent effect of TLR2 signaling on IFN-γ secretion and TH1 differentiation. We also report that, TLR2 signaling in CD4 + T cells increased expression of transcription factors BATF and PU.1, known to positively regulate TH9 differentiation. These results reveal a novel role of T-cell expressed TLR2 in enhancing the differentiation and function of TH9 T cells. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice.

PubMed

Soria, I; López-Relaño, J; Viñuela, M; Tudela, J-I; Angelina, A; Benito-Villalvilla, C; Díez-Rivero, C M; Cases, B; Manzano, A I; Fernández-Caldas, E; Casanovas, M; Palomares, O; Subiza, J L

2018-04-01

Polymerized allergoids coupled to nonoxidized mannan (PM-allergoids) may represent novel vaccines targeting dendritic cells (DCs). PM-allergoids are better captured by DCs than native allergens and favor Th1/Treg cell responses upon subcutaneous injection. Herein we have studied in mice the in vivo immunogenicity of PM-allergoids administered sublingually in comparison with native allergens. Three immunization protocols (4-8 weeks long) were used in Balb/c mice. Serum antibody levels were tested by ELISA. Cell responses (proliferation, cytokines, and Tregs) were assayed by flow cytometry in spleen and lymph nodes (LNs). Allergen uptake was measured by flow cytometry in myeloid sublingual cells. A quick antibody response and higher IgG2a/IgE ratio were observed with PM-allergoids. Moreover, stronger specific proliferative responses were seen in both submandibular LNs and spleen cells assayed in vitro. This was accompanied by a higher IFNγ/IL-4 ratio with a quick IL-10 production by submandibular LN cells. An increase in CD4 + CD25 high FOXP3 + Treg cells was detected in LNs and spleen of mice treated with PM-allergoids. These allergoids were better captured than native allergens by antigen-presenting (CD45 + MHC-II + ) cells obtained from the sublingual mucosa, including DCs (CD11b + ) and macrophages (CD64 + ). Importantly, all the differential effects induced by PM-allergoids were abolished when using oxidized instead of nonoxidized PM-allergoids. Our results demonstrate for the first time that PM-allergoids administered through the sublingual route promote the generation of Th1 and FOXP3 + Treg cells in a greater extent than native allergens by mechanisms that might well involve their better uptake by oral antigen-presenting cells. © 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.

Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development

PubMed Central

Zimara, Nicole; Chanyalew, Menberework; Aseffa, Abraham; van Zandbergen, Ger; Lepenies, Bernd; Schmid, Maximilian; Weiss, Richard; Rascle, Anne; Wege, Anja Kathrin; Jantsch, Jonathan; Schatz, Valentin; Brown, Gordon D.; Ritter, Uwe

2018-01-01

Resistant mouse strains mount a protective T cell-mediated immune response upon infection with Leishmania (L.) parasites. Healing correlates with a T helper (Th) cell-type 1 response characterized by a pronounced IFN-γ production, while susceptibility is associated with an IL-4-dependent Th2-type response. It has been shown that dermal dendritic cells are crucial for inducing protective Th1-mediated immunity. Additionally, there is growing evidence that C-type lectin receptor (CLR)-mediated signaling is involved in directing adaptive immunity against pathogens. However, little is known about the function of the CLR Dectin-1 in modulating Th1- or Th2-type immune responses by DC subsets in leishmaniasis. We characterized the expression of Dectin-1 on CD11c+ DCs in peripheral blood, at the site of infection, and skin-draining lymph nodes of L. major-infected C57BL/6 and BALB/c mice and in peripheral blood of patients suffering from cutaneous leishmaniasis (CL). Both mouse strains responded with an expansion of Dectin-1+ DCs within the analyzed tissues. In accordance with the experimental model, Dectin-1+ DCs expanded as well in the peripheral blood of CL patients. To study the role of Dectin-1+ DCs in adaptive immunity against L. major, we analyzed the T cell stimulating potential of bone marrow-derived dendritic cells (BMDCs) in the presence of the Dectin-1 agonist Curdlan. These experiments revealed that Curdlan induces the maturation of BMDCs and the expansion of Leishmania-specific CD4+ T cells. Based on these findings, we evaluated the impact of Curdlan/Dectin-1 interactions in experimental leishmaniasis and were able to demonstrate that the presence of Curdlan at the site of infection modulates the course of disease in BALB/c mice: wild-type BALB/c mice treated intradermally with Curdlan developed a protective immune response against L. major whereas Dectin-1−/− BALB/c mice still developed the fatal course of disease after Curdlan treatment. Furthermore, the vaccination of BALB/c mice with a combination of soluble L. major antigens and Curdlan was able to provide a partial protection from severe leishmaniasis. These findings indicate that the ligation of Dectin-1 on DCs acts as an important checkpoint in adaptive immunity against L. major and should therefore be considered in future whole-organism vaccination strategies. PMID:29535708

MIF: a down-regulator of early T cell-dependent IFN-γ responses in Plasmodium chabaudi adami (DK) infected mice

PubMed Central

Tshikudi Malu, Diane; Bélanger, Benoit; Desautels, François; Kelendji, Karine; Dalko, Esther; Sanchez-Dardon, Jaime; Leng, Lin; Bucala, Richard; Satoskar, Abhay; Scorza, Tatiana

2012-01-01

Neutralization of macrophage migration inhibitory factor (MIF) increases anti-tumor cytotoxic T cell responses in vivo and IFN-γ responses in vitro, suggesting a plausible regulatory role for MIF in T cell activation. Considering that IFN-γ production by CD4+ T cells is pivotal to resolve murine malaria and that secretion of MIF is induced by Plasmodium chabaudi adami parasites, we investigated the effect of MIF deficiency on the infection with this pathogen. Infections with P.c. adami DK parasites were more efficiently controlled in MIF-neutralized and MIF-deficient (KO) BALB/c mice. The reduction in parasitemia was associated with reduced production of IL-4 by non-T/non-B cells throughout patent infection. At day 4 post-infection, higher numbers of activated CD4+ cells were measured in MIF KO mice, which secreted more IFN-γ, less IL-4 and less IL-10 than CD4+ T cells from WT mice. Enhanced IFN-γ and decreased IL-4 responses also were measured in MIF KO CD4+ T cells stimulated with or without IL-12 and anti-IL-4 blocking antibody to induce Th1 polarization. However, MIF KO CD4+ T cells efficiently acquired a Th2 phenotype when stimulated in the presence of IL-4 and anti-IL-12 antibody, indicating normal responsiveness to IL-4/STAT6 signaling. These results suggest that by promoting IL-4 responses in cells other than T/B cells during early P.c. adami infection, MIF decreases IFN-γ secretion in CD4+ T cells and in addition, has the intrinsic ability to render CD4+ T cells less capable of acquiring a robust Th1 phenotype when stimulated in the presence of IL-12. PMID:21518974

EFFECT OF SHORT TERM DIESEL EXHAUST EXPOSURE ON NASAL RESPONSES TO INFLUENZA IN ALLERGIC RHINITICS.

EPA Science Inventory

Introduction: Recently published data suggest that diesel exhaust (DE) has special impact on allergic inflammation, suppressing Th1 and augmenting Th2 responses to allergen via oxidant stress effects on airway cells. Exposures to particulate air pollutants including DE are also a...

Role of T cells in the B-cell response: glutaraldehyde-fixed T-helper hybridoma cells synergize with the lymphokine IL-4 to induce B-cell activation and proliferation.

PubMed

Kubota, E; McKenzie, D T; Dutton, R W; Swain, S L

1991-01-01

Antigen-unselected helper T-cell hybridomas (Th) which activate normal resting B cells to RNA synthesis and proliferation in the presence of concanavalin A (Con A) have been developed. The response is completely Th cell dependent, and not restricted by the haplotype of the B-cell major histocompatibility complex (MHC). Culture supernatants from the Con A-stimulated Th hybridomas contain interleukin-4 (IL-4) and IL-2, but undetectable level of IL-5. The supernatant alone, however, does not induce B-cell activation or proliferation. Although the Con A-mediated Th cell-dependent B-cell response occurs in an MHC-unrestricted manner, the response of resting B cells can be blocked by monoclonal Ia antibody specific for the surface class II molecules of the responding B cell. The response is also blocked by monoclonal antibody to L3T4. Significant activation and proliferation of resting B cells can also be triggered by glutaraldehyde-fixed Th hybridomas and Con A when exogenous IL-4 is added. The stimulation with fixed Th hybridomas plus IL-4 can be inhibited by monoclonal anti-L3T4 or anti-Ia. These results suggest that maximal B-cell activation requires a direct helper T cell-B cell interaction which depends on availability of Ia on the B cell and L3T4 on the T cell, even when Con A overcomes the requirement for MHC-restricted T-cell recognition. We suggest that this signal, in conjunction with T-cell produced lymphokine IL-4, is responsible for the activation and subsequent proliferation of the B cells which occurs following interaction with T cells.

Modulation of tyrosine hydroxylase expression by melatonin in human SH-SY5Y neuroblastoma cells.

PubMed

McMillan, Catherine R; Sharma, Rohita; Ottenhof, Tom; Niles, Lennard P

2007-06-04

We have previously reported in vivo preservation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, following treatment with physiological doses of melatonin, in a 6-hydroxydopamine model of Parkinson's disease. Based on these findings, we postulated that melatonin would similarly modulate the expression of TH in vitro. Therefore, using human SH-SY5Y neuroblastoma cells which can differentiate into dopaminergic neurons following treatment with retinoic acid, we first examined whether these cells express melatonin receptors. Subsequently, the physiological dose-dependent effects of melatonin on TH expression were examined in both undifferentiated and differentiated cells. The novel detection of the G protein-coupled melatonin MT(1) receptor in SH-SY5Y cells by RT-PCR was confirmed by sequencing and Western blotting. In addition, following treatment of SH-SY5Y cells with melatonin (0.1-100 nM) for 24h, Western analysis revealed a significant increase in TH protein levels. A biphasic response, with significant increases in TH protein at 0.5 and 1 nM melatonin and a reversal at higher doses was seen in undifferentiated cells; whereas in differentiated cells, melatonin was effective at doses of 1 and 100 nM. These findings suggest a physiological role for melatonin in modulating TH expression, possibly via the MT(1) receptor.

Interleukin-18: a regulator of cancer and autoimmune diseases.

PubMed

Esmailbeig, Maryam; Ghaderi, Abbas

2017-11-01

Interleukin (IL)-18, structurally similar to IL-1β, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi. Recent evidences showing the involvement of IL-18 in Th2 differentiation and ultimately IgE production from B cells have shed a new insight on the dual effects of IL-18 on Th1 and Th2 inflammatory responses. IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-γ and, therefore, may contribute to tumor immunity. The biological activity of IL-18 is not limited to these cells, but it also plays a role in development of Th17 cell responses. IL-18 synergistically with IL-23 can induce IL-17 secretion from Th17 cells. The diverse biological activity of IL-18 on T-cell subsets and other immune cells has made this cytokine a good target for investigating its role in various inflammatory-based diseases. Lately, the discovery of IL-18 binding protein (IL-18BP), a physiological inhibitor of IL-18 and a hallmark of IL-18 biology, made this cytokine an attractive target for studying its pros and cons in the treatment of various diseases. In recent years, the biology, genetics, and pathological role of IL-18 have been studied in a number of diseases. In this article, we aimed to present an updated review on these aspects regarding the contribution of IL-18 to important diseases such as cancer, autoimmunity, and inflammatory-mediated conditions including allergic diseases, metabolic syndrome, and atherosclerosis. Emerging data indicating prognostic, diagnostic, and therapeutic features of IL-18 and its related molecules will also be discussed.

Immunology mini-review: the basics of T(H)17 and interleukin-6 in transplantation.

PubMed

Nakagiri, T; Inoue, M; Minami, M; Shintani, Y; Okumura, M

2012-05-01

The outcomes of organ transplantation are determined by graft rejection, the mechanisms of which are some of the most important areas of study in the transplantation field. The main cause of rejection is the immunologic response of the recipient toward the transplanted organ. The immunologic responses are regulated by T-cell subsets, especially helper T-cells, which have been characterized as T(H)1 or T(H)2 cells according to their profiles of cytokines production. A unique subset of recently identified lymphocytes, the regulatory T cells (T(reg)s), seem to play a role in tolerance. The recently identified T(H)17 cells are a subset of effector-helper lymphocytes that specifically secrete interleukin (IL) 17. Interestingly, T(H)17 and T(reg) both develop from naïve T cells on stimulation by transforming growth factor β. The difference is only the existence of IL-6, a proinflammatory cytokine. T(H)17 clears pathogens that are not adequately handled by T(H)1 and T(H)2 elements, as well as contributing to autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory diseases. Autoimmune diseases are caused by reactions to self-antigens. T(H)17 (or IL-17) and IL-6 are also thought to be involved in rejection after organ transplantation. We examined the contributions of T(H)17 and IL-6 in bronchiolitis obliterans (BO), the histologic finding in chronic rejection of lung transplantations. Earlier studies have reported that T(H)17 and IL-6 contribute not only to chronic rejection of lung transplantations, but also to the rejection of other solid organs, e.g., heart, liver, and kidney. In addition, prospective avenues of research on T(H)17 and IL-6 in transplantation have emerged from the perspectives of recent studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Treatment of mice with fenbendazole attenuates allergic airways inflammation and Th2 cytokine production in a model of asthma.

PubMed

Cai, Yeping; Zhou, Jiansheng; Webb, Dianne C

2009-01-01

Mouse models have provided a significant insight into the role of T-helper (Th) 2 cytokines such as IL-5 and IL-13 in regulating eosinophilia and other key features of asthma. However, the validity of these models can be compromised by inadvertent infection of experimental mouse colonies with pathogens such as oxyurid parasites (pinworms). While the benzimidazole derivative, fenbendazole (FBZ), is commonly used to treat such outbreaks, the effects of FBZ on mouse models of Th2 disease are largely unknown. In this investigation, we show that mice fed FBZ-supplemented food during the in utero and post-weaning period developed attenuated lung eosinophilia, antigen-specific IgG1 and Th2 cytokine responses in a model of asthma. Treatment of the mediastinal lymph node cells from allergic mice with FBZ in vitro attenuated cell proliferation, IL-5 and IL-13 production and expression of the early lymphocyte activation marker, CD69 on CD4(+) T cells and CD19(+) B cells. In addition, eosinophilia and Th2 responses remained attenuated after a 4-week withholding period in allergic mice treated preweaning with FBZ. Thus, FBZ modulates the amplitude of Th2 responses both in vivo and in vitro.

Chemokine CXCL11 links microbial stimuli to intestinal inflammation

PubMed Central

Liu, Z; Chen, X; Wang, X; Chen, X; Song, C-H; Du, Y; Su, J; Yaseen, S A; Yang, P-C

2011-01-01

Interleukin (IL)-17 plays an important role in the pathogenesis in a number of immune inflammatory disorders. This study aims to investigate the mechanism by which microbial product flagellin is involved in the development of T helper type (Th)17 cells. Serum levels of IL-17 and CXCL9-11 in patients with ulcerative colitis (UC) were evaluated. The source and mechanism of CXC11 release in intestinal mucosa were examined with colonic biopsies from UC patients and a colitis mouse model. The role of flagellin in the development of Th17 cells was studied with a cell co-culture system. High serum levels of CXCL11 and IL-17 were observed in UC. Flagellin could induce the production of CXCL11 in CD14+ cells that facilitated the development of Th17 cells. In a skewed Th1 response environment flagellin induces intestinal inflammation, with IL-17 expression predominant. CXCR3/CXCL11 pathway is involved in microbial product flagellin-induced intestinal inflammation in which the Th17 response plays an important role. PMID:21438871

Induction of Broad CD4+ and CD8+ T-Cell Responses and Cross- Neutralizing Antibodies against Hepatitis C Virus by Vaccination with Th1-Adjuvanted Polypeptides Followed by Defective Alphaviral Particles Expressing Envelope Glycoproteins gpE1 and gpE2 and Nonstructural Proteins 3, 4, and 5▿ †

PubMed Central

Lin, Yinling; Kwon, Taewoo; Polo, John; Zhu, Yi-Fei; Coates, Stephen; Crawford, Kevin; Dong, Christine; Wininger, Mark; Hall, John; Selby, Mark; Coit, Doris; Medina-Selby, Angelica; McCoin, Colin; Ng, Philip; Drane, Debbie; Chien, David; Han, Jang; Vajdy, Michael; Houghton, Michael

2008-01-01

Broad, multispecific CD4+ and CD8+ T-cell responses to the hepatitis C virus (HCV), as well as virus-cross-neutralizing antibodies, are associated with recovery from acute infection and may also be associated in chronic HCV patients with a favorable response to antiviral treatment. In order to recapitulate all of these responses in an ideal vaccine regimen, we have explored the use of recombinant HCV polypeptides combined with various Th1-type adjuvants and replication-defective alphaviral particles encoding HCV proteins in various prime/boost modalities in BALB/c mice. Defective chimeric alphaviral particles derived from the Sindbis and Venezuelan equine encephalitis viruses encoding either the HCV envelope glycoprotein gpE1/gpE2 heterodimer (E1E2) or nonstructural proteins 3, 4, and 5 (NS345) elicited strong CD8+ T-cell responses but low CD4+ T helper responses to these HCV gene products. In contrast, recombinant E1E2 glycoproteins adjuvanted with MF59 containing a CpG oligonucleotide elicited strong CD4+ T helper responses but no CD8+ T-cell responses. A recombinant NS345 polyprotein also stimulated strong CD4+ T helper responses but no CD8+ T-cell responses when adjuvanted with Iscomatrix containing CpG. Optimal elicitation of broad CD4+ and CD8+ T-cell responses to E1E2 and NS345 was obtained by first priming with Th1-adjuvanted proteins and then boosting with chimeric, defective alphaviruses expressing these HCV genes. In addition, this prime/boost regimen resulted in the induction of anti-E1E2 antibodies capable of cross-neutralizing heterologous HCV isolates in vitro. This vaccine formulation and regimen may therefore be optimal in humans for protection against this highly heterogeneous global pathogen. PMID:18508900

Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant.

PubMed

Dinc, Gunes; Pennington, Jarrod M; Yolcu, Esma S; Lawrenz, Matthew B; Shirwan, Haval

2014-09-03

The lead candidate plague subunit vaccine is the recombinant fusion protein rF1-V adjuvanted with alum. While alum generates Th2 regulated robust humoral responses, immune protection against Yersinia pestis has been shown to also involve Th1 driven cellular responses. Therefore, the rF1-V-based subunit vaccine may benefit from an adjuvant system that generates a mixed Th1 and humoral immune response. We herein assessed the efficacy of a novel SA-4-1BBL costimulatory molecule as a Th1 adjuvant to improve cellular responses generated by the rF1-V vaccine. SA-4-1BBL as a single adjuvant had better efficacy than alum in generating CD4(+) and CD8(+) T cells producing TNFα and IFNγ, signature cytokines for Th1 responses. The combination of SA-4-1BBL with alum further increased this Th1 response as compared with the individual adjuvants. Analysis of the humoral response revealed that SA-4-1BBL as a single adjuvant did not generate a significant Ab response against rF1-V, and SA-4-1BBL in combination with alum did not improve Ab titers. However, the combined adjuvants significantly increased the ratio of Th1 regulated IgG2c in C57BL/6 mice to the Th2 regulated IgG1. Finally, a single vaccination with rF1-V adjuvanted with SA-4-1BBL+alum had better protective efficacy than vaccines containing individual adjuvants. Taken together, these results demonstrate that SA-4-1BBL improves the protective efficacy of the alum adjuvanted lead rF1-V subunit vaccine by generating a more balanced Th1 cellular and humoral immune response. As such, this adjuvant platform may prove efficacious not only for the rF1-V vaccine but also against other infections that require both cellular and humoral immune responses for protection. Copyright © 2014 Elsevier Ltd. All rights reserved.

B cell function in the immune response to helminths

PubMed Central

Harris, Nicola

2010-01-01

Similar T helper (Th)2-type immune responses are generated against different helminths parasites, but the mechanisms that initiate Th2 immunity, and the specific immune components that mediate protection against these parasites, can vary greatly. B cells are increasingly recognized as important during the Th2-type immune response to helminths, and B cell activation might be a target for effective vaccine development. Antibody production is a function of B cells during helminth infection and understanding how polyclonal and antigen-specific antibodies contribute should provide important insights into how protective immunity develops. In addition, B cells might also contribute to the host response against helminths through antibody-independent functions including, antigen-presentation, as well as regulatory and effector activity. In this review, we examine the role of B cells during Th2-type immune response to these multicellular parasites. PMID:21159556

Specific T cell induction using iron oxide based nanoparticles as subunit vaccine adjuvant.

PubMed

Neto, Lázaro Moreira Marques; Zufelato, Nicholas; de Sousa-Júnior, Ailton Antônio; Trentini, Monalisa Martins; da Costa, Adeliane Castro; Bakuzis, Andris Figueiroa; Kipnis, André; JunqueiraKipnis, Ana Paula

2018-06-18

Metal-based nanoparticles (NPs) stimulate innate immunity; however, they have never been demonstrated to be capable of aiding the generation of specific cellular immune responses. Therefore, our objective was to evaluate whether iron oxide-based NPs have adjuvant properties in generating cellular Th1, Th17 and TCD8 (Tc1) immune responses. For this purpose, a fusion protein (CMX) composed of Mycobacterium tuberculosis antigens was used as a subunit vaccine. Citrate-coated MnFe 2 O 4 NPs were synthesized by co-precipitation and evaluated by transmission electron microscopy. The vaccine was formulated by homogenizing NPs with the recombinant protein, and protein corona formation was determined by dynamic light scattering and field-emission scanning electron microscopy. The vaccine was evaluated for the best immunization route and strategy using subcutaneous and intranasal routes with 21-day intervals between immunizations. When administered subcutaneously, the vaccine generated specific CD4 + IFN-γ + (Th1) and CD8 + IFN-γ + responses. Intranasal vaccination induced specific Th1, Th17 (CD4 + IL-17 + ) and Tc1 responses, mainly in the lungs. Finally, a mixed vaccination strategy (2 subcutaneous injections followed by one intranasal vaccination) induced a Th1 (in the spleen and lungs) and splenic Tc1 response but was not capable of inducing a Th17 response in the lungs. This study shows for the first time a subunit vaccine with iron oxide based NPs as an adjuvant that generated cellular immune responses (Th1, Th17 and TCD8), thereby exhibiting good adjuvant qualities. Additionally, the immune response generated by the subcutaneous administration of the vaccine diminished the bacterial load of Mtb challenged animals, showing the potential for further improvement as a vaccine against tuberculosis.

Defective IL-17- and IL-22-dependent mucosal host response to Candida albicans determines susceptibility to oral candidiasis in mice expressing the HIV-1 transgene.

PubMed

Goupil, Mathieu; Cousineau-Côté, Vincent; Aumont, Francine; Sénéchal, Serge; Gaboury, Louis; Hanna, Zaher; Jolicoeur, Paul; de Repentigny, Louis

2014-10-26

The tissue-signaling cytokines IL-17 and IL-22 are critical to host defense against oral Candida albicans infection, by their induction of oral antimicrobial peptide expression and recruitment of neutrophils. Mucosal Th17 cells which produce these cytokines are preferentially depleted in HIV-infected patients. Here, we tested the hypothesis that defective IL-17- and IL-22-dependent host responses to C. albicans determine the phenotype of susceptibility to oropharyngeal candidiasis (OPC) in transgenic (Tg) mice expressing HIV-1. Naïve CD4+ T-cells and the differentiated Th1, Th2, Th17, Th1Th17 and Treg lineages were all profoundly depleted in cervical lymph nodes (CLNs) of these Tg mice. However, naive CD4+ cells from Tg mice maintained the capacity to differentiate into these lineages in response to polarizing cytokines in vitro. Expression of Il17, Il22, S100a8 and Ccl20 was enhanced in oral mucosal tissue of non-Tg, but not of Tg mice, after oral infection with C. albicans. Treatment of infected Tg mice with the combination of IL-17 and IL-22, but not IL-17 or Il-22 alone, significantly reduced oral burdens of C. albicans and abundance of Candida hyphae in the epithelium of tongues of infected Tg mice, and restored the ability of the Tg mice to up-regulate expression of S100a8 and Ccl20 in response to C. albicans infection. These findings demonstrate that defective IL-17- and IL-22-dependent induction of innate mucosal immunity to C. albicans is central to the phenotype of susceptibility to OPC in these HIV transgenic mice.

Different competitive capacities of Stat4- and Stat6-deficient CD4+ T cells during lymphophenia-driven proliferation.

PubMed

Sanchez-Guajardo, Vanesa; Borghans, José A M; Marquez, Maria-Elena; Garcia, Sylvie; Freitas, Antonio A

2005-02-01

The outcome of an immune response relies on the competitive capacities acquired through differentiation of CD4(+) T cells into Th1 or Th2 effector cells. Because Stat4 and Stat6 proteins are implicated in the Th1 vs Th2 generation and maintenance, respectively, we compare in this study the kinetics of Stat4(-/-) and Stat6(-/-) CD4(+) T cells during competitive bone marrow reconstitution and lymphopenia-driven proliferation. After bone marrow transplantation, both populations reconstitute the peripheral T cell pools equally well. After transfer into lymphopenic hosts, wild-type and Stat6(-/-) CD4(+) T cells show a proliferation advantage, which is early associated with the expression of an active phospho-Stat4 and the down-regulation of Stat6. Despite these differences, Stat4- and Stat6-deficient T cells reach similar steady state numbers. However, when both Stat4(-/-) and Stat6(-/-) CD4(+) T cells are coinjected into the same hosts, the Stat6(-/-) cells become dominant and out-compete Stat4(-/-) cells. These findings suggest that cell activation, through the Stat4 pathway and the down-regulation of Stat6, confers to pro-Th1 T cells a slight proliferation advantage that in a competitive situation has major late repercussions, because it modifies the final homeostatic equilibrium of the populations and favors the establishment of Th1 CD4(+) T cell dominance.

Comparison of Th17 cells mediated immunological response among asthmatic children with or without allergic rhinitis.

PubMed

Qing, Miao; Yongge, Liu; Wei, Xu; Yan, Wang; Zhen, Li; Yixin, Ren; Hui, Guan; Li, Xiang

2018-03-31

To investigate whether there were differences in Th17 cells mediated immunological responses among asthmatics with or without allergic rhinitis. A case-control comparison was conducted in a cohort of 67 children with asthma (AS), 50 children with allergic rhinitis (AR), 52 children with both AS and AR (ASR), 25 infectious rhinitis (IR), and 55 healthy controls (HC). The percentages of circulating Th17 cells were determined by flow cytometry. The Th2- and Th17-related cytokines in plasma and culture supernatants were measured by enzyme-linked immunosorbent assay. The effect of proinflammation cytokine IL-17E on Th2 cytokines production from human T helper (Th) lymphocytes was analyzed. (1) A inter-group comparison revealed that Th17 cells levels were highest in ASR group [(0.89% ± 0.27) %], following by AS group [(0.82 ± 0.29) %] and AR group[(0.78 ± 0.17) %] (P< 0.05). (2) After in-vitro stimulation with house dust mite (HDM) antigen, the levels of IL-4 and IL-17E in culture supernatants of PBMCs from allergic children (AS group, AR group and ASR group) were significantly enhanced. (3) The release of Th2 cytokines from IL-17E treated Th cells of allergic children (AS group, AR group and ASR group) were significantly induced, no similar result was observed in IR group and HC group. Our findings preliminarily revealed that Th17 cell and its related cytokines might be involved in pathogenesis of airway inflammation diseases, and also presenting varying immunological characteristics among asthmatic children with or without allergic rhinitis.

Synthesis of truncated analogues of the iNKT cell agonist, α-galactosyl ceramide (KRN7000), and their biological evaluation

PubMed Central

Veerapen, Natacha; Reddington, Faye; Salio, Mariolina; Cerundolo, Vincenzo; Besra, Gurdyal S.

2011-01-01

Stimulation of iNKT cells by α-galactosyl ceramide (α-GalCer), also known as KRN7000, and its truncated analogue OCH induces both Th1- and Th2-cytokines, with OCH inducing a Th2-cytokine bias. Skewing of the iNKT cells’ response towards either a Th1- or Th2-cytokine profile offers potential therapeutic benefits. The length of both the acyl and the sphingosine chains in α-galactosyl ceramides is known to influence the cytokine release profile. We have synthesized analogues of α-GalCer with truncated sphingosine chains for biological evaluation, with particular emphasis on the Th1/Th2 distribution. Starting from a common precursor, d-lyxose, the sphingosine derivatives were synthesised via a straightforward Wittig condensation. PMID:21145749

Berberine Attenuates Inflammation Associated with Delayed-Type Hypersensitivity via Suppressing Th1 Response and Inhibiting Apoptosis.

PubMed

Wang, Zhigang; Chen, Zhe; Chen, Tao; Yi, Tao; Zheng, Zhou; Fan, Hong; Chen, Zebin

2017-02-01

Berberine, one of the active alkaloids from Rhizoma Coptidis, has been indicated to have anti-inflammatory and immunosuppressive properties. The aim of this study was to determine the role of berberine on ovalbumin (OVA)-induced delayed-type hypersensitivity (DTH) and its potential mechanisms. Berberine treatment significantly reduced footpad swelling, inflammatory cells infiltration, anti-OVA IgG levels, IgE concentration in serum, and the tetramer + CD8 + cells. In homogenized footpad tissue, the production of Th1-mediated cytokines including IFN-γ, TNF-α, and IL-2 were suppressed following the administration of berberine. Detailed studies revealed that berberine prevented differentiation into Th1 cells in the OVA-primed lymphocytes, resulting from suppressing the expression of T-bet and secretion of IFN-γ but not IL-4. Concanavalin A stimulation assay and MTT assay also indicated inhibiting effect of berberine treatment on IFN-γ production and decreased cytotoxicity in lymphocytes proliferation, respectively. Additionally, berberine obviously decreased the cell apoptosis and enzymatic activity of caspase-3, which was further confirmed by the facts that berberine clearly lowered Bax/Bcl-2 ratio and expression of cleaved caspase-3 protein. On correlation analysis, the percentage of apoptotic cells showed a significant positive relationship with IFN-γ/IL-4 ratio of supernatant from footpad tissue in berberine-treated DTH mice. These results demonstrated that berberine attenuated Th1-mediated inflammation in OVA-induced DTH by curbing Th1 response and inhibiting cell apoptosis, suggesting a therapeutic potential for berberine for the treatment of type IV hypersensitivity.

Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response.

PubMed

McKallip, Robert J; Nagarkatti, Mitzi; Nagarkatti, Prakash S

2005-03-15

In the current study, we tested the central hypothesis that exposure to Delta-9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component in marijuana, can lead to enhanced growth of tumors that express low to undetectable levels of cannabinoid receptors by specifically suppressing the antitumor immune response. We demonstrated that the human breast cancer cell lines MCF-7 and MDA-MB-231 and the mouse mammary carcinoma 4T1 express low to undetectable levels of cannabinoid receptors, CB1 and CB2, and that these cells are resistant to Delta9-THC-induced cytotoxicity. Furthermore, exposure of mice to Delta9-THC led to significantly elevated 4T1 tumor growth and metastasis due to inhibition of the specific antitumor immune response in vivo. The suppression of the antitumor immune response was mediated primarily through CB2 as opposed to CB1. Furthermore, exposure to Delta9-THC led to increased production of IL-4 and IL-10, suggesting that Delta9-THC exposure may specifically suppress the cell-mediated Th1 response by enhancing Th2-associated cytokines. This possibility was further supported by microarray data demonstrating the up-regulation of a number of Th2-related genes and the down-regulation of a number of Th1-related genes following exposure to Delta9-THC. Finally, injection of anti-IL-4 and anti-IL-10 mAbs led to a partial reversal of the Delta9-THC-induced suppression of the immune response to 4T1. Such findings suggest that marijuana exposure either recreationally or medicinally may increase the susceptibility to and/or incidence of breast cancer as well as other cancers that do not express cannabinoid receptors and are resistant to Delta9-THC-induced apoptosis.

Suppression of IL-7-dependent Effector T-cell Expansion by Multipotent Adult Progenitor Cells and PGE2

PubMed Central

Reading, James L; Vaes, Bart; Hull, Caroline; Sabbah, Shereen; Hayday, Thomas; Wang, Nancy S; DiPiero, Anthony; Lehman, Nicholas A; Taggart, Jen M; Carty, Fiona; English, Karen; Pinxteren, Jef; Deans, Robert; Ting, Anthony E; Tree, Timothy I M

2015-01-01

T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients. PMID:26216515

Effects of wear particles of polyether-ether-ketone and cobalt-chromium-molybdenum on CD4- and CD8-T-cell responses

PubMed Central

Du, Zhe; Wang, Shujun; Yue, Bing; Wang, Ying; Wang, You

2018-01-01

T-cells, second only to macrophages, are often considered as the potential cells involved in debris-related failure of arthroplasty. Here, we assessed the effects of particulate wear debris on T-cells and inflammatory reactions. Blood samples from 25 donors were incubated with polyether-ether-ketone (PEEK) and cobalt-chromium-molybdenum (CoCrMo) particles generated by custom cryo-milling and pulverization. The T-cell phenotypes were assessed using immunostaining and flow cytometry. For the in vivo study, 0.1 mL of each particle suspension (approximately 1.0 × 108 wear particles) was injected into murine knee joints; the synovium and spleen were collected one week after the operation for histological examination and immunofluorescence staining. The T-cell responses observed included low-level activation of Th1, Th2, Th17, and CD8+ pathways after 72 h of co-culture of the particles with peripheral blood mononuclear cells. Obvious CD8+ T-cell responses were observed in local synovium and peripheral spleen, with higher inflammatory cytokine expression in the CoCrMo group. Relatively minor cytotoxic and immunological reactions were observed in vitro, with PEEK and CoCrMo particle-induced immune responses being primarily mediated by CD8+ T-cells, rather than CD4+ T-cells, in vivo. Overall, PEEK wear particles induced fewer inflammatory reactions than CoCrMo particles. This study verified that PEEK was suitable as a potential alternative for metals in total knee replacements in terms of the immunological reaction to PEEK particles, and shed light on the effects of wear particles from polymer and metal-based implants on immune responses. PMID:29541407

Effects of wear particles of polyether-ether-ketone and cobalt-chromium-molybdenum on CD4- and CD8-T-cell responses.

PubMed

Du, Zhe; Wang, Shujun; Yue, Bing; Wang, Ying; Wang, You

2018-02-16

T-cells, second only to macrophages, are often considered as the potential cells involved in debris-related failure of arthroplasty. Here, we assessed the effects of particulate wear debris on T-cells and inflammatory reactions. Blood samples from 25 donors were incubated with polyether-ether-ketone (PEEK) and cobalt-chromium-molybdenum (CoCrMo) particles generated by custom cryo-milling and pulverization. The T-cell phenotypes were assessed using immunostaining and flow cytometry. For the in vivo study, 0.1 mL of each particle suspension (approximately 1.0 × 10 8 wear particles) was injected into murine knee joints; the synovium and spleen were collected one week after the operation for histological examination and immunofluorescence staining. The T-cell responses observed included low-level activation of Th1, Th2, Th17, and CD8+ pathways after 72 h of co-culture of the particles with peripheral blood mononuclear cells. Obvious CD8+ T-cell responses were observed in local synovium and peripheral spleen, with higher inflammatory cytokine expression in the CoCrMo group. Relatively minor cytotoxic and immunological reactions were observed in vitro , with PEEK and CoCrMo particle-induced immune responses being primarily mediated by CD8+ T-cells, rather than CD4+ T-cells, in vivo . Overall, PEEK wear particles induced fewer inflammatory reactions than CoCrMo particles. This study verified that PEEK was suitable as a potential alternative for metals in total knee replacements in terms of the immunological reaction to PEEK particles, and shed light on the effects of wear particles from polymer and metal-based implants on immune responses.

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells.

PubMed

Arbore, Giuseppina; West, Erin E; Spolski, Rosanne; Robertson, Avril A B; Klos, Andreas; Rheinheimer, Claudia; Dutow, Pavel; Woodruff, Trent M; Yu, Zu Xi; O'Neill, Luke A; Coll, Rebecca C; Sher, Alan; Leonard, Warren J; Köhl, Jörg; Monk, Pete; Cooper, Matthew A; Arno, Matthew; Afzali, Behdad; Lachmann, Helen J; Cope, Andrew P; Mayer-Barber, Katrin D; Kemper, Claudia

2016-06-17

The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to "innate immune cells" but is an integral component of normal adaptive T(H)1 responses. Copyright © 2016, American Association for the Advancement of Science.

Anti-retroviral therapy fails to restore the severe Th-17: Tc-17 imbalance observed in peripheral blood during simian immunodeficiency virus infection.

PubMed

Kader, M; Bixler, S; Piatak, M; Lifson, J; Mattapallil, J J

2009-10-01

Human immuno deficiency virus and simian immunodeficiency virus infections are characterized by a severe loss of Th-17 cells (IL-17(+)CD4(+) T cells) that has been associated with disease progression and systemic dissemination of bacterial infections. Anti-retroviral therapy (ART) has led to repopulation of CD4(+) T cells in peripheral tissues with little sustainable repopulation in mucosal tissues. Given the central importance of Th-17 cells in mucosal homeostasis, it is not known if the failure of ART to permanently repopulate mucosal tissues is associated with a failure to restore Th-17 cells that are lost during infection. Dynamics of alpha4(+)beta7(hi) CD4(+) T cells in peripheral blood of SIV infected rhesus macaques were evaluated and compared to animals that were treated with ART. The frequency of Th-17 and Tc-17 cells was determined following infection and after therapy. Relative expression of IL-21, IL-23, and TGFbeta was determined using Taqman PCR. Treatment of SIV infected rhesus macaques with anti-retroviral therapy was associated with a substantial repopulation of mucosal homing alpha4(+)beta7(hi)CD4(+) T cells in peripheral blood. This repopulation, however, was not accompanied by a restoration of Th-17 responses. Interestingly, SIV infection was associated with an increase in Tc-17 responses (IL-17(+)CD8(+) T cells) suggesting to a skewing in the ratio of Th-17: Tc-17 cells from a predominantly Th-17 phenotype to a predominantly Tc-17 phenotype. Surprisingly, Tc-17 responses remained high during the course of therapy suggesting that ART failed to correct the imbalance in Th-17 : Tc-17 responses induced following SIV infection. ART was associated with substantial repopulation of alpha4(+)beta7(hi) CD4(+) T cells in peripheral blood with little or no rebound of Th-17 cells. On the other hand, repopulation of alpha4(+)beta7(hi) CD4(+) T cells was accompanied by persistence of high levels of Tc-17 cells in peripheral blood. The dysregulation of Th-17 and Tc-17 responses likely plays a role in disease progression.

IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis

PubMed Central

Chang, Kai-Kai; Liu, Li-Bing; Jin, Li-Ping; Zhang, Bing; Mei, Jie; Li, Hui; Wei, Chun-Yan; Zhou, Wen-Jie; Zhu, Xiao-Yong; Shao, Jun; Li, Da-Jin; Li, Ming-Qing

2017-01-01

Endometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10+Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β. Compared with peripheral CD4+ T cells, endometrial CD4+ T cells highly expressed IL-27 receptors, especially the ectopic endometrium. Under external (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and local (estrogen, IL-6 and TGF-β) environmental regulation, IL-27 from macrophages and endometrial stromal cells (ESCs) induces IL-10 production in Th17 cells in vitro and in vivo. This process may be mediated through the interaction between c-musculoaponeurotic fibrosarconna (c-Maf) and retinoic acid-related orphan receptor gamma t (RORγt), and associated with the upregulation of downstream B lymphocyte-induced maturation protein-1 (Blimp-1). IL-10+Th17 cells, in turn, stimulate the proliferation and implantation of ectopic lesions and accelerate the progression of endometriosis. These results suggest that IL-27 is a pivotal regulator in endometriotic immune tolerance by triggering Th17 cells to produce IL-10 and promoting the rapid growth and implantation of ectopic lesions. This finding provides a scientific basis for potential therapeutic strategies aimed at preventing the development of endometriosis, especially for patients with high levels of IL-10+Th17 cells. PMID:28300844

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sun-Mi, E-mail: lala1647@hanmail.net; Kim, Bo-Young, E-mail: kimboyoung@pusan.ac.kr; Lee, Sae-A, E-mail: saeah486@nate.com

Th1 lymphocytes are predominant in atherosclerotic lesions. However, mechanisms involved in the Th1 predominance are unknown. We have investigated the possibility of Th1 lymphocyte recruitment in a cholesterol-rich milieu. A high cholesterol diet resulted in enhanced expression of CCR5 ligands, including CCL3 and CCL4, but not of proatherogenic CXCR3 ligands, in atherosclerotic arteries of ApoE{sup −/−} mice. 27-Hydroxycholesterol and 7α-hydroxycholesterol, cholesterol oxides (oxysterols) detected in abundance in atherosclerotic lesions, greatly induced the transcription of CCL3 and CCL4 genes in addition to enhancing secretion of corresponding proteins by THP-1 monocytic cells. However, an identical or even higher concentration of cholesterol, 7β-hydroxycholesterol,more » and 7-ketocholsterol did not influence expression of these chemokines. Conditioned media containing the CCR5 ligands secreted from THP-1 cells induced migration of Jurkat T cells expressing CCR5, a characteristic chemokine receptor of Th1 cells, but not of Jurkat T cells that do not express CCR5. The migration of CCR5-expressing Jurkat T cells was abrogated in the presence of a CCR5-neutralizing antibody. 27-Hydroxycholesterol and 7α-hydroxycholesterol enhanced phosphorylation of Akt. Pharmacological inhibitors of phosphoinositide-3-kinase/Akt pathways blocked transcription as well as secretion of CCL3 and CCL4 in conjunction with attenuated migration of CCR5-expressing Jurkat T cells. This is the first report on the involvement of cholesterol oxides in migration of distinct subtype of T cells. We propose that 27-hydroxycholesterol and 7α-hydroxycholesterol can trigger a sequence of events that leads to recruitment of Th1 lymphocytes and phosphoinositide-3-kinase/Akt pathways play a major role in the process. - Graphical abstract: Th1 lymphocytes are predominant in atherosclerotic lesions. However, mechanisms involved in the Th1 predominance are unknown. We have investigated the possibility of Th1 lymphocyte recruitment in a cholesterol-rich milieu. We propose a model via which 27OHChol and 7αOHChol contribute to the predominance of Th1 cells in atherosclerotic lesions on the basis of our results and previous findings. Cholesterol deposited in the artery undergoes oxidative modification to oxysterols. Exposure of monocytic cells to 27OHChol or 7αOHChol results in increased transcription and secretion of CCR5 ligands, like CCL3 and CCL4, which leads to a concentration gradient of the chemokines. Among the lymphocytes attached to cell adhesion molecules expressed on endothelial cells, Th1 cells that express CCR5 recognize the gradient and follow the signal of increasing chemokine concentration towards the source of the chemokines, whereas other subtypes of T cells that do not express CCR5 (Tregs and Th2 cells) do not respond. The preferential infiltration of Th1 cells leads to predominance of Th1 cells. Since oxidized LDL (oxLDL) enhances the expression of cell adhesion molecules on endothelial cells, existence of oxLDL will accelerate the recruitment of Th1 lymphocytes into atherosclerotic lesions in response to the oxysterols. - Highlights: • High-cholesterol diet induces CCR5L expression, like CCL3 and CCL4, in ApoE{sup −/−} mice. • 27OHChol and 7αOHChol enhance secretion of CCL3 and CCL4 by monocytic cells. • The secreted CCR5 ligands promote migration of CCR5-expressing Th1 cells. • We report a mechanism underlying Th1 cell recruitment into atherosclerotic lesions.« less

Up-regulated Th17 cell function is associated with increased peptic ulcer disease in Helicobacter pylori-infection.

PubMed

Bagheri, Nader; Razavi, Alireza; Pourgheysari, Batoul; Azadegan-Dehkordi, Fatemeh; Rahimian, Ghorbanali; Pirayesh, Ashkan; Shafigh, Mohammedhadi; Rafieian-Kopaei, Mahmoud; Fereidani, Rana; Tahmasbi, Kamran; Shirzad, Hedayatollah

2018-06-01

During Helicobacter pylori (H. pylori) infection CD4 + T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. The objective of this study was to determine the number of Th17 cells in gastric mucosa of patients with gastritis and peptic ulcer and determined the relationship between main virulence factor of H. pylori and Th17 cells. A total of 89 H. pylori-infected gastritis patients, 63 H. pylori-infected peptic ulcer patients and 48 H. pylori-negative non-ulcer dysplasia patients were enrolled in this study. The number of Th17 was determined by immunohistochemistry. IL-8 and IL-17A expressions were determined by real-time polymerase chain reaction (qPCR). Also, the grade of chronic and active inflammation was investigated for involvement according to the density of neutrophils and mononuclear in gastric mucosal crypts, from one to all crypts. The number of Th17 cells and the expression of IL-8 and IL-17A in infected patients were significantly higher than uninfected subjects. The number of Th17 cells and the expression of IL-8 and IL-17A in infected patients with peptic ulcer were significantly higher than patients with gastritis. Additionally, the numbers of Th17 cells as well as the expression of IL-8 and IL-17A were positively correlated with the degree of H. pylori density in infected patients with peptic ulcer, while this correlation was negative in infected patients with gastritis. The numbers of Th17 cells as well as the expression of IL-8 and IL-17A were positively correlated with the degree of chronic inflammation. The predominant Th17 cell responses may play a role in the pathogenesis of peptic ulcers disease in infected patients. Copyright © 2018 Elsevier B.V. All rights reserved.

The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

PubMed Central

Khor, Bernard; Gagnon, John D; Goel, Gautam; Roche, Marly I; Conway, Kara L; Tran, Khoa; Aldrich, Leslie N; Sundberg, Thomas B; Paterson, Alison M; Mordecai, Scott; Dombkowski, David; Schirmer, Melanie; Tan, Pauline H; Bhan, Atul K; Roychoudhuri, Rahul; Restifo, Nicholas P; O'Shea, John J; Medoff, Benjamin D; Shamji, Alykhan F; Schreiber, Stuart L; Sharpe, Arlene H; Shaw, Stanley Y; Xavier, Ramnik J

2015-01-01

The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. DOI: http://dx.doi.org/10.7554/eLife.05920.001 PMID:25998054

Mycobacterium tuberculosis impairs dendritic cell functions through the serine hydrolase Hip1.

PubMed

Madan-Lala, Ranjna; Sia, Jonathan Kevin; King, Rebecca; Adekambi, Toidi; Monin, Leticia; Khader, Shabaana A; Pulendran, Bali; Rengarajan, Jyothi

2014-05-01

Mycobacterium tuberculosis is a highly successful human pathogen that primarily resides in host phagocytes, such as macrophages and dendritic cells (DCs), and interferes with their functions. Although multiple strategies used by M. tuberculosis to modulate macrophage responses have been discovered, interactions between M. tuberculosis and DCs are less well understood. DCs are the primary APCs of the immune system and play a central role in linking innate and adaptive immune responses to microbial pathogens. In this study, we show that M. tuberculosis impairs DC cytokine secretion, maturation, and Ag presentation through the cell envelope-associated serine hydrolase, Hip1. Compared to wild-type, a hip1 mutant strain of M. tuberculosis induced enhanced levels of the key Th1-inducing cytokine IL-12, as well as other proinflammatory cytokines (IL-23, IL-6, TNF-α, IL-1β, and IL-18) in DCs via MyD88- and TLR2/9-dependent pathways, indicating that Hip1 restricts optimal DC inflammatory responses. Infection with the hip1 mutant also induced higher levels of MHC class II and costimulatory molecules CD40 and CD86, indicating that M. tuberculosis impairs DC maturation through Hip1. Further, we show that M. tuberculosis promotes suboptimal Ag presentation, as DCs infected with the hip1 mutant showed increased capacity to present Ag to OT-II- and early secreted antigenic target 6-specific transgenic CD4 T cells and enhanced Th1 and Th17 polarization. Overall, these data show that M. tuberculosis impairs DC functions and modulates the nature of Ag-specific T cell responses, with important implications for vaccination strategies.

Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL).

PubMed

Ahmadi, Majid; Abdolmohammadi-Vahid, Samaneh; Ghaebi, Mahnaz; Aghebati-Maleki, Leili; Afkham, Amir; Danaii, Shahla; Abdollahi-Fard, Sedigheh; Heidari, Lida; Jadidi-Niaragh, Farhad; Younesi, Vahid; Nouri, Mohammad; Yousefi, Mehdi

2017-08-01

Women with elevated natural killer (NK) cell frequency and function during pregnancy, suffer from recurrent pregnancy loss (RPL). In the present study, the possible effect of intravenous immunoglobulin (IVIG) administration on Th1 and Th2 cell frequency, cytokine secretion, and expression of transcription factors is compared between RPL patients and control group. Totally, 44 women with a history of RPL (32 women as treated group and 12 as control group) were enrolled in the study. The frequency of Th1 and Th2 lymphocytes, the expression of transcription factors related to these cells and the serum levels of associated cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. All, assessments were performed both before and after treatment with IVIG. A significant reduction in Th1 lymphocyte frequency, transcription factor expression and cytokine levels were observed in IVIG-treated group, while all the above parameters indicated a significant increase for Th2 lymphocytes. Th1/Th2 ratio decreased significantly (p value<0.0001) at the end of treatment and 28 out of 32 (87.5%) women in IVIG-treated group had live birth in comparison with 5 out of 12 (41.6%) in untreated group. IVIG administration proves to be an efficient therapeutic strategy which is able to enhance the success rate of pregnancy through a shift in Th2 responses. Furthermore, IVIG presents efficacy for the treatment of reproduction failures especially in subjects with immune cell abnormalities and increased NK cell level and function. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Polymorphonuclear Neutrophils Are Necessary for the Recruitment of CD8+ T Cells in the Liver in a Pregnant Mouse Model of Chlamydophila abortus (Chlamydia psittaci Serotype 1) Infection

PubMed Central

de Oca, Roberto Montes; Buendía, Antonio J.; Del Río, Laura; Sánchez, Joaquín; Salinas, Jesús; Navarro, Jose A.

2000-01-01

The role of polymorphonuclear neutrophils (PMNs) in the development of the specific immune response against Chlamydophila abortus (Chlamydia psittaci serotype 1) infection was studied in a pregnant mouse model involving treatment with RB6-8C5 monoclonal antibody. PMN depletion significantly affected the immune response in the liver, in which the T-lymphocyte and F4/80+ cell populations decreased, particularly the CD8+ T-cell population. A Th1-like response, characterized by high levels of gamma interferon without detectable levels of interleukin 4 (IL-4) in serum, was observed in both depleted and nondepleted mice, although an increased production of IL-10 was detected in the depleted group. Our results suggest that PMNs play a very important role in the recruitment of other leukocyte populations to the inflammatory foci but have little influence in the polarization of the immune specific response toward a Th1-like response. PMID:10679002

Differentiated State of Initiating Tumor Cells Is Key to Distinctive Immune Responses Seen in H-RasG12V-Induced Squamous Tumors.

PubMed

Podolsky, Michael A; Bailey, Jacob T; Gunderson, Andrew J; Oakes, Carrie J; Breech, Kyle; Glick, Adam B

2017-03-01

Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-Ras G12V is targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On a Rag1 -/- background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more tumors with shorter latency than Rag1 +/+ controls. Adoptive transfer and depletion studies revealed that B-cell and CD4 T-cell cooperation was critical for tumor yield, lymphocyte polarization, and tumor immune phenotype in Rag1 +/+ mice of both models. Coculture of tumor-conditioned B cells with CD4 T cells implicated direct contact for Th1 and regulatory T cell (Treg) polarization, and CD40-CD40L for Th1, Th2, and Treg generation, a response not observed from splenic B cells. Anti-CD40L caused regression of InvRas tumors but enhanced growth in K14Ras, whereas a CD40 agonist mAb had opposite effects in each tumor model. These data show that position of tumor-initiating cells within a stratified squamous epithelial tissue provokes distinct B- and CD4 T-cell interactions, which establish unique tumor microenvironments that regulate tumor development and response to immunotherapy. Cancer Immunol Res; 5(3); 198-210. ©2017 AACR . ©2017 American Association for Cancer Research.

Nongenetically modified Lactococcus lactis-adjuvanted vaccination enhanced innate immunity against Helicobacter pylori.

PubMed

Liu, Wei; Tan, Zhoulin; Liu, Hai; Zeng, Zhiqin; Luo, Shuanghui; Yang, Huimin; Zheng, Lufeng; Xi, Tao; Xing, Yingying

2017-10-01

Gram-positive enhancer matrix particles (GEM) produced by Lactococcus lactis can enhance vaccine-induced immune response. However, the mechanism under which this adjuvant mounts the efficacy of orally administered vaccines remains unexplored. We used a prophylactic mice model to investigate the mechanism of GEM-adjuvanted vaccination. Helicobacter pylori urease-specific antibody response was monitored and detected in murine serum by ELISA. Urease-specific splenic cytokine profile was examined. Gastric inflammatory responses were measured on day 43 or 71 by quantitative real-time PCR, flow cytometry and histology. We found that GEM enhanced the efficiency of oral H. pylori vaccine by promoting innate immunity. The vaccine CUE-GEM composed of GEM particles and recombinant antigen CTB-UE provided protection of immunized mice against H. pylori insult. The protective response was associated with induction of postimmunization gastritis and local Th1/Th17 cell-medicated immune response. We showed that innate inflammatory responses including neutrophil chemokines CXCL1-2, neutrophils, and antimicrobial proteins S100A8 and MUC1 were significantly elevated. Within all infected mice, S100A8 and MUC1 levels were negatively correlated with H. pylori burden. Strikingly, mice receiving GEM also show reduction of colonization, possibly through natural host response pathways to recruit CD4 + T cells and promote S100A8 expression. These findings suggest that GEM-based vaccine may impact Th1/Th17 immunity to orchestrate innate immune response against H. pylori infection. © 2017 John Wiley & Sons Ltd.

Immunoregulation of Bone Marrow-Derived Mesenchymal Stem Cells on the Chronic Cigarette Smoking-Induced Lung Inflammation in Rats

PubMed Central

Li, Xiaoyan; Wang, Junyan; Cao, Jing; Ma, Lijuan; Xu, Jianying

2015-01-01

Impact of bone mesenchymal stem cell (BMSC) transfusion on chronic smoking-induced lung inflammation is poorly understood. In this study, a rat model of smoking-related lung injury was induced and the rats were treated with vehicle or BMSCs for two weeks. Different subsets of CD4+ T cells, cytokines, and anti-elastin in the lungs as well as the lung injury were characterized. Serum and lung inducible nitric oxide synthase (iNOS) and STAT5 phosphorylation in lymphocytes from lung tissue were also analyzed. Results indicated that transfusion of BMSCs significantly reduced the chronic smoking-induced lung injury, inflammation, and levels of lung anti-elastin in rats. The frequency of Th1 and Th17 cells and the levels of IL-2, IL-6, IFN-γ, TNF-α, IL-17, IP-10, and MCP-1 increased, but the frequency of Tregs and IL-10 decreased. Transfusion of BMSCs significantly modulated the imbalance of immune responses by mitigating chronic smoking-increased Th1 and Th17 responses, but enhancing Treg responses in the lungs of rats. Transfusion of BMSCs limited chronic smoking-related reduction in the levels of serum and lung iNOS and mitigated smoking-induced STAT5 phosphorylation in lymphocytes from lung tissue. BMSCs negatively regulated smoking-induced autoimmune responses in the lungs of rats and may be promising for the intervention of chronic smoking-related lung injury. PMID:26665150

Listeria arpJ gene modifies T helper type 2 subset differentiation.

PubMed

Kanoh, Makoto; Maruyama, Saho; Shen, Hua; Matsumoto, Akira; Shinomiya, Hiroto; Przybilla, Karin; Gouin, Edith; Cossart, Pascale; Goebel, Werner; Asano, Yoshihiro

2015-07-15

Although the T-cell subset differentiation pathway has been characterized extensively from the view of host gene regulation, the effects of genes of the pathogen on T-cell subset differentiation during infection have yet to be elucidated. Especially, the bacterial genes that are responsible for this shift have not yet been determined. Utilizing a single-gene-mutation Listeria panel, we investigated genes involved in the host-pathogen interaction that are required for the initiation of T-cell subset differentiation in the early phase of pathogen infection. We demonstrate that the induction of T helper types 1 and 2 (Th1 and Th2) subsets are separate phenomena and are mediated by distinct Listeria genes. We identified several candidate Listeria genes that appear to be involved in the host-Listeria interaction. Among them, arpJ is the strongest candidate gene for inhibiting Th2 subset induction. Furthermore, the analysis utilizing arpJ-deficient Listeria monocytogenes (Lm) revealed that the tumor necrosis factor (TNF) superfamily (Tnfsf) 9-TNF receptor superfamily (Tnfrsf) 9 interaction inhibits the Th2 response during Lm infection. arpJ is the candidate gene for inhibiting Th2 T-cell subset induction. The arpJ gene product influences the expression of Tnfsf/Tnfrsf on antigen-presenting cells and inhibits the Th2 T-cell subset differentiation during Listeria infection. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Lupus Nephritis: An Overview of Recent Findings

PubMed Central

de Zubiria Salgado, Alberto; Herrera-Diaz, Catalina

2012-01-01

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) since it is the major predictor of poor prognosis. In susceptible individuals suffering of SLE, in situ formation and deposit of immune complexes (ICs) from apoptotic bodies occur in the kidneys as a result of an amplified epitope immunological response. IC glomerular deposits generate release of proinflammatory cytokines and cell adhesion molecules causing inflammation. This leads to monocytes and polymorphonuclear cells chemotaxis. Subsequent release of proteases generates endothelial injury and mesangial proliferation. Presence of ICs promotes adaptive immune response and causes dendritic cells to release type I interferon. This induces maturation and activation of infiltrating T cells, and amplification of Th2, Th1 and Th17 lymphocytes. Each of them, amplify B cells and activates macrophages to release more proinflammatory molecules, generating effector cells that cannot be modulated promoting kidney epithelial proliferation and fibrosis. Herein immunopathological findings of LN are reviewed. PMID:22536486

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells

PubMed Central

Ogasawara, Takashi; Kohashi, Yuko; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hatano, Masahiko; Hirata, Hirokuni; Fukushima, Yasutsugu; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi; Arima, Masafumi

2018-01-01

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3′ distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies. PMID:29696026

Role of Macrophages in the Repair Process during the Tissue Migrating and Resident Helminth Infections

PubMed Central

Faz-López, Berenice

2016-01-01

The Th1/Th2/Th17 balance is a fundamental feature in the regulation of the inflammatory microenvironment during helminth infections, and an imbalance in this paradigm greatly contributes to inflammatory disorders. In some cases of helminthiasis, an initial Th1 response could occur during the early phases of infection (acute), followed by a Th2 response that prevails in chronic infections. During the late phase of infection, alternatively activated macrophages (AAMs) are important to counteract the inflammation caused by the Th1/Th17 response and larval migration, limiting damage and repairing the tissue affected. Macrophages are the archetype of phagocytic cells, with the primary role of pathogen destruction and antigen presentation. Nevertheless, other subtypes of macrophages have been described with important roles in tissue repair and immune regulation. These types of macrophages challenge the classical view of macrophages activated by an inflammatory response. The role of these subtypes of macrophages during helminthiasis is a controversial topic in immunoparasitology. Here, we analyze some of the studies regarding the role of AAMs in tissue repair during the tissue migration of helminths. PMID:27648452

Neurofascin and Compact Myelin Antigen-Specific T Cell Response Pattern in Chronic Inflammatory Demyelinating Polyneuropathy Subtypes.

PubMed

Diederich, Jan-Markus; Staudt, Maximilian; Meisel, Christian; Hahn, Katrin; Meinl, Edgar; Meisel, Andreas; Klehmet, Juliane

2018-01-01

The objective of this study is to investigate whether chronic inflammatory demyelinating polyneuropathy (CIDP) and its subtypes differ in their type 1 T-helper (TH1) cell response against nodal/paranodal neurofascin (NF186, NF155) as well as myelin protein zero (P0 180-199) and myelin basic protein (MBP 82-100). Interferon-gamma (IFN-γ) enzyme-linked immunospot assay was used to detect antigen-specific T cell responses in 48 patients suffering typical CIDP ( n  = 18), distal acquired demyelinating polyneuropathy ( n  = 8), multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM; n  = 9), and sensory CIDP ( n  = 13) compared to other non-immune polyneuropathy (ON; n  = 19) and healthy controls ( n  = 9). Compared to controls, MADSAM and sensory CIDP patients showed broadest IFN-γ T cell responses to all four antigens. Positive IFN-γ responses against two or more antigens were highly predictive for CIDP (positive predictive value = 0.95) and were found in 77% of CIDP patients. Patients with limited antigen-specific response were females, more severely affected with neuropathic pain and proximal paresis. The area under the receiver operating characteristics curve (AUC) of NF186 in MADSAM was 0.94 [95% confidential interval (CI) 0.82-1.00] compared to ON. For sensory CIDP, AUC of P0 180-199 was 0.94 (95% CI 0.86-1.00) and for MBP 82-100 0.95 (95% CI 0.88-1.00) compared to ON. Cell-mediated immune responses to (para)nodal and myelin-derived antigens are common in CIDP. TH1 response against NF186 may be used as a biomarker for MADSAM and TH1 responses against P0 180-199 and MBP 82-100 as biomarkers for sensory CIDP. Larger multicenter studies study are warranted in order to establish these immunological markers as a diagnostic tools.

Aberrant in Vivo T Helper Type 2 Cell Response and Impaired Eosinophil Recruitment in Cc Chemokine Receptor 8 Knockout Mice

PubMed Central

Chensue, Stephen W.; Lukacs, Nicholas W.; Yang, Tong-Yuan; Shang, Xiaozhou; Frait, Kirsten A.; Kunkel, Steven L.; Kung, Ted; Wiekowski, Maria T.; Hedrick, Joseph A.; Cook, Donald N.; Zingoni, Alessandra; Narula, Satwant K.; Zlotnik, Albert; Barrat, Franck J.; O'Garra, Anne; Napolitano, Monica; Lira, Sergio A.

2001-01-01

Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (−/−) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8−/− mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo. PMID:11238588

Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells.

PubMed

Luz-Crawford, Patricia; Kurte, Monica; Bravo-Alegría, Javiera; Contreras, Rafael; Nova-Lamperti, Estefania; Tejedor, Gautier; Noël, Danièle; Jorgensen, Christian; Figueroa, Fernando; Djouad, Farida; Carrión, Flavio

2013-06-04

Mesenchymal stem cells (MSCs) are adult, multipotent, stem cells with immunomodulatory properties. The mechanisms involved in the capacity of MSCs to inhibit the proliferation of proinflammatory T lymphocytes, which appear responsible for causing autoimmune disease, have yet to be fully elucidated. One of the underlying mechanisms studied recently is the ability of MSCs to generate T regulatory (Treg) cells in vitro and in vivo from activated peripheral blood mononuclear cells (PBMC), T-CD4+ and also T-CD8(+) cells. In the present work we investigated the capacity of MSCs to generate Treg cells using T-CD4(+) cells induced to differentiate toward the proinflammatory Th1 and Th17 lineages. MSCs were obtained from mouse bone marrow and characterized according to their surface antigen expression and their multilineage differentiation potential. CD4(+) T cells isolated from mouse spleens were induced to differentiate into Th1 or Th17 cells and co-cultured with MSCs added at day 0, 2 or 4 of the differentiation processes. After six days, CD25, Foxp3, IL-17 and IFN-γ expression was assessed by flow cytometry and helios and neuropilin 1 mRNA levels were assessed by RT-qPCR. For the functional assays, the 'conditioned' subpopulation generated in the presence of MSCs was cultured with concanavalin A-activated CD4(+) T cells labeled with carboxyfluorescein succinimidyl ester. Finally, we used the encephalomyelitis autoimmune diseases (EAE) mouse model, in which mice were injected with MSCs at day 18 and 30 after immunization. At day 50, the mice were euthanized and draining lymph nodes were extracted for Th1, Th17 and Treg detection by flow cytometry. MSCs were able to suppress the proliferation, activation and differentiation of CD4(+) T cells induced to differentiate into Th1 and Th17 cells. This substantial suppressive effect was associated with an increase of the percentage of functional induced CD4(+)CD25(+)Foxp3(+) regulatory T cells and IL-10 secretion. However, using mature Th1 or Th17 cells our results demonstrated that while MSCs suppress the proliferation and phenotype of mature Th1 and Th17 cells they did not generate Treg cells. Finally, we showed that the beneficial effect observed following MSC injection in an EAE mouse model was associated with the suppression of Th17 cells and an increase in the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes when administrated at early stages of the disease. This study demonstrated that MSCs contribute to the generation of an immunosuppressive environment via the inhibition of proinflammatory T cells and the induction of T cells with a regulatory phenotype. Together, these results might have important clinical implications for inflammatory and autoimmune diseases.

IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps.

PubMed

Shaw, Joanne L; Fakhri, Samer; Citardi, Martin J; Porter, Paul C; Corry, David B; Kheradmand, Farrah; Liu, Yong-Jun; Luong, Amber

2013-08-15

Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined. The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS. Relative gene expression was evaluated using quantitative real-time polymerase chain reaction. Innate lymphoid cells in inflamed ethmoid sinus mucosa from patients with CRSsNP and CRSwNP were characterized using flow cytometry. Cytokine production from lymphoid cells isolated from inflamed mucosa of patients with CRS was examined using ELISA and intracellular cytokine staining. Elevated expression of ST2, the ligand-binding chain of the IL-33 receptor, was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP and healthy control subjects. An increased percentage of innate lymphoid cells was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP. ST2(+) innate lymphoid cells are a consistent source of IL-13 in response to IL-33 stimulation. Significant induction of IL-33 was observed in epithelial cells derived from patients with CRSwNP compared with patients with CRSsNP in response to stimulation with Aspergillus fumigatus extract. These data suggest a role for sinonasal epithelial cell-derived IL-33 and an IL-33-responsive innate lymphoid cell population in the pathophysiology of CRSwNP demonstrating the functional importance of innate lymphoid cells in Th2-mediated inflammatory disease.

Applications and mechanisms of immunotherapy in allergic rhinitis and asthma.

PubMed

Kappen, Jasper H; Durham, Stephen R; Veen, Hans In 't; Shamji, Mohamed H

2017-01-01

Clinical and immunologic tolerance are hallmarks of successful allergen immunotherapy (AIT). Clinical benefits such as reduced symptoms, pharmacotherapy intake and improvement of quality of life persist following cessation of treatment. Successful AIT is associated with suppression of allergic inflammatory cells such as mast cells, eosinophils and basophils in target organs. Furthermore, AIT down-regulates type 2 innate lymphoid cells and allergen-specific type 2 T-helper (Th2) cells. The immunologic tolerant state following AIT is associated with the induction of distinct phenotypes of regulatory T-cells (T-regs) including interleukin (IL)-10-, IL-35- and transforming growth factor (TGF)-β- producing T-regs and FoxP3 + T-regs. B-cell responses, including the induction of IL-10 + regulatory B-cells (B-regs) and the production of IgG4-associated blocking antibodies are also induced following successful AIT. These events are associated with the suppression of antigen-specific Th2 responses and delayed immune deviation in favour of Th1 type responses. Insight into the mechanisms of AIT has allowed identification of novel biomarkers with potential to predict the clinical response to AIT and also novel therapeutic strategies for more effective and safer AIT.

Exogenous C3 protein enhances the adaptive immune response to polymicrobial sepsis through down-regulation of regulatory T cells.

PubMed

Yuan, Yujie; Ren, Jianan; Cao, Shougen; Zhang, Weiwei; Li, Jieshou

2012-01-01

The role of complement system in bridging innate and adaptive immunity has been confirmed in various invasive pathogens. It is still obscure how complement proteins promote T cell-mediated immune response during sepsis. The aim of this study is to investigate the role of exogenous C3 protein in the T-cell responses to sepsis. Sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type C57BL/6 mice, sham-operated mice for control. Human purified C3 protein (HuC3, 1 mg) was intraperitoneally injected at 6 h post-surgery, with 200 μl phosphate-buffered saline as control. The levels of C3 and cytokines, the expression of FOXP3 and NF-κB, and the percentages of CD4(+) T-cell subsets were compared among the groups at given time points. The polymicrobial sepsis produced considerable release of TNF-α and IL-10, and caused complement C3 exhaustion. Exogenous C3 administration markedly improved the 48 h survival rate, as compared with nontreatment (40% vs. 5%, P<0.01). The expression of FOXP3 protein was increased during sepsis, but can be suppressed by HuC3 administration. A single injection of HuC3 postponed the decline of differentiated Th1 cells, and depressed the activation of Th2/Th17 cells. Besides, the Th1-Th2 shift in late stage of sepsis can be controlled under C3 supplementation. The suppression of NF-κB pathway might be related to the appearance of immunocompromise. The study confirmed the important role of exogenous C3 in up-regulation of adaptive immune response to sepsis. The complement pathway would be a pivotal target for severe sepsis management. Copyright © 2011 Elsevier B.V. All rights reserved.

Airway responses of healthy farmers and nonfarmers to exposure in a swine confinement building.

PubMed

Palmberg, Lena; Larssson, Brit-Marie; Malmberg, Per; Larsson, Kjell

2002-08-01

The objective of the study was to determine whether swine farmers continuously exposed to the farming environment react differently to acute exposure than previously unexposed nonfarmers. Nine healthy nonfarmers, not previously exposed to a farming environment, and eight swine farmers were exposed in a swine confinement building for 3 hours while weighing pigs. Lung function measurements, methacholine challenge tests, and nasal lavages were performed before and after the exposure. Blood samples were drawn repeatedly during the exposure day. Differential cell counts and cytokine levels were analyzed in the nasal lavage fluid and blood. The exposure levels were the same in both groups. Bronchial responsiveness to methacholine increased by a median of 4.0 (25th-75th percentiles 2.2-10.1 among the nonfarmers) and 0.7 (25th-75th percentiles 0.01-3.5 among the farmers) doubled concentration steps. The median serum levels of interleukin-6 increased from 3.8 (25th-75th percentiles <3-5.8) ng/l to 23.7 (25th-75th percentiles 11.6-41.6) ng/l among the nonfarmers and from <3 to 3.8 (25th-75th percentiles 3.1-11.6) ng/l among the swine farmers after the exposure. Swine dust exposure induced a ninefold increase in the total cell counts in the nasal lavage fluid of the nonfarmers, but no significant increase among the swine farmers. The exposure altered lung function and bronchial responsiveness, as well as cell number and cytokines in blood and nasal lavage fluid in previously unexposed nonfarming subjects, whereas only minor alterations were found in the farmers. This finding suggests possible adaptation mechanisms in chronically exposed swine farmers.

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

PubMed Central

Zhu, Jinfang

2015-01-01

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these “type 2 immune response-related” cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. PMID:26044597

A common structural motif in immunopotentiating peptides with sequences present in human autoantigens. Elicitation of a response mediated by monocytes and Th1 cells.

PubMed

López-Moratalla, N; Ruíz, E; López-Zabalza, M J; Santiago, E

1996-12-16

We have found a common structural motif in human autoantigens, heat shock proteins and viral proteins. Peptides modelled after sequences present in those molecules were synthesized and immunomodulating properties tested. They share a core of 15 amino acid residues and a common pattern ('2-6-11' motif) characterized by requirements at fixed positions with respect to a Pro (position 6); an apolar residue or a Lys at position 2; and a Glu, Asp or Lys at position 11. Any of these peptides, when added to cultures of lymphomononuclear cells, caused the activation of monocytes manifested by a release of IL-1 alpha, IL-1 beta and TNF alpha. A release of INF gamma and IL-2 took also place; this release was abolished by anti-DR antibodies. Neither IL-4 nor IL-5 could be detected. This suggests a presentation by APCs and the appearance of cells with a Th1 phenotype. Monocytes and Th1 cells freshly obtained from 12 patients of Graves' disease, 8 of Hashimoto's disease and 8 of primary biliary cirrhosis exhibited activation features similar to those found in cells from healthy subjects incubated in the presence of peptides with a "2-6-11' motif and representing fragments of autoantigens. Their immunopotentiating properties suggest their involvement in the initiation or progression of the autoimmune response mediated by activated monocytes and Th1 cells.

Th17 Cells Coordinate with Th22 Cells in Maintaining Homeostasis of Intestinal Tissues and both are Depleted in SIV-Infected Macaques.

PubMed

Xu, Huanbin; Wang, Xiaolei; Veazey, Ronald S

2014-05-01

Th17 and Th22 cells are thought to function as innate regulators of mucosal antimicrobial responses, tissue inflammation and mucosal integrity, yet their role in persistent SIV infection is still unclear. Here we compared Th17 and Th22 cells in their phenotype, effector/cytokine function, and frequency in blood and intestinal mucosal tissues, and correlate levels with mucosal damage in SIV-infected rhesus macaques. We found that Th17/Th22 cells share similar features in that both highly produce TNF-α and IL-2 and express CCR5 in intestinal tissues; yet very few show cytotoxic functions, as evidenced by lack of IFN-γ and granzyme B production. Further, Th17/Th22 cells display distinct tissue-specific distributions. Both Th17 and Th22 cells and cytokine secretion were significantly depleted in both blood and intestine in chronically SIV-infected macaques. The frequency of Th17 and Th22 cells in the intestine positively correlated with percentages of intestinal CD4+ T cells and negatively with damage to intestinal mucosa, and plasma viral loads in SIV infection. These findings indicate Th17 and Th22 cells share considerable functions, and may coordinate in innate mucosal immune responses, and their regional loss in the intestine may be associated with local mucosal immune dysfunction in persistent HIV/SIV infection.

Th17 Cells Coordinate with Th22 Cells in Maintaining Homeostasis of Intestinal Tissues and both are Depleted in SIV-Infected Macaques

PubMed Central

Xu, Huanbin; Wang, Xiaolei; Veazey, Ronald S.

2014-01-01

Th17 and Th22 cells are thought to function as innate regulators of mucosal antimicrobial responses, tissue inflammation and mucosal integrity, yet their role in persistent SIV infection is still unclear. Here we compared Th17 and Th22 cells in their phenotype, effector/cytokine function, and frequency in blood and intestinal mucosal tissues, and correlate levels with mucosal damage in SIV-infected rhesus macaques. We found that Th17/Th22 cells share similar features in that both highly produce TNF-α and IL-2 and express CCR5 in intestinal tissues; yet very few show cytotoxic functions, as evidenced by lack of IFN-γ and granzyme B production. Further, Th17/Th22 cells display distinct tissue-specific distributions. Both Th17 and Th22 cells and cytokine secretion were significantly depleted in both blood and intestine in chronically SIV-infected macaques. The frequency of Th17 and Th22 cells in the intestine positively correlated with percentages of intestinal CD4+ T cells and negatively with damage to intestinal mucosa, and plasma viral loads in SIV infection. These findings indicate Th17 and Th22 cells share considerable functions, and may coordinate in innate mucosal immune responses, and their regional loss in the intestine may be associated with local mucosal immune dysfunction in persistent HIV/SIV infection. PMID:25364618

Cytokines in the host response to Candida vaginitis: Identifying a role for non-classical immune mediators, S100 alarmins

PubMed Central

Yano, Junko; Noverr, Mairi C.; Fidel, Paul L.

2011-01-01

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects a significant number of women during their reproductive years. More than two decades of research have been focused on the mechanisms associated with susceptibility or resistance to symptomatic infection. Adaptive immunity by Th1-type CD4+ T cells and downstream cytokine responses are considered the predominant host defense mechanisms against mucosal Candida infections. However, numerous clinical and animal studies have indicated no or limited protective role of cells and cytokines of the Th1 or Th2 lineage against vaginal infection. The role for Th17 is only now begun to be investigated in-depth for VVC with results already showing significant controversy. On the other hand, a clinical live-challenge study and an established animal model have shown that a symptomatic condition is intimately associated with the vaginal infiltration of polymorphonuclear leukocytes (PMNs) but with no effect on vaginal fungal burden. Subsequent studies identified S100A8 and S100A9 Alarmins as key chemotactic mediators of the acute PMN response. These chemotactic danger signals appear to be secreted by vaginal epithelial cells upon interaction and early adherence of Candida. Thus, instead of a putative immunodeficiency against Candida involving classical immune cells and cytokines of the adaptive response, the pathological inflammation in VVC is now considered a consequence of a non-productive innate response initiated by non-classical immune mediators. PMID:22182685

Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation.

PubMed

Piconese, Silvia; Gri, Giorgia; Tripodo, Claudio; Musio, Silvia; Gorzanelli, Andrea; Frossi, Barbara; Pedotti, Rosetta; Pucillo, Carlo E; Colombo, Mario P

2009-09-24

The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell-derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17-producing T cells (Th17). In vivo analysis of lymph nodes hosting T-cell priming in experimental autoimmune encephalomyelitis revealed activated MCs, Tregs, and Th17 cells displaying tight spatial interactions, further supporting the occurrence of an MC-mediated inhibition of Treg suppression in the establishment of Th17-mediated inflammatory responses.

Functional characterization of CD4 and CD8 T cell responses among human papillomavirus infected patients with ano-genital warts.

PubMed

Singh, Manjula; Thakral, Deepshi; Rishi, Narayan; Kar, Hemanta Kumar; Mitra, Dipendra Kumar

2017-06-01

Ano-genital warts are considered one of the commonest and highly infectious sexually transmitted infections. These warts are primarily caused by the human papillomavirus (HPV) of the family Papillomaviridae , genus alpha - papillomavirus , species 10 and types 6 and 11. However the high recurrence rate of warts is a matter of serious concern to the patients and a challenge for the treating physician. The conventional treatment options are targeted only to the local site of warts. There is no systemic treatment modality as there is limited understanding of the disease immune-pathogenesis. The role of cell-mediated immunity in combating HPV infection is not clearly defined. Hence the present study is aimed at investigating the CD4 + T helper (Th1 and Th2) and CD8 + T cell responses among wart patients. In this study, we compared HPV6 and HPV11 antigen-specific T cell responses among venereal wart patients relative to healthy controls. Significant decrease in percent frequencies of IFN-γ producing CD4 + and CD8 + T cells were observed in HPV infected wart patients. On the other hand, the frequency of CD4 + T cells expressing IL-4 was significantly increased in these patients as compared to healthy controls. The observed functional skewing of HPV specific T cells from Th1 to Th2 response in patients indicated suppressed immunity against the HPV. Moreover, decrease in CD8 T cell function correlated with poor wart clearance. Our findings open future avenues for exploring potential immunomodulation strategies as an adjunct to standard treatment for better management of these patients and prevention of recurrence.

Endogenous galectin-3 expression levels modulate immune responses in galectin-3 transgenic mice.

PubMed

Chaudhari, Aparna D; Gude, Rajiv P; Kalraiya, Rajiv D; Chiplunkar, Shubhada V

2015-12-01

Galectin-3 (Gal-3), a β-galactoside-binding mammalian lectin, is involved in cancer progression and metastasis. However, there is an unmet need to identify the underlying mechanisms of cancer metastasis mediated by endogenous host galectin-3. Galectin-3 is also known to be an important regulator of immune responses. The present study was aimed at analysing how expression of endogenous galectin-3 regulates host immunity and lung metastasis in B16F10 murine melanoma model. Transgenic Gal-3(+/-) (hemizygous) and Gal-3(-/-) (null) mice exhibited decreased levels of Natural Killer (NK) cells and lower NK mediated cytotoxicity against YAC-1 tumor targets, compared to Gal-3(+/+) (wild-type) mice. On stimulation, Gal-3(+/-) and Gal-3(-/-) mice splenocytes showed increased T cell proliferation than Gal-3(+/+) mice. Intracellular calcium flux was found to be lower in activated T cells of Gal-3(-/-) mice as compared to T cells from Gal-3(+/+) and Gal-3(+/-) mice. In Gal-3(-/-) mice, serum Th1, Th2 and Th17 cytokine levels were found to be lowest, exhibiting dysregulation of pro-inflammatory and anti-inflammatory cytokines balance. Marked decrease in serum IFN-γ levels and splenic IFN-γR1 (IFN-γ Receptor 1) expressing T and NK cell percentages were observed in Gal-3(-/-) mice. On recombinant IFN-γ treatment of splenocytes in vitro, Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 protein expression was higher in Gal-3(-/-) mice compared to that in Gal-3(+/+) and Gal-3(+/-) mice; suggesting possible attenuation of Signal Transducer and Activator of Transcription (STAT) 1 mediated IFN-γ signaling in Gal-3(-/-) mice. The ability of B16F10 melanoma cells to form metastatic colonies in the lungs of Gal-3(+/+) and Gal-3(-/-) mice remained comparable, whereas it was found to be reduced in Gal-3(+/-) mice. Our data indicates that complete absence of endogenous host galectin-3 facilitates lung metastasis of B16F10 cells in mice, which may be contributed by dysregulated immune responses resulting from decreased NK cytotoxicity, disturbed serum Th1, Th2, Th17 cytokine milieu, reduced serum IFN-γ levels and attenuation of splenic STAT1 mediated IFN-γ signalling in Gal-3(-/-) mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

T-cell suppression and selective in vivo activation of TH2 subpopulation by the Entamoeba histolytica 220-kilodalton lectin.

PubMed Central

Talamás-Rohana, P; Schlie-Guzmán, M A; Hernández-Ramírez, V I; Rosales-Encina, J L

1995-01-01

A 220-kDa surface protein (L220) with lectin activity from Entamoeba histolytica trophozoites has been characterized previously (J. L. Rosales-Encina, I. Meza, A. López-de-León, P. Talamás-Rohana, and M. Rojkind, J. Infect. Dis. 156:790-797, 1987). This molecule is involved in the adhesion process (I. Meza, F. Cázares, J. L. Rosales-Encina, P. Talamás-Rohana, and M. Rojkind, J. Infect. Dis. 156:798-805, 1987) and is very immunogenic. In this work, we studied both the humoral and the cellular immune responses to L220. We compared L220 with L220-derived components, such as a fusion peptide (M-11) and chemically obtained peptides (by treating the 220-kDa molecule with N-chlorosuccinimide-urea). Spleen cells from L220-immunized mice were unable to proliferate in vitro when stimulated with the protein. However, a proliferative response was obtained when mice were immunized with the L220-derived fusion peptide or the cleaved lectin. To find out if there was a correlation between the observed responses and TH1 or TH2 activation, we analyzed patterns of cytokine secretion (interleukin-2 [IL-2], IL-4, IL-10, and gamma interferon). Cells from mice immunized with peptides that induced cell proliferation (100, 80, and 47 kDa) with the peptides (P < 0.01) and with the intact molecule secreted IL-2 and gamma interferon, showing a TH1-subset pattern. Conversely, cells from mice immunized with the intact 220-kDa molecule secreted IL-4 and IL-10, typical of a TH2 subpopulation; however, antibodies from each group recognized the 220-kDa molecule as determined by Western blotting (immunoblotting). These results suggest that various epitopes in the 220-kDa molecule generate different response patterns, suppressing or activating T-cell responses. PMID:7558304

Recombinant ESAT-6-CFP10 Fusion Protein Induction of Th1/Th2 Cytokines and FoxP3 Expressing Treg Cells in Pulmonary TB

PubMed Central

Jackson-Sillah, Dolly; Cliff, Jacqueline M.; Mensah, Gloria Ivy; Dickson, Emmanuel; Sowah, Sandra; Tetteh, John K A.; Addo, Kwasi K.; Ottenhoff, Tom H. M.; Bothamley, Graham; Dockrell, Hazel M.

2013-01-01

Background Early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are Mycobacterium tuberculosis (Mtb)–specific antigens that are secreted by actively metabolising bacteria and contribute to the virulence of the bacteria. Their ability to induce Treg and Th2 responses, particularly during the first two weeks of treatment, has not been comprehensively examined to date. The purpose of this work was to characterise Th1, Th2 and Treg responses to rESAT-6-CFP10 fusion protein in TB patients before and during the intensive phase of treatment and in healthy M.bovis BCG vaccinated donors. Methods Forty-six newly diagnosed, HIV-negative, smear-positive pulmonary TB patients and 20 healthy donors were recruited in the UK and Ghana. Their peripheral blood mononuclear cells (PBMC) were used in ex vivo ELISPOT and in vitro cultures to identify immunological parameters of interest. Results The study confirmed that protective immune responses to rESAT-6-CFP10 are impaired in active TB but improved during treatment: circulating antigen-specific IL-4-producing T-cells were increased in untreated TB but declined by two weeks of treatment while the circulating antigen-specific IFN-γ producing T cells which showed a transient rise at one week of treatment, persisted at baseline levels at two months of treatment. In vitro T cell proliferation and IFN-γ production were reduced, while IL-4 and CD4+FoxP3+CD25hi cell expression were increased in response to rESAT-6-CFP10 fusion protein in untreated TB. These responses were reversed during early treatment of TB. Conclusions These observations support further investigations into the possible utility of these parameters as markers of active disease and favourable treatment outcomes. PMID:23826366

Regulatory T cells and TH1/TH2 cytokines as immunodiagnosis keys in systemic autoimmune diseases.

PubMed

Ursaciuc, Cornel; Surcel, Mihaela; Ciotaru, Dan; Dobre, Maria; Pirvu, Ioana Ruxandra; Munteanu, Adriana Narcisa; Alecu, Mihail; Huică, Radu

2010-01-01

We assessed Helper T-cell involvement and possibilities to quantify the cell-based immune response in systemic autoimmune diseases (SAID) in 14 systemic lupus erythematosus (SLE) and 7 rheumatoid arthritis (RA) patients. The goals of investigation were T-CD4+/T-CD8+ ratio, regulatory T cells (Treg) status and TH1/TH2 serum cytokine profiles (IFN-gamma and IL-2, respectively IL-4 and IL-6). SLE group proved significant decreased average Treg value as compared to RA group and controls and showed significant low Treg incidence (86% patients). The distribution of high T-CD4+/T-CD8+ ratio registered no significant distinction among LES and RA groups. SAID patients presented low serum IFN-gamma (86% RA, 60% SLE), high IL-2 (57% RA) and high IL-6 (53% LES), but no significant IL-4 modification. We conclude that Treg percentage remains the only cellular criterion for SAID immune evaluation. In the same time, different secretion mechanisms seem to be involved in SAID, i.e. TH2 in SLE and TH1 in RA.

The in Vitro Inhibitory Effect of Ectromelia Virus Infection on Innate and Adaptive Immune Properties of GM-CSF-Derived Bone Marrow Cells Is Mouse Strain-Independent

PubMed Central

Szulc-Dąbrowska, Lidia; Struzik, Justyna; Cymerys, Joanna; Winnicka, Anna; Nowak, Zuzanna; Toka, Felix N.; Gieryńska, Małgorzata

2017-01-01

Ectromelia virus (ECTV) belongs to the Orthopoxvirus genus of the Poxviridae family and is a natural pathogen of mice. Certain strains of mice are highly susceptible to ECTV infection and develop mousepox, a lethal disease similar to smallpox of humans caused by variola virus. Currently, the mousepox model is one of the available small animal models for investigating pathogenesis of generalized viral infections. Resistance and susceptibility to ECTV infection in mice are controlled by many genetic factors and are associated with multiple mechanisms of immune response, including preferential polarization of T helper (Th) immune response toward Th1 (protective) or Th2 (non-protective) profile. We hypothesized that viral-induced inhibitory effects on immune properties of conventional dendritic cells (cDCs) are more pronounced in ECTV-susceptible than in resistant mouse strains. To this extent, we confronted the cDCs from resistant (C57BL/6) and susceptible (BALB/c) mice with ECTV, regarding their reactivity and potential to drive T cell responses following infection. Our results showed that in vitro infection of granulocyte-macrophage colony-stimulating factor-derived bone marrow cells (GM-BM—comprised of cDCs and macrophages) from C57BL/6 and BALB/c mice similarly down-regulated multiple genes engaged in DC innate and adaptive immune functions, including antigen uptake, processing and presentation, chemokines and cytokines synthesis, and signal transduction. On the contrary, ECTV infection up-regulated Il10 in GM-BM derived from both strains of mice. Moreover, ECTV similarly inhibited surface expression of major histocompatibility complex and costimulatory molecules on GM-BM, explaining the inability of the cells to attain full maturation after Toll-like receptor (TLR)4 agonist treatment. Additionally, cells from both strains of mice failed to produce cytokines and chemokines engaged in T cell priming and Th1/Th2 polarization after TLR4 stimulation. These data strongly suggest that in vitro modulation of GM-BM innate and adaptive immune functions by ECTV occurs irrespective of whether the mouse strain is susceptible or resistant to infection. Moreover, ECTV limits the GM-BM (including cDCs) capacity to stimulate protective Th1 immune response. We cannot exclude that this may be an important factor in the generation of non-protective Th2 immune response in susceptible BALB/c mice in vivo. PMID:29312229

Initial immunological changes as predictors for house dust mite immunotherapy response.

PubMed

Gómez, E; Fernández, T D; Doña, I; Rondon, C; Campo, P; Gomez, F; Salas, M; Gonzalez, M; Perkins, J R; Palomares, F; Blanca, M; Torres, M J; Mayorga, C

2015-10-01

Although specific immunotherapy is the only aetiological treatment for allergic disorders, the underlying mechanisms are not fully understood. Specific immunotherapy induces changes in lymphocyte Th subsets from Th2 to Th1/Treg. Whether differences in immunological patterns underlie patient response to immunotherapy has not yet been established. We studied the immunological changes occurring during a 1-year period of Dermatophagoides pteronyssinus (DP) immunotherapy and their relation with clinical outcome. We included 34 patients with DP allergy who received subcutaneous specific immunotherapy (SCIT) for 1 year. Following treatment, patients were classified as responders or non-responders. Fourteen allergic subjects who did not receive SCIT were included as controls. Peripheral blood was obtained at 0, 1, 3, 6 and 12 months and cultured with nDer p 1. Phenotypic changes, cytokine production and basophil response were analysed by flow cytometry; transcription factors were measured by mRNA quantification. Serum immunoglobulin levels were also measured. After 1 year of SCIT, 82% of cases showed improved symptoms (responders). Although increases in sIgG4 were observed, BAT reactivity was not modified in these patients. Increases in T-BET/FOXP3 as well as nDer p 1-specific Th1/Treg frequencies were also observed, along with a decrease in Th2, Th9 and Th17. These changes corresponded to changes in cytokine levels. Patients who respond well to DP-SCIT show immunological differences compared to non-responders. In responders, basal differences include a lower frequency of Th1 and higher frequencies of Th2, Th9 and Th17 cells. After 1 year of treatment, an increased production of sIgG4 was observed in responders, along with a change in Th2 response towards Th1/Treg. © 2015 John Wiley & Sons Ltd.

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy

PubMed Central

Mackenzie, Karen J.; Nowakowska, Dominika J.; Leech, Melanie D.; McFarlane, Amanda J.; Wilson, Claire; Fitch, Paul M.; O’Connor, Richard A.; Howie, Sarah E. M.; Schwarze, Jürgen; Anderton, Stephen M.

2014-01-01

Peptide immunotherapy (PIT) offers realistic prospects for the treatment of allergic diseases, including allergic asthma. Much is understood of the behavior of naive T cells in response to PIT. However, treatment of patients with ongoing allergic disease requires detailed understanding of the responses of allergen-experienced T cells. CD62L expression by allergen-experienced T cells corresponds to effector/effector memory (CD62Llo) and central memory (CD62Lhi) subsets, which vary with allergen exposure (e.g., during, or out with, pollen season). The efficacy of PIT on different T helper 2 (Th2) cell memory populations is unknown. We developed a murine model of PIT in allergic airway inflammation (AAI) driven by adoptively transferred, traceable ovalbumin-experienced Th2 cells. PIT effectively suppressed AAI driven by unfractionated Th2 cells. Selective transfer of CD62Lhi and CD62Llo Th2 cells revealed that these two populations behaved differently from one another and from previously characterized (early deletional) responses of naive CD4+ T cells to PIT. Most notably, allergen-reactive CD62Llo Th2 cells were long-lived within the lung after PIT, before allergen challenge, in contrast to CD62Lhi Th2 cells. Despite this, PIT was most potent against CD62Llo Th2 cells in protecting from AAI, impairing their ability to produce Th2 cytokines, whereas this capacity was heightened in PIT-treated CD62Lhi Th2 cells. We conclude that Th2 cells do not undergo an early deletional form of tolerance after PIT. Moreover, memory Th2 subsets respond differently to PIT. These findings have implications for the clinical translation of PIT in different allergic scenarios. PMID:24516158

Peroxisome proliferator-activated receptor δ agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis

PubMed Central

Kanakasabai, Saravanan; Chearwae, Wanida; Walline, Crystal C; Iams, Wade; Adams, Suzanne M; Bright, John J

2010-01-01

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARγ, α and δ agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARδ agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-γ and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARδ agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARδ agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases. PMID:20406305

Effect of bacterial endotoxin LPS on expression of INF-gamma and IL-5 in T-lymphocytes from asthmatics.

PubMed

Koch, Andrea; Knobloch, Jürgen; Dammhayn, Cathrin; Raidl, Maria; Ruppert, Andrea; Hag, Haitham; Rottlaender, Dennis; Müller, Katja; Erdmann, Erland

2007-11-01

Epidemiological evidence, in vitro studies and animal models suggest that exposure to the bacterial endotoxin lipopolysaccharide (LPS) can influence the development and severity of asthma. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 and 2 responses, it is unclear whether the LPS ligand TLR 4 is expressed on CD4(+) and CD8(+) T-lymphocytes and if so, whether LPS could modulate the T(H)1 or T(H)2 response in this context. The present authors have, therefore, examined the expression of TLR 4 on peripheral blood CD4(+) and CD8(+) T-lymphocytes using RT-PCR method and FACS analyses. Furthermore, the authors have studied the IL-12-induced expression of the T(H)1-associated cytokine INF-gamma and the IL-4-induced expression of the T(H)2-specific cytokine IL-5 in the presence of LPS using ELISA and compared nine atopic asthmatic subjects and eleven nonatopic normal volunteers. There was an increased anti-CD3/anti-CD28-induced IL-5 expression in T cells of asthmatics compared with normals (p<0.01). In the presence of IL-4 (10 ng/ml), there was an additional increase in IL-5 expression and this additional increase was greater in T cells of normals compared with asthmatics (p<0.05). There was an expression of INF-gamma in anti-CD3/anti-CD28-induced T-lymphocytes without differences between both groups (NS). In the presence of IL-12 (10 ng/ml), there was an increase in INF-gamma release without differences between normals and asthmatics (NS). In the presence of different concentrations of LPS (10 ng/ml, 1 mug/ml), there was a decrease in IL-4-induced IL-5 expression without differences in both groups, indicating an intact T(H)2 response to bacterial endotoxin LPS in asthma. Interestingly, LPS increased the IL-12-induced INF-gamma release in a concentration-dependent manner in T-lymphocytes of normals but this could not be found in T cells of asthmatics, indicating an impaired T(H)1 response to bacterial endotoxin LPS in asthma. In addition, there was a TLR 4 expression on CD4(+) T-lymphocytes of normals and to a lesser extent in asthmatics but this TLR 4 expression could not be found on CD8(+) T cells of both groups. In conclusion, there may be an impaired concentration-dependent LPS-induced T(H)1 rather than a T(H)2 response in allergic adult asthmatics compared with normal volunteers. One reason for this could be a reduced TLR 4 expression on CD4(+) T-lymphocytes of asthmatic subjects.

Dendritic cells pulsed with Pythium insidiosum (1,3)(1,6)-β-glucan, Heat-inactivated zoospores and immunotherapy prime naïve T cells to Th1 differentiation in vitro.

PubMed

Ledur, Pauline C; Tondolo, Juliana S M; Jesus, Francielli P K; Verdi, Camila M; Loreto, Érico S; Alves, Sydney H; Santurio, Janio M

2018-03-01

Pythiosis is a life-threatening disease caused by the fungus-like microorganism Pythium insidiosum that can lead to death if not treated. Since P. insidiosum has particular cell wall characteristics, pythiosis is difficult to treat, as it does not respond well to traditional antifungal drugs. In our study, we investigated a new immunotherapeutic approach with potential use in treatment and in the acquisition of immunity against pythiosis. Dendritic cells from both human and mouse, pulsed with P. insidiosum heat-inactivated zoospore, (1,3)(1,6)-β-glucan and the immunotherapeutic PitiumVac ® efficiently induced naïve T cell differentiation in a Th1 phenotype by the activation of specific Th1 cytokine production in vitro. Heat-inactivated zoospores showed the greatest Th1 response among the tested groups, with a significant increase in IL-6 and IFN-γ production in human cells. In mice cells, we also observed a Th17 pathway induction, with an increase on the IL-17A levels in lymphocytes cultured with β-glucan pulsed DCs. These results suggest a potential use of DCs pulsed with P. insidiosum antigens as a new therapeutic strategy in the treatment and acquisition of immunity against pythiosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Influence of immunotherapy with autologous dendritic cells on innate and adaptive immune response in cancer.

PubMed

Matias, Bruna F; de Oliveira, Tânia M; Rodrigues, Cláudia M; Abdalla, Douglas R; Montes, Letícia; Murta, Eddie F C; Michelin, Márcia A

2013-01-01

The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN-γ, TNF-α, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-β) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-α+ population was significantly increased (P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease (P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-γ and IL-12 and reduced secretion of TGF-β. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer.

Influence of Immunotherapy with Autologous Dendritic Cells on Innate and Adaptive Immune Response in Cancer

PubMed Central

Matias, Bruna F.; de Oliveira, Tânia M.; Rodrigues, Cláudia M.; Abdalla, Douglas R.; Montes, Letícia; Murta, Eddie F.C.; Michelin, Márcia A.

2013-01-01

The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN-γ, TNF-α, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-β) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-α+ population was significantly increased (P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease (P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-γ and IL-12 and reduced secretion of TGF-β. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer. PMID:23926442

Role of distinct CD4(+) T helper subset in pathogenesis of oral lichen planus.

PubMed

Wang, Hui; Zhang, Dunfang; Han, Qi; Zhao, Xin; Zeng, Xin; Xu, Yi; Sun, Zheng; Chen, Qianming

2016-07-01

Oral lichen planus (OLP) is one of the most common chronic inflammatory oral mucosal diseases with T-cell-mediated immune pathogenesis. In subepithelial and lamina propria of OLP local lesions, the presence of CD4(+) T helper (CD4(+) Th) cells appeared as the major lymphocytes. These CD4(+) T lymphocytes can differentiate into distinct Th cell types such as Th1, Th2, Treg, Th17, Th22, Th9, and Tfh within the context of certain cytokines environment. Growing evidence indicated that Th1/Th2 imbalance may greatly participate into the cytokine network of OLP immunopathology. In addition, Th1/Th2 imbalance can be regulated by the Treg subset and also greatly influenced by the emerging novel CD4(+) Th subset Th17. Furthermore, the presence of novel subsets Th22, Th9 and Tfh in OLP patients is yet to be clarified. All these Th subsets and their specific cytokines may play a critical role in determining the character, extent and duration of immune responses in OLP pathogenesis. Therefore, we review the roles of distinct CD4(+) Th subsets and their signature cytokines in determining disease severity and susceptibility of OLP and also reveal the novel therapeutic strategies based on T lymphocytes subsets in OLP treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells

PubMed Central

Spolski, Rosanne; Robertson, Avril A. B.; Klos, Andreas; Rheinheimer, Claudia; Dutow, Pavel; Woodruff, Trent M.; Yu, Zu Xi; O'Neill, Luke A.; Coll, Rebecca C.; Sher, Alan; Leonard, Warren J.; Köhl, Jörg; Monk, Pete; Cooper, Matthew A.; Arno, Matthew; Afzali, Behdad; Lachmann, Helen J.; Cope, Andrew P.; Mayer-Barber, Katrin D.; Kemper, Claudia

2016-01-01

The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4+ T cells and initiates caspase-1–dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (TH1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to “innate immune cells” but is an integral component of normal adaptive TH1 responses. PMID:27313051

HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses in fractionated γ-irradiated mice by modulating the IL-12p70-STAT4 signaling pathway.

PubMed

Park, Hae-Ran; Jo, Sung-Kee; Choi, Nam-Hee; Jung, Uhee

2012-05-01

Whole body irradiated mice appear to experience a down-regulation of the helper T (Th)1-like immune response, and maintain a persistent immunological imbalance. In the current study, we evaluated the effect of HemoHIM (an herbal product made from Angelica Radix, Cnidium officinale , and Paeonia japonica cultivated in Korea) to ameliorate the immunological imbalance induce in fractionated γ-irradiated mice. The mice were exposed to γ rays twice a week (0.5 Gy fractions) for a total dose of 5 Gy, and HemoHIM was administrated orally from 1 week before the first irradiation to 1 week before the final analysis. All experiments were performed 4 and 6 months after their first exposure. HemoHIM ameliorated the Th1- and Th2-related immune responses normally occur in irradiated mice with or without dinitrophenylated keyhole limpet hemocyanin immunization. HemoHIM also restored the natural killer cell activities without changing the percentage of natural killer cells in irradiated mice. Furthermore, the administration of HemoHIM prevented the reduction in levels of interleukin-12p70 in irradiated mice. Finally, we found that HemoHIM enhanced the phosphorylation of signal transducer and activator of transcription (STAT) 4 that was reduced in irradiated mice. Our findings suggest that HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses by modulating the IL-12p70/pSTAT4 signaling pathway.

Outer membrane protein a of Salmonella enterica serovar Typhimurium activates dendritic cells and enhances Th1 polarization

PubMed Central

2010-01-01

Background Typhoid, which is caused by Salmonella enterica serovar Typhimurium, remains a major health concern worldwide. Multidrug-resistant strains of Salmonella have emerged which exhibit increased survivability and virulence, thus leading to increased morbidity. However, little is known about the protective immune response against this microorganism. The outer membrane protein (Omp)A of bacteria plays an important role in pathogenesis. Results We purified OmpA from S. enterica serovar Typhimurium (OmpA-sal) and characterized the role of OmpA-sal in promoting adaptive and innate immune responses. OmpA-sal functionally activated bone marrow-derived dendritic cells by augmenting expression of CD80, CD86, and major histocompatibility complex classes I and II. Interestingly, OmpA-sal induced production of interferon-γ from T cells in mixed lymphocyte reactions, thus indicating Th1-polarizing capacity. The expression of surface markers and cytokine production in dendritic cells was mediated by the TLR4 signaling pathway in a TLR4 Knock-out system. Conclusions Our findings suggest that OmpA-sal modulates the adaptive immune responses to S. enterica serovar Typhimurium by activating dendritic cells and driving Th1 polarization, which are important properties to consider in the development of effective S. enterica serovar Typhimurium vaccines and immunotherapy adjuvant. PMID:20950448

Definition of a pool of epitopes that recapitulates the T cell reactivity against major house dust mite allergens.

PubMed

Hinz, D; Oseroff, C; Pham, J; Sidney, J; Peters, B; Sette, A

2015-10-01

Allergens from house dust mites (HDM) are a common cause of asthma. Der p and Der f from Dermatophagoides sp. are strong immunogens in humans. Allergen extracts are used to study T helper (Th2) cell responses to HDM, which are implicated in the development and regulation of allergic disease. To define an epitope mixture that recapitulates, and might substitute for, HDM extract in terms of detecting and characterizing Th2 cell responses. Peripheral blood mononuclear cells (PBMC) from 52 HDM allergic and 10 non-allergic individuals were stimulated with HDM extracts and assayed with a set of 178 peptides spanning mite allergens group Der p 1, 2, 23 and Der f group 1 and 2 allergens. A pool of the most dominant T cell epitopes identified in the present study and from published literature was assembled and tested for ex vivo T cell responses. Correlation with HDM-specific IgE titres was examined. Patterns of T cell reactivity to Der p and Der f - derived peptides revealed a large number of epitopes. Clear patterns of immunodominance were apparent, with HDM allergen group 1 and 2 dominant over group 23. Furthermore, within a given antigen, 6-11 epitopes accounted for the vast majority of responses. Based on these results and published data, a comprehensive dust mite pool (DMP) of epitopes was designed and found to allow detection of ex vivo T cell responses. DMP ex vivo reactivity correlated with HDM-specific IgE titres and was similar to that detected with commonly used HDM extracts. Ex vivo DMP stimulation was associated with a predominant Th2 response in allergic donors, and minor reactivity of T cells producing IFNγ, IL17 and IL10. A detailed map of Der p and Der f antigens defined a pool of epitopes that can be used to detect ex vivo HDM responses. © 2015 John Wiley & Sons Ltd.

Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides-As Antigens for Th Cells.

PubMed

Aas-Hanssen, Kristin; Thompson, Keith M; Bogen, Bjarne; Munthe, Ludvig A

2015-01-01

Systemic lupus erythematosus (SLE) is marked by a T helper (Th) cell-dependent B cell hyperresponsiveness, with frequent germinal center reactions, and gammaglobulinemia. A feature of SLE is the finding of IgG autoantibodies specific for dsDNA. The specificity of the Th cells that drive the expansion of anti-dsDNA B cells is unresolved. However, anti-microbial, anti-histone, and anti-idiotype Th cell responses have been hypothesized to play a role. It has been entirely unclear if these seemingly disparate Th cell responses and hypotheses could be related or unified. Here, we describe that H chain CDR3 idiotypes from IgG(+) B cells of lupus mice have sequence similarities with both microbial and self peptides. Matched sequences were more frequent within the mutated CDR3 repertoire and when sequences were derived from lupus mice with expanded anti-dsDNA B cells. Analyses of histone sequences showed that particular histone peptides were similar to VDJ junctions. Moreover, lupus mice had Th cell responses toward histone peptides similar to anti-dsDNA CDR3 sequences. The results suggest that Th cells in lupus may have multiple cross-reactive specificities linked to the IgVH CDR3 Id-peptide sequences as well as similar DNA-associated protein motifs.

T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic programming

PubMed Central

Yang, Kai; Shrestha, Sharad; Zeng, Hu; Karmaus, Peer W.F.; Neale, Geoffrey; Vogel, Peter; Guertin, David A.; Lamb, Richard F.; Chi, Hongbo

2014-01-01

SUMMARY Naïve T cells respond to antigen stimulation by exiting from quiescence and initiating clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor-mTORC1-dependent metabolic programming is a central determinant of this transitional process. Loss of Raptor abrogated T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinated multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further linked glucose metabolism to the initiation of Th2 cell differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor-mTORC1 integrated T cell receptor and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor-mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity. PMID:24315998

The effect of three-monthly albendazole treatment on Th2 responses: Differential effects on IgE and IL-5.

PubMed

de Ruiter, K; Tahapary, D L; Wammes, L J; Wiria, A E; Hamid, F; van Lieshout, L; Smit, J W A; Houwing-Duistermaat, J J; Sartono, E; Supali, T; Yazdanbakhsh, M

2017-06-01

Helminth parasites induce a strong Th2 response, characterized by high levels of IgE and elevated signature cytokines such as IL-5. As many global deworming programmes are underway, there is concern that this might lead to emergence of Th1-mediated pathologies when the counterbalancing helminth-induced Th2 response is absent. Therefore, we assessed the effect of deworming on Th2-mediated responses in a household-clustered randomized controlled trial in Indonesia. Total plasma IgE and whole-blood IL-5 responses to mitogen phytohaemagglutinin (PHA) were measured in 1494 and 682 subjects, respectively, at baseline, 9 and 21 months after three-monthly single-dose treatment with albendazole or placebo. Anthelmintic treatment did not result in complete removal of helminth infections in the community. However, treatment significantly decreased IgE levels in albendazole- compared to placebo-treated subjects. IL-5 responses to PHA were not significantly affected by anthelmintic treatment and tended to increase in albendazole-treated subjects, indicating that intensive treatment of helminth parasites has different outcomes on B-cell (IgE levels) and T-cell (IL-5) responses. The data shows that 2 years of deworming can have differential effects on responses typified as Th2-mediated, which needs to be taken into account when examining the impact of helminths on noncommunicable diseases. © 2017 John Wiley & Sons Ltd.

Evaluation of Th1/Th2-Related Immune Response against Recombinant Proteins of Brucella abortus Infection in Mice.

PubMed

Im, Young Bin; Park, Woo Bin; Jung, Myunghwan; Kim, Suk; Yoo, Han Sang

2016-06-28

Brucellosis is a zoonotic disease caused by Brucella, a genus of gram-negative bacteria. Cytokines have key roles in the activation of innate and acquired immunities. Despite several research attempts to reveal the immune responses, the mechanism of Brucella infection remains unclear. Therefore, immune responses were analyzed in mice immunized with nine recombinant proteins. Cytokine production profiles were analyzed in the RAW 264.7 cells and naive splenocytes after stimulation with three recombinant proteins, metal-dependent hydrolase (r0628), bacterioferritin (rBfr), and thiamine transporter substrate-binding protein (rTbpA). Immune responses were analyzed by ELISA and ELISpot assay after immunization with proteins in mice. The production levels of NO, TNF-α, and IL-6 were time-dependently increased after having been stimulated with proteins in the RAW 264.7 cells. In naive splenocytes, the production of IFN-γ and IL-2 was increased after stimulation with the proteins. It was concluded that two recombinant proteins, r0628 and rTbpA, showed strong immunogenicity that was induced with Th1-related cytokines IFN-γ, IL-2, and TNF-α more than Th2-related cytokines IL-6, IL-4, and IL-5 in vitro. Conversely, a humoral immune response was activated by increasing the number of antigen-secreting cells specifically. Furthermore, these could be candidate diagnosis antigens for better understanding of brucellosis.

Mycobacterium tuberculosis Rv1987 induces Th2 immune responses and enhances Mycobacterium smegmatis survival in mice.

PubMed

Sha, Shanshan; Shi, Xiaoxia; Deng, Guoying; Chen, Lina; Xin, Yi; Ma, Yufang

2017-04-01

Mycobacterium tuberculosis can interfere with host immune response and escape clearance through its specific antigens. M. tuberculosis Rv1987 encoded by region of difference (RD)-2 gene is a secretory protein with immunogenic potency. Here, we investigated the impact of Rv1987 on host cytokine responses and T cell polarization in mouse aerosol model. A recombinant M. smegmatis mc 2 155 strain that overexpressed Rv1987 protein (named MS1987) was constructed and used to infect C57BL/6 mice. The mc 2 155 harbored the empty vector (named MSVec) was as a control. The results showed that MS1987 challenged mice promoted Th2-biased cytokine responses with lower secretion of IFN-γ but higher production of IL-4 and Rv1987-specific IgG antibody compared to MSVec infected mice. Neutrophilic inflammation and high bacterial burden were observed in the lung tissues of MS1987 infected mice probably own to the failed Th1 cell immunity. Besides, subcutaneous injection of Rv1987 protein could mediate the Th1 cytokine responses caused by M. bovis BCG in mice. These results indicated that M. tuberculosis Rv1987 protein could modulate host immune response towards Th2 profile, which probably contributed to the immune evasion of bacteria from host elimination. Copyright © 2017 Elsevier GmbH. All rights reserved.

Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage

PubMed Central

Quispe Calla, Nirk E.; Pavelko, Stephen D.; Cherpes, Thomas L.

2016-01-01

While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response. PMID:27606424

Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo.

PubMed

Ulges, Alexander; Klein, Matthias; Reuter, Sebastian; Gerlitzki, Bastian; Hoffmann, Markus; Grebe, Nadine; Staudt, Valérie; Stergiou, Natascha; Bohn, Toszka; Brühl, Till-Julius; Muth, Sabine; Yurugi, Hajime; Rajalingam, Krishnaraj; Bellinghausen, Iris; Tuettenberg, Andrea; Hahn, Susanne; Reißig, Sonja; Haben, Irma; Zipp, Frauke; Waisman, Ari; Probst, Hans-Christian; Beilhack, Andreas; Buchou, Thierry; Filhol-Cochet, Odile; Boldyreff, Brigitte; Breloer, Minka; Jonuleit, Helmut; Schild, Hansjörg; Schmitt, Edgar; Bopp, Tobias

2015-03-01

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3(+) Treg cell subpopulation that was unable to control the maturation of IRF4(+)PD-L2(+) dendritic cells required for the development of TH2 responses in vivo.

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

PubMed Central

Rui, Yuxiang; Honjo, Tasuku; Chikuma, Shunsuke

2013-01-01

Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1−/−) develop spontaneous autoimmune diseases. PD-1−/− mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1−/− mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1−/− recombination activating gene (RAG)2−/− mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2−/− mice. This result suggested PD-1’s involvement in the regulation of innate immune responses. Mice reconstituted with PD-1−/− RAG2−/− bone marrow and PD-1+/+ CD4+ T cells developed more severe EAE compared with the ones reconstituted with PD-1+/+ RAG2−/− bone marrow and PD-1+/+ CD4+ T cells. We found that upon recognition of HKMTB, CD11b+ macrophages from PD-1−/− mice produced very high levels of IL-6, which helped promote naive CD4+ T-cell differentiation into IL-17–producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells. PMID:24043779

Mycobacterium tuberculosis impairs dendritic cell functions through the serine hydrolase Hip1

PubMed Central

Madan-Lala, Ranjna; Sia, Jonathan Kevin; King, Rebecca; Adekambi, Toidi; Monin, Leticia; Khader, Shabaana A; Pulendran, Bali; Rengarajan, Jyothi

2014-01-01

Mycobacterium tuberculosis (Mtb) is a highly successful human pathogen that primarily resides in host phagocytes, such as macrophages and dendritic cells (DCs), and interferes with their functions. While multiple strategies used by Mtb to modulate macrophage responses have been discovered, interactions between Mtb and DCs are less well understood. DCs are the primary antigen presenting acells (APCs) of the immune system and play a central role in linking innate and adaptive immune responses to microbial pathogens. In this study we show that Mtb impairs DC cytokine secretion, maturation and antigen presentation through the cell envelope-associated serine hydrolase Hip1. Compared to wild type, a hip1 mutant strain of Mtb induced enhanced levels of the key T helper 1 (Th1)-inducing cytokine IL-12, as well as other proinflammatory cytokines (IL-23, IL-6, TNF-α, IL-1β, IL-18) in DCs via MyD88- and TLR2/9-dependent pathways, indicating that Hip1 restricts optimal DC inflammatory responses. Infection with the hip1 mutant also induced higher levels of MHC class II and co-stimulatory molecules, CD40 and CD86, indicating that Mtb impairs DC maturation through Hip1. Further, we show that Mtb promotes sub-optimal antigen presentation, as DCs infected with the hip1 mutant showed increased capacity to present antigen to OT-II- and early secreted antigenic target 6 (ESAT-6)-specific transgenic CD4 T cells and enhanced Th1 and Th17 polarization. Overall, these data show that Mtb impairs DC functions and modulates the nature of antigen-specific T cell responses, with important implications for vaccination strategies. PMID:24659689

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation.

PubMed

Link, C S; Teipel, R; Heidenreich, F; Rücker-Braun, E; Schmiedgen, M; Reinhardt, J; Oelschlägel, U; von Bonin, M; Middeke, J M; Muetherig, A; Trautmann-Grill, K; Platzbecker, U; Bornhäuser, M; Schetelig, J

2016-06-01

Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

Hygiene hypothesis and prevalence of glomerulonephritis.

PubMed

Hurtado, Abdias; Johnson, Richard J

2005-08-01

The hygiene hypothesis was proposed to explain the marked increase in allergies that has been observed in industrialized (Westernized) societies. This hypothesis proposes that early and frequent exposure to bacterial and other antigens, such as is common in developing nations, leads to a normal Th1 response, but that better public hygiene and less infections observed in industrialized nations may lead to persistence of the Th2 phenotype and thereby increase our risk for developing allergies. Infection early in life with measles or hepatitis A virus, immunization with bacille Calmette-Guérin, certain gastrointestinal bacteria (lactobacillus), and environmental endotoxin exposure may protect individuals from developing allergy in adulthood. Paradoxically, infestation by parasites stimulates a Th2-cell response; however, the incidence of allergic disease is very low, perhaps due to the stimulation of T-regulatory lymphocytes that can downregulate Th1 and Th2 responses. Some types of human glomerulonephritis (GN) have Th1-predominant immune responses, including crescentic and membranoproliferative GN, whereas other types of GN have a predominant Th2 immune response, including membranous nephropathy, minimal change disease, and immunoglobulin A nephropathy. A review of the prevalence of specific GN shows that the higher prevalence of membranoproliferative GN in developing countries and the higher frequency of immunoglobulin A nephropathy and minimal change disease in industrialized countries could be explained by the hygiene hypothesis. We suggest that studies examining Th1/Th2 balance, particularly as it develops in childhood, should be performed to determine if early polarization of the immune response is responsible for the later development of specific forms of GN.

Th-1 polarization is regulated by dendritic-cell comparison of MHC class I and class II antigens

PubMed Central

Xing, Dongxia; Li, Sufang; Robinson, Simon N.; Yang, Hong; Steiner, David; Komanduri, Krishna V.; Shpall, Elizabeth J.

2009-01-01

In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) must interpret a complex array of stimuli, many of which are poorly understood. Here we demonstrate that Th-1 polarization is heavily influenced by DC-autonomous phenomena triggered by the loading of DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, class I and II peptide epitopes exhibiting significant amino acid sequence overlap (such as would be physiologically present during infectious processes requiring Th-1 immunity for clearance). Data were derived from 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these “Th-1 DCs” exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance generation of CD8+ T lymphocytes. Mechanistically, tRNA-synthetases were implicated as components of a putative sensor complex involved in the comparison of class I and II epitopes. These data provide rigorous conceptual explanations for the process of Th-1 polarization and the antigenic specificity of cognate T-cell help, enhance the understanding of Th-1 responses, and should contribute to the formulation of more effective vaccination strategies. PMID:19171878

Cellular and humoral immune responses during tuberculosis infection: useful knowledge in the era of biological agents.

PubMed

Matucci, Andrea; Maggi, Enrico; Vultaggio, Alessandra

2014-05-01

In this review, recent insights into innate and adaptive cellular and humoral immune response to Mycobacterium tuberculosis (Mtb) are discussed and the role of specific cytokines such as tumor necrosis factor-α (TNF-α) is highlighted. According to recent findings, the immune system plays a key role in avoiding mycobacteria dissemination. The importance of different cell types (macrophages, dendritic cells, interferon-γ-producing T cells) as well as the production of proinflammatory cytokines such as interleukin 6 (IL-6), IL-12, and IL-23/IL-17 have been demonstrated. Alveolar macrophages are considered the first cells infected by Mtb during respiratory infection. Mtb proliferates within alveolar macrophages and dendritic cells and induces the release of cytokines such as TNF-α, IL-1, IL-6, and IL-12. Toll-like receptors-stimulated dendritic cells link innate and adaptive immunity by promoting polarization of effector T cells. The efficient induction of Th1 immunity is decisive in defense against Mtb. In fact, host effector immune response against Mtb is related to the presence of a Th1 response. The definition of the cellular and molecular mechanisms involved in the immune response to Mtb can be helpful in developing new preventive strategies to avoid infection relapse, particularly in patients treated with biological agents.

Diverse functions of miR-17-92 cluster microRNAs in T helper cells.

PubMed

Baumjohann, Dirk

2018-06-01

T helper (Th) cells are critically involved in adaptive immune responses against various pathogens. In contrast, dysregulated T helper cell responses are associated with a variety of diseases, including autoimmunity, allergies, and cancer. Differentiation of naïve CD4 + T cells into effector T helper cell subsets, including Th1, Th2, Th17, Treg, and T follicular helper (Tfh), requires precise dosing of signaling molecules and transcription factors. MicroRNAs (miRNAs), which are small endogenously expressed RNAs that regulate gene expression, play important roles in these processes. The miR-17-92 cluster, a miRNA polycistron also known as oncomiR-1, has emerged as a central integrator of gene expression events that govern T helper cell differentiation pathways. The complexity of miR-17-92-mediated gene regulation lies in the nature of this miRNA cluster, which consists of six different miRNAs. Individual miR-17-92 miRNAs, albeit initially transcribed as one transcript, can have cooperative or opposing effects on biological processes. Therefore, a better understanding of the molecular regulation of miR-17-92 and its downstream networks will provide important insights into T helper cell differentiation and diversity that may be harnessed for the design of advanced T cell-targeting therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

T helper type 17 cells contribute to anti-tumour immunity and promote the recruitment of T helper type 1 cells to the tumour.

PubMed

Nuñez, Sarah; Saez, Juan Jose; Fernandez, Dominique; Flores-Santibañez, Felipe; Alvarez, Karla; Tejon, Gabriela; Ruiz, Paulina; Maldonado, Paula; Hidalgo, Yessia; Manriquez, Valeria; Bono, Maria Rosa; Rosemblatt, Mario; Sauma, Daniela

2013-05-01

T helper type 17 (Th17) lymphocytes are found in high frequency in tumour-burdened animals and cancer patients. These lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, have a well-defined role in the development of inflammatory and autoimmune pathologies; however, their function in tumour immunity is less clear. We explored possible opposing anti-tumour and tumour-promoting functions of Th17 cells by evaluating tumour growth and the ability to promote tumour infiltration of myeloid-derived suppressor cells (MDSC), regulatory T cells and CD4(+)  interferon-γ(+) cells in a retinoic acid-like orphan receptor γt (RORγt) -deficient mouse model. A reduced percentage of Th17 cells in the tumour microenvironment in RORγt-deficient mice led to enhanced tumour growth, that could be reverted by adoptive transfer of Th17 cells. Differences in tumour growth were not associated with changes in the accumulation or suppressive function of MDSC and regulatory T cells but were related to a decrease in the proportion of CD4(+) T cells in the tumour. Our results suggest that Th17 cells do not affect the recruitment of immunosuppressive populations but favour the recruitment of effector Th1 cells to the tumour, thereby promoting anti-tumour responses. © 2012 Blackwell Publishing Ltd.

A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation.

PubMed

Montoya, Misty M; Maul, Julia; Singh, Priti B; Pua, Heather H; Dahlström, Frank; Wu, Nanyan; Huang, Xiaozhu; Ansel, K Mark; Baumjohann, Dirk

2017-07-15

Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6 + RAR-related orphan receptor (ROR)γt + Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt, and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in mouse and human CD4 + T cells, revealing functional conservation. miR-18a directly targeted Smad4 , Hif1a , and Rora , all key transcription factors in the Th17 cell gene-expression program. These findings indicate that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster. Copyright © 2017 by The American Association of Immunologists, Inc.

Interleukin-21-Producing CD4(+) T Cells Promote Type 2 Immunity to House Dust Mites.

PubMed

Coquet, Jonathan M; Schuijs, Martijn J; Smyth, Mark J; Deswarte, Kim; Beyaert, Rudi; Braun, Harald; Boon, Louis; Karlsson Hedestam, Gunilla B; Nutt, Steven L; Hammad, Hamida; Lambrecht, Bart N

2015-08-18

Asthma is a T helper 2 (Th2)-cell-mediated disease; however, recent findings implicate Th17 and innate lymphoid cells also in regulating airway inflammation. Herein, we have demonstrated profound interleukin-21 (IL-21) production after house dust mite (HDM)-driven asthma by using T cell receptor (TCR) transgenic mice reactive to Dermatophagoides pteronyssinus 1 and an IL-21GFP reporter mouse. IL-21-producing cells in the mediastinal lymph node (mLN) bore characteristics of T follicular helper (Tfh) cells, whereas IL-21(+) cells in the lung did not express CXCR5 (a chemokine receptor expressed by Tfh cells) and were distinct from effector Th2 or Th17 cells. Il21r(-/-) mice developed reduced type 2 responses and the IL-21 receptor (IL-21R) enhanced Th2 cell function in a cell-intrinsic manner. Finally, administration of recombinant IL-21 and IL-25 synergistically promoted airway eosinophilia primarily via effects on CD4(+) lymphocytes. This highlights an important Th2-cell-amplifying function of IL-21-producing CD4(+) T cells in allergic airway inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

Bifidobacterium breve attenuates murine dextran sodium sulfate-induced colitis and increases regulatory T cell responses.

PubMed

Zheng, Bin; van Bergenhenegouwen, Jeroen; Overbeek, Saskia; van de Kant, Hendrik J G; Garssen, Johan; Folkerts, Gert; Vos, Paul; Morgan, Mary E; Kraneveld, Aletta D

2014-01-01

While some probiotics have shown beneficial effects on preventing or treating colitis development, others have shown no effects. In this study, we have assessed the immunomodulating effects of two probiotic strains, Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) on T cell polarization in vitro, using human peripheral blood mononuclear cells (PBMC), and in vivo, using murine dextran sodium sulfate (DSS) colitis model. With respect to the latter, the mRNA expression of T cell subset-associated transcription factors and cytokines in the colon was measured and the T helper type (Th) 17 and regulatory T cell (Treg) subsets were determined in the Peyer's patches. Both L. rhamnosus and B. breve incubations in vitro reduced Th17 and increased Th2 cell subsets in human PBMCs. In addition, B. breve incubation was also able to reduce Th1 and increase Treg cell subsets in contrast to L. rhamnosus. In vivo intervention with B. breve, but not L. rhamnosus, significantly attenuated the severity of DSS-induced colitis. In DSS-treated C57BL/6 mice, intervention with B. breve increased the expression of mRNA encoding for Th2- and Treg-associated cytokines in the distal colon. In addition, intervention with B. breve led to increases of Treg and decreases of Th17 cell subsets in Peyer's patches of DSS-treated mice. B. breve modulates T cell polarization towards Th2 and Treg cell-associated responses in vitro and in vivo. In vivo B. breve intervention ameliorates DSS-induced colitis symptoms and this protective effect may mediated by its effects on the T-cell composition.

Bifidobacterium breve Attenuates Murine Dextran Sodium Sulfate-Induced Colitis and Increases Regulatory T Cell Responses

PubMed Central

Zheng, Bin; van Bergenhenegouwen, Jeroen; Overbeek, Saskia; van de Kant, Hendrik J. G.; Garssen, Johan; Folkerts, Gert; Vos, Paul; Morgan, Mary E.; Kraneveld, Aletta D.

2014-01-01

While some probiotics have shown beneficial effects on preventing or treating colitis development, others have shown no effects. In this study, we have assessed the immunomodulating effects of two probiotic strains, Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) on T cell polarization in vitro, using human peripheral blood mononuclear cells (PBMC), and in vivo, using murine dextran sodium sulfate (DSS) colitis model. With respect to the latter, the mRNA expression of T cell subset-associated transcription factors and cytokines in the colon was measured and the T helper type (Th) 17 and regulatory T cell (Treg) subsets were determined in the Peyer's patches. Both L. rhamnosus and B. breve incubations in vitro reduced Th17 and increased Th2 cell subsets in human PBMCs. In addition, B. breve incubation was also able to reduce Th1 and increase Treg cell subsets in contrast to L. rhamnosus. In vivo intervention with B. breve, but not L. rhamnosus, significantly attenuated the severity of DSS-induced colitis. In DSS-treated C57BL/6 mice, intervention with B. breve increased the expression of mRNA encoding for Th2- and Treg-associated cytokines in the distal colon. In addition, intervention with B. breve led to increases of Treg and decreases of Th17 cell subsets in Peyer's patches of DSS-treated mice. B. breve modulates T cell polarization towards Th2 and Treg cell-associated responses in vitro and in vivo. In vivo B. breve intervention ameliorates DSS-induced colitis symptoms and this protective effect may mediated by its effects on the T-cell composition. PMID:24787575

Interleukin 22 Promotes Blood Pressure Elevation and Endothelial Dysfunction in Angiotensin II-Treated Mice.

PubMed

Ye, Jing; Ji, Qingwei; Liu, Jianfang; Liu, Ling; Huang, Ying; Shi, Ying; Shi, Lei; Wang, Menglong; Liu, Mengling; Feng, Ying; Jiang, Huimin; Xu, Yao; Wang, Zhen; Song, Junlong; Lin, Yingzhong; Wan, Jun

2017-10-03

CD4+ T helper (Th) cells, including Th1, Th2, and Th17 cells, play critical roles in angiotensin II-induced hypertension. Th22 cells, a novel subset of Th cells, take part in cardiovascular diseases by producing IL-22 (interleukin 22). This study aimed to investigate whether IL-22 is involved in hypertension. Th22 cells and IL-22 levels were detected in angiotensin II-infused mice, and the results showed that Th22 cells and IL-22 levels significantly increased. To determine the effect of Th22/IL-22 on blood pressure regulation, angiotensin II-infused mice were treated with recombinant mouse IL-22, an anti-IL-22 neutralizing monoclonal antibody, or control. Treatment with recombinant IL-22 resulted in increased blood pressure, amplified inflammatory responses, and aggravated endothelial dysfunction, whereas the anti-IL-22 neutralizing monoclonal antibody decreased blood pressure, reduced inflammatory responses, and attenuated endothelial dysfunction. To determine whether the STAT3 (signal transducer and activator of transcription 3) pathway mediates the effect of IL-22 on blood pressure regulation, the special STAT3 pathway inhibitor S31-201 was administered to mice treated with recombinant IL-22. S31-201 treatment significantly ameliorated the IL-22 effects of increased blood pressure and endothelial dysfunction. In addition, serum IL-22 levels were significantly increased in hypertensive patients compared with healthy persons. Correlation analysis showed a positive correlation between IL-22 levels and blood pressure. IL-22 amplifies the inflammatory response, induces endothelial dysfunction and promotes blood pressure elevation in angiotensin II-induced hypertensive mice. The STAT3 pathway mediates the effect of IL-22 on hypertension. Blocking IL-22 may be a novel therapeutic strategy to prevent and treat hypertension. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Oral Gene Application Using Chitosan-DNA Nanoparticles Induces Transferable Tolerance

PubMed Central

Ensminger, Stephan M.; Spriewald, Bernd M.

2012-01-01

Oral tolerance is a promising approach to induce unresponsiveness to various antigens. The development of tolerogenic vaccines could be exploited in modulating the immune response in autoimmune disease and allograft rejection. In this study, we investigated a nonviral gene transfer strategy for inducing oral tolerance via antigen-encoding chitosan-DNA nanoparticles (NP). Oral application of ovalbumin (OVA)-encoding chitosan-DNA NP (OVA-NP) suppressed the OVA-specific delayed-type hypersensitivity (DTH) response and anti-OVA antibody formation, as well as spleen cell proliferation following OVA stimulation. Cytokine expression patterns following OVA stimulation in vitro showed a shift from a Th1 toward a Th2/Th3 response. The OVA-NP-induced tolerance was transferable from donor to naïve recipient mice via adoptive spleen cell transfer and was mediated by CD4+CD25+ T cells. These findings indicate that nonviral oral gene transfer can induce regulatory T cells for antigen-specific immune modulation. PMID:22933401

Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection

PubMed Central

Muir, Roshell; Metcalf, Talibah; Tardif, Virginie; Takata, Hiroshi; Phanuphak, Nittaya; Kroon, Eugene; Colby, Donn J.; Trichavaroj, Rapee; Valcour, Victor; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat; Trautmann, Lydie; Haddad, Elias K.

2016-01-01

The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. PMID:27463374

A High RORγT/CD3 Ratio is a Strong Prognostic Factor for Postoperative Survival in Advanced Colorectal Cancer: Analysis of Helper T Cell Lymphocytes (Th1, Th2, Th17 and Regulatory T Cells).

PubMed

Yoshida, Naohiro; Kinugasa, Tetsushi; Miyoshi, Hiroaki; Sato, Kensaku; Yuge, Kotaro; Ohchi, Takafumi; Fujino, Shinya; Shiraiwa, Sachiko; Katagiri, Mitsuhiro; Akagi, Yoshito; Ohshima, Koichi

2016-03-01

Tumor-infiltrating lymphocytes (TILs), part of the host immune response, have been widely reported as influential factors in the tumor microenvironment for the clinical outcome of colorectal cancer (CRC). However, the network of helper T cells is very complex, and which T-cell subtypes affect the progression of CRC and postoperative prognosis remains unclear. This study investigated the expression of several subtypes of TILs including T helper type 1 (Th1), Th2, Th17, and regulatory T (Treg) cells to determine their correlation with clinicopathologic features and postoperative prognosis. The study investigated the expression of TILs using immunohistochemistry of tissue microarray samples for 199 CRC patients. The number of each T-cell subtype infiltrating tumors was counted using ImageJ software. The relationship between TIL marker expression, clinicopathologic features, and prognosis was analyzed. A high RORγT/CD3 ratio (Th17 ratio) was significantly correlated with lymph node metastasis (p = 0.002), and a high of Foxp3/CD3 ratio (Treg ratio) was correlated with tumor location in the colon (p = 0.04), as shown by the Chi square test. In multivariate analysis, a high RORγT/CD3 ratio was the only independent prognostic factor for overall survival (p = 0.04; hazard ratio [HR], 1.84; 95% confidence interval [CI] 1.02-3.45). This study confirmed a high RORγT/CD3 ratio as a strong prognostic marker for postoperative survival. The immunohistochemistry results suggest that Th17 may affect lymph node metastasis in CRC. If new immunotherapies reducing Th17 expression are established, they may improve the efficiency of cancer treatment and prolong the survival of patients with CRC.

Interleukin-12 Induces a Th1-Like Response to Burkholderia mallei and Limited Protection in BALB/c Mice

DTIC Science & Technology

2006-01-01

sublethal and lethal intraperitoneal glanders ( Burkholderia mallei ). Vet Pathol 2000;37:626–36. [34] Jankovic D, Caspar P, Zweig M, Garcia-Moll M...Vaccine 24 (2006) 1413–1420 Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice Kei Amemiya...IL)-12 on the immune response to Burkholderia mallei in BALB/c mice. Mice were vaccinated with non-viable B. mallei cells with or without IL-12

Biocompatible chitosan nanoparticles as an efficient delivery vehicle for Mycobacterium tuberculosis lipids to induce potent cytokines and antibody response through activation of γδ T cells in mice

NASA Astrophysics Data System (ADS)

Das, Ishani; Padhi, Avinash; Mukherjee, Sitabja; Dash, Debi P.; Kar, Santosh; Sonawane, Avinash

2017-04-01

The activation of cell-mediated and humoral immune responses to Mycobacterium tuberculosis (Mtb) is critical for protection against the pathogen and nanoparticle-mediated delivery of antigens is a more potent way to induce different immune responses. Herein, we show that mice immunized with Mtb lipid-bound chitosan nanoparticles (NPs) induce secretion of prominent type-1 T-helper (Th-1) and type-2 T-helper (Th-2) cytokines in lymph node and spleen cells, and also induces significantly higher levels of IgG, IgG1, IgG2 and IgM in comparison to control mice. Furthermore, significantly enhanced γδ-T-cell activation was observed in lymph node cells isolated from mice immunized with Mtb lipid-coated chitosan NPs as compared to mice immunized with chitosan NPs alone or Mtb lipid liposomes. In comparison to CD8+ cells, significantly higher numbers of CD4+ cells were present in both the lymph node and spleen cells isolated from mice immunized with Mtb lipid-coated chitosan NPs. In conclusion, this study represents a promising new strategy for the efficient delivery of Mtb lipids using chitosan NPs to trigger an enhanced cell-mediated and antibody response against Mtb lipids.

Leptin, immune responses and autoimmune disease. Perspectives on the use of leptin antagonists.

PubMed

Peelman, F; Iserentant, H; Eyckerman, S; Zabeau, L; Tavernier, J

2005-01-01

The pivotal role of leptin in regulating body weight and energy homeostasis is very well established. More recently, leptin also emerged as an important regulator of T-cell-dependent immunity. Reduced leptin levels, as observed during periods of starvation, correlate with an impaired cellular immune response, whereby especially the T(H)1 pro-inflammatory immune response appears to be affected. Physiologically, this could reflect the high energy demand of such processes, which are suppressed in animals or people with nutrient shortage. Several autoimmune diseases are T(H)1 T-cell dependent. In line with a pro-inflammatory role for leptin, animal models of leptin deficiency are markedly resistant to a variety of T-cell dependent autoimmune diseases. Here, we review the role of leptin in immune responses, with emphasis on autoimmune diseases. The design and potential use of leptin antagonists is also discussed.

Comparisons of the humoral and cellular immunity induced by live A16R attenuated spore and AVA-like anthrax vaccine in mice.

PubMed

Lv, Jin; Zhang, Ying-Ying; Lu, Xun; Zhang, Hao; Wei, Lin; Gao, Jun; Hu, Bin; Hu, Wen-Wei; Hu, Dun-Zhong; Jia, Na; Feng, Xin

2017-03-01

The live attenuated anthrax vaccine and anthrax vaccine adsorbed (AVA) are two main types of anthrax vaccines currently used in human. However, the immunoprotective mechanisms are not fully understood. In this study, we compared humoral and cellular immunity induced by live A16R spore vaccine and A16R strain derived AVA-like vaccine in mice peripheral blood, spleen and bone marrow. Both A16R spores and AVA-like vaccines induced a sustained IgG antibody response with IgG1/IgG2b subtype dominance. However, A16R spores vaccine induced higher titer of IgG2a compared with AVA-like vaccine, indicating a stronger Th1 response to A16R spores. Using antigen-specific ELISpot assay, we observed a significant response of ASCs (antibody secreting cells) and IL4-CSCs (cytokine secreting cells) in mice. Specially, there was a positive correlation between the frequencies of antigen specific ASCs and IL4-CSCs in bone marrow derived cells, either by A16R spore or AVA-like vaccine vaccination. Moreover, we also found A16R spore vaccine, not AVA-like vaccine, could induce sustained frequency of IFN-γ-CSCs in bone marrow derived cells. Collectively, both the vaccines induced a mixed Th1/Th2 response with Th2 dominance in mice and A16R spore vaccine might provide a more comprehensive protection because of humoral and cellular immunity induced in bone marrow. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

B cells and TCR avidity determine distinct functions of CD4+ T cells in retroviral infection1

PubMed Central

Ploquin, Mickaël J-Y; Eksmond, Urszula; Kassiotis, George

2011-01-01

The T-cell-dependent B-cell response relies on cognate interaction between B cells and CD4+ Th cells. However, the consequences of this interaction for CD4+ T cells are not entirely known. B cells generally promote CD4+ T-cell responses to pathogens, albeit to a variable degree. In contrast, CD4+ T-cell responses to self or tumor antigens are often suppressed by B cells. Here we demonstrated that interaction with B cells dramatically inhibited the function of virus-specific CD4+ T cells in retroviral infection. We have used Friend virus (FV) infection of mice as a model for retroviral infection, in which the behavior of virus-specific CD4+ T cells was monitored according to their TCR avidity. We report that avidity for antigen and interaction with B cells determine distinct aspects of the primary CD4+ T-cell response to FV infection. Virus-specific CD4+ T cells followed exclusive Th1 and T follicular helper (Tfh) differentiation. High avidity for antigen facilitated expansion during priming and enhanced the capacity for IFN-γ and IL-21 production. In contrast, Tfh differentiation was not affected by avidity for antigen. By reducing or preventing B-cell interaction we found that B cells promoted Tfh differentiation, induced programmed death 1 (PD-1) expression and inhibited IFN-γ production by virus-specific CD4+ T cells. Ultimately, B cells protected hosts from CD4+ T-cell-mediated immune pathology, at the detriment of CD4+ T-cell-mediated protective immunity. Our results suggest that B-cell presentation of vaccine antigens could be manipulated to direct the appropriate CD4+ T-cell response. PMID:21841129

The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation

PubMed Central

Carpenter, Andrea C.; Grainger, John R.; Xiong, Yumei; Kanno, Yuka; Chu, H. Hamlet; Wang, Lie; Naik, Shruti; dos Santos, Liliane; Wei, Lai; Jenkins, Marc K.; O’Shea, John J.; Belkaid, Yasmine; Bosselut, Rémy

2014-01-01

Summary T helper (Th) cells are critical for defenses against infection and recognize peptides bound to Class II Major Histocompatibility Complex (MHC-II) molecules. Although transcription factors have been identified that direct helper cells into specific effector fates, whether a ‘master’ regulator controls the developmental program common to all Th cells remains unclear. Here we showed that the two transcription factors Thpok and LRF share this function. Although disruption of both factors did not prevent the generation of MHC II-specific T cells, these cells failed to express Th cell genes or undergo Th cell differentiation in vivo. In contrast, T cells lacking Thpok only displayed LRF-dependent functions and contributed to multiple effector responses, both in vitro and in vivo, with the notable exception of Th2 cell responses that control extra-cellular parasites. These findings identify the Thpok-LRF pair as a core node of Th cell differentiation and function. PMID:23041065

Oral delivery of Brucella spp. recombinant protein U-Omp16 abrogates the IgE-mediated milk allergy.

PubMed

Smaldini, Paola Lorena; Ibañez, Andrés Esteban; Fossati, Carlos Alberto; Cassataro, Juliana; Docena, Guillermo Horacio

2014-01-01

Food allergies are increasingly common disorders and no therapeutic strategies are yet approved. The unlipidated Omp16 (U-Omp16) is the outer membrane protein of 16 kDa from B. abortus and possesses a mucosal adjuvant property. In this study, we aimed to examine the U-Omp16 capacity to abrogate an allergen-specific Th2 immune response when it is administered as an oral adjuvant in a mouse model of food allergy.   Balb/c mice were sensitized with cholera toxin and cow's milk proteins (CMP) by gavage and simultaneously treated with U-Omp16 and CMP. Oral challenge with CMP was performed to evaluate the allergic status of mice. Symptoms, local (small bowel cytokine and transcription factor gene expression) and systemic (specific isotypes and spleen cell-secreted cytokines) parameters, and skin tests were done to evaluate the immune response. We found that the oral administration of U-Omp16 with CMP during sensitization dampened the allergic symptoms, with negativization of immediate skin test and increased skin DTH response. Serum specific IgE and IL-5 were inhibited and a Th1 response was promoted (specific IgG2a antibodies and CMP-induced IFN-γ secretion). We found at the mucosal site an inhibition of the gene expression corresponding to IL-13 and Gata-3, with an induction of IFN-γ and T-bet. These results indicated that the oral administration of U-Omp16 significantly controlled the allergic response in sensitized mice with a shift of the balance of Th1- and Th2-T cells toward Th1 predominance. These findings suggest that U-Omp16 may be useful as a Th1-directing adjuvant in an oral vaccine.

Oral delivery of Brucella spp. recombinant protein U-Omp16 abrogates the IgE-mediated milk allergy

PubMed Central

Smaldini, Paola Lorena; Ibañez, Andrés Esteban; Fossati, Carlos Alberto; Cassataro, Juliana; Docena, Guillermo Horacio

2014-01-01

Food allergies are increasingly common disorders and no therapeutic strategies are yet approved. The unlipidated Omp16 (U-Omp16) is the outer membrane protein of 16 kDa from B. abortus and possesses a mucosal adjuvant property. In this study, we aimed to examine the U-Omp16 capacity to abrogate an allergen-specific Th2 immune response when it is administered as an oral adjuvant in a mouse model of food allergy.   Balb/c mice were sensitized with cholera toxin and cow’s milk proteins (CMP) by gavage and simultaneously treated with U-Omp16 and CMP. Oral challenge with CMP was performed to evaluate the allergic status of mice. Symptoms, local (small bowel cytokine and transcription factor gene expression) and systemic (specific isotypes and spleen cell-secreted cytokines) parameters, and skin tests were done to evaluate the immune response. We found that the oral administration of U-Omp16 with CMP during sensitization dampened the allergic symptoms, with negativization of immediate skin test and increased skin DTH response. Serum specific IgE and IL-5 were inhibited and a Th1 response was promoted (specific IgG2a antibodies and CMP-induced IFN-γ secretion). We found at the mucosal site an inhibition of the gene expression corresponding to IL-13 and Gata-3, with an induction of IFN-γ and T-bet. These results indicated that the oral administration of U-Omp16 significantly controlled the allergic response in sensitized mice with a shift of the balance of Th1- and Th2-T cells toward Th1 predominance. These findings suggest that U-Omp16 may be useful as a Th1-directing adjuvant in an oral vaccine. PMID:25424811

IL-27 regulates the adherence, proliferation, and migration of MSCs and enhances their regulatory effects on Th1 and Th2 subset generations.

PubMed

Xu, Fenghuang; Yi, Junzhu; Wang, Zhuoya; Hu, Yejia; Han, Chunlei; Xue, Qun; Zhang, Xueguang; Luan, Xiying

2017-08-01

Interleukin 27 (IL-27) regulates T cell function and is involved in inflammation. It has been reported that human placenta-derived mesenchymal stromal cells (hPMSCs) can inhibit T cell responses and attenuate inflammation reactions. However, it is unclear whether IL-27 can regulate hPMSC function. Here, we examined the effects of IL-27 upon adherence, migration, and proliferation as well as the immunomodulatory effects of hPMSCs. The results show that IL-27 receptor α chain (IL-27Rα) is expressed in hPMSCs. IL-27 at 30 ng/ml inhibited hPMSC adherence and proliferation, while the migration of hPMSCs was promoted with IL-27 at doses of 20 or 30 ng/ml, as determined with use of real-time cell analysis (RTCA). Moreover, IL-27 promoted regulatory effects of hPMSCs through enhancing Th2 and suppressing Th1 subset generation from activated T cells in human peripheral blood. IL-27 also enhanced the ability of hPMSCs to secrete IL-10 from CD4 + T cells through increased expression levels of the programmed death ligand 1 (PDL1) in hPMSCs via the Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway. In conclusion, IL-27 has significant modulatory effects on adherence, proliferation, and migration of hPMSCs. IL-27 increased PDL1 expression levels in hPMSCs via the JAK/STAT1 pathway, which then enhanced the regulatory effects of hPMSCs upon Th1 and Th2 cell generations and IL-10 secretion from CD4 + T cells.

Th1/Th17/Th22 immune response and their association with joint pain, imagenological bone loss, RANKL expression and osteoclast activity in temporomandibular joint osteoarthritis: A preliminary report.

PubMed

Monasterio, G; Castillo, F; Rojas, L; Cafferata, E A; Alvarez, C; Carvajal, P; Núñez, C; Flores, G; Díaz, W; Vernal, R

2018-05-15

It is well accepted that the presence of cytokines belonging to the Th1/Th17/Th22 axis of immuno-inflammatory response in the joint environment, such as IL-1β, IL-17 and IL-22, respectively, are associated with pathogenesis of several synovial joint degenerative disorders. During temporomandibular joint osteoarthritis (TMJ-OA), IL-1β and IL-17 have been implicated in the inflammation and resorption of sub-chondral bone; however, the role of Th22 response in the TMJ-OA pathophysiology has not been established. This study aimed to compare the expression of Th1/Th17/Th22-type cytokines, chemokines and chemokine receptors in synovial fluid samples obtained from TMJ-OA or disk displacement with reduction (DDWR) patients. In addition, it aimed to associate these levels with joint pain, imagenological signs of bone degeneration, RANKL production, osteoclastogenesis and osteoclast-induced bone resorption. Higher levels of IL-1β, IL-17 and IL-22 were expressed in TMJ-OA compared with DDWR subjects, and these increased levels significantly correlated with RANKL expression, joint pain and articular bone degeneration. Higher levels of CCR5, CCR6 and CCR7, as well as their respective ligands CCL5 and CCL20, responsible for recruitment of IL-1β, IL-17 and IL-22-producing cells, were over-expressed in TMJ-OA compared with DDWR subjects. Osteoclastogenesis and osteoclast-induced bone resorption were significantly greater in presence of synovial fluid from TMJ-OA compared with DDWR subjects. These data demonstrate that cytokines, CCLs and CCRs associated with the Th1/Th17/Th22 axis of immuno-inflammatory response are involved in TMJ-OA pathogenesis. These findings suggest that IL-22 is involved in the RANKL expression in TMJ-OA, which in turn induces differentiation of osteoclasts and subsequent resorption of sub-chondral bone. © 2018 John Wiley & Sons Ltd.

Chitosan Nanoparticles Act as an Adjuvant to Promote both Th1 and Th2 Immune Responses Induced by Ovalbumin in Mice

PubMed Central

Wen, Zheng-Shun; Xu, Ying-Lei; Zou, Xiao-Ting; Xu, Zi-Rong

2011-01-01

The study was conducted to investigate the promoted immune response to ovalbumin in mice by chitosan nanoparticles (CNP) and its toxicity. CNP did not cause any mortality or side effects when mice were administered subcutaneously twice with a dose of 1.5 mg at 7-day intervals. Institute of Cancer Research (ICR) mice were immunized subcutaneously with 25 μg ovalbumin (OVA) alone or with 25 μg OVA dissolved in saline containing Quil A (10 μg), chitosan (CS) (50 μg) or CNP (12.5, 50 or 200 μg) on days 1 and 15. Two weeks after the secondary immunization, serum OVA-specific antibody titers, splenocyte proliferation, natural killer (NK) cell activity, and production and mRNA expression of cytokines from splenocytes were measured. The serum OVA-specific IgG, IgG1, IgG2a, and IgG2b antibody titers and Con A-, LPS-, and OVA-induced splenocyte proliferation were significantly enhanced by CNP (P < 0.05) as compared with OVA and CS groups. CNP also significantly promoted the production of Th1 (IL-2 and IFN-γ) and Th2 (IL-10) cytokines and up-regulated the mRNA expression of IL-2, IFN-γ and IL-10 cytokines in splenocytes from the immunized mice compared with OVA and CS groups. Besides, CNP remarkably increased the killing activities of NK cells activity (P < 0.05). The results suggested that CNP had a strong potential to increase both cellular and humoral immune responses and elicited a balanced Th1/Th2 response, and that CNP may be a safe and efficacious adjuvant candidate suitable for a wide spectrum of prophylactic and therapeutic vaccines. PMID:21747747

Cyanidin-3-glucoside suppresses Th2 cytokines and GATA-3 transcription factor in EL-4 T cells.

PubMed

Pyo, Myoung Yun; Yoon, Soo Jeong; Yu, Yeonsil; Park, Sunyoung; Jin, Mirim

2014-01-01

Allergic disease is dominated by Th2 immune responses. Interleukin (IL)-4 and IL-13, representative Th2 cytokines, play pivotal roles in the pathogenic activation of the Th2 immune response. In this study, we found that cyanidin-3-glucoside chloride (C3G), an anthocyanin suppressed IL-4 and IL-13 produced in activated EL-4 T cells but not Th1 cytokines including IL-2, interferon-γ, or IL-12. IL-4 and IL-13 mRNA levels and luciferase activation in cells transiently transfected with IL-4 and IL-13 promoter reporter plasmids were significantly inhibited by C3G, suggesting that suppression might be, at least in part, regulated at the transcriptional level. Data from western blot and reverse transcription-polymerase chain reaction analyses of transcription factors involved in cytokine expression suggested that expression of GATA-3, but not T-bet, was downregulated in the nucleus by C3G. Taken together, our data indicate that C3G may has potential as an anti-allergic agent suppressing Th2 activation by downregulating Th2 cytokines and the GATA3 transcription factor in allergies.

Tetravalent dengue DIIIC protein together with alum and ODN elicits a Th1 response and neutralizing antibodies in mice.

PubMed

Zuest, Roland; Valdes, Iris; Skibinski, David; Lin, Yufang; Toh, Ying Xiu; Chan, Katherine; Hermida, Lisset; Connolly, John; Guillen, Gerardo; Fink, Katja

2015-03-17

Dengue disease is a global challenge for healthcare systems particularly during outbreaks, and millions of dollars are spent every year for vector control. An efficient and safe vaccine that is cost-effective could resolve the burden that dengue virus imposes on affected countries. We describe here the immunogenicity of a tetravalent formulation of a recombinant fusion protein consisting of E domain III and the capsid protein of dengue serotypes 1-4 (Tetra DIIIC). E domain III is an epitope for efficient neutralizing antibodies while the capsid protein contains T cell epitopes. Besides combining B and T cell epitopes, Tetra DIIIC is highly immunogenic due to its aggregate form and a two-component adjuvant. Following previous studies assessing the monovalent DIIIC formulations, we addressed here the quality and breadth of the T cell- and antibody response of Tetra DIIIC in mice. Tetra DIIIC induced a Th1-type response against all four DENV serotypes and dengue-specific antibodies were predominantly IgG1 and IgG2a and neutralizing, while the induction of neutralizing antibodies was dependent on IFN signaling. Importantly, the Th1 and IgG1/IgG2a profile of the DIIIC vaccine approach is similar to an efficient natural anti-dengue response. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synergistic immunosuppression by candida in HIV infection: a cytokine based analysis.

PubMed

Bajaj, J S; Singh, A; Aggarwal, S K; Chattopadhya, D; Baveja, U K

2000-03-01

Candida is a common opportunistic pathogen in HIV infection and is regarded a signal infection for progression to AIDS. Cytokine imbalances between Th1/Th2 groups have been described in both candida and HIV infections. A study was undertaken to assess the role of candida in furthering immunosuppression in HIV infection based on cytokine levels and CD4 cell counts. 30 Indian subjects were enrolled; 10 HIV positive patients with and 10 without mucosal candidiasis and 10 age matched controls. Th1 cytokines; interleukin (IL) 2, IL 12 and interferon (IFN) gamma, Th2 cytokines; IL 4, IL 6, IL 10 and tumor necrosis factor (TNF) alpha with CD 4 cell counts were estimated using ELISA in all subjects. CD4 cell counts were reduced in both patient groups as compared to controls; significantly more in patients with both HIV and candida infections. There was a decrease in Th1 cytokine levels in all patients; lower levels of Th1 cytokines were seen in patients with both infections. Among the Th2 cytokines, there was a significant increase in the levels of IL 6, IL 10 and TNF alpha in both patient groups; IL 10 and TNF alpha values were significantly raised in patients with dual HIV and candida infections as compared to the other patients. There was no difference in IL 4 values across the subject groups. A positive correlation between CD4 cell counts and Th1 cytokine levels and a negative correlation with Th2 cytokines were noted; these were stronger in patients with both HIV and candidiasis. Thus, there was a Th1/Th2 cytokine imbalance with CD4 cell count reduction in all HIV infected patients, which was more pronounced in patients with both infections. It can be concluded that, owing to the depressed CD4 cell count and Th1 response and increased Th2 cytokines in patients with both candidiasis and HIV as compared to patients with only HIV candidiasis may have a synergistic immunosuppressive effect with HIV in patients with dual infections.

Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut.

PubMed

Yue, Mengfan; Xia, Yufeng; Shi, Can; Guan, Chunge; Li, Yunfan; Liu, Rui; Wei, Zhifeng; Dai, Yue

2017-09-01

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg -1 , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. © 2017 Federation of European Biochemical Societies.

Oral Treatment with Extract of Agaricus blazei Murill Enhanced Th1 Response through Intestinal Epithelial Cells and Suppressed OVA-Sensitized Allergy in Mice

PubMed Central

Bouike, Go; Nishitani, Yosuke; Shiomi, Hideyuki; Yoshida, Masaru; Azuma, Takeshi; Hashimoto, Takashi; Kanazawa, Kazuki; Mizuno, Masashi

2011-01-01

To clarify the mechanism of the antiallergic activity of Agaricus blazei Murill extract (ABME), the present paper used an in vivo allergy model and an in vitro intestinal gut model. During OVA sensitization, the serum IgE levels decreased significantly in ABME group. Interleukin (IL)-4 and -5 produced from OVA-restimulated splenocytes was significantly decreased, and anti-CD3ε/CD28 antibody treatment also reduced IL-10, -4, and -5 production and increased IFN-γ production in ABME group. These results suggest that oral administration of ABME improves Th1/Th2 balance. Moreover, a coculture system constructed of Caco-2 cells and splenocytes from OT-II mice or RAW 264.7 cells indicated that the significant increases in IFN-γ production by ABME treatment. Therefore, it was concluded that the antiallergic activity of ABME was due to the activation of macrophages by epithelial cells and the promotion of the differentiation of naïve T cells into Th1 cells in the immune. PMID:20953432

Design of new acid-activated cell-penetrating peptides for tumor drug delivery

PubMed Central

Zhang, Wei; Li, Li; Zhang, Yun; Zhang, Li; Liu, Hui; Wang, Rui

2017-01-01

TH(AGYLLGHINLHHLAHL(Aib)HHIL-NH2), a histidine-rich, cell-penetrating peptide with acid-activated pH response, designed and synthesized by our group, can effectively target tumor tissues with an acidic extracellular environment. Since the protonating effect of histidine plays a critical role in the acid-activated, cell-penetrating ability of TH, we designed a series of new histidine substituents by introducing electron donating groups (Ethyl, Isopropyl, Butyl) to the C-2 position of histidine. This resulted in an enhanced pH-response and improved the application of TH in tumor-targeted delivery systems. The substituents were further utilized to form the corresponding TH analogs (Ethyl-TH, Isopropyl-TH and Butyl-TH), making them easier to protonate for positive charge in acidic tumor microenvironments. The pH-dependent cellular uptake efficiencies of new TH analogs were further evaluated using flow cytometry and confocal laser scanning microscopy, demonstrating that ethyl-TH and butyl-TH had an optimal pH-response in an acidic environment. Importantly, the new TH analogs exhibited relatively lower toxicity than TH. In addition, these new TH analogs were linked to the antitumor drug camptothecin (CPT), while butyl-TH modified conjugate presented a remarkably stronger pH-dependent cytotoxicity to cancer cells than TH and the other conjugates. In short, our work opens a new avenue for the development of improved acid-activated, cell-penetrating peptides as efficient anticancer drug delivery vectors. PMID:28603674

Mice immunized with bone marrow-derived dendritic cells stimulated with recombinant Coxiella burnetii Com1 and Mip demonstrate enhanced bacterial clearance in association with a Th1 immune response.

PubMed

Xiong, Xiaolu; Meng, Yanfen; Wang, Xile; Qi, Yong; Li, Jiaming; Duan, Changsong; Wen, Bohai

2012-11-06

The recombinant membrane-associated proteins of Coxiella burnetii, Com1, Mip and GroEL, were used in vitro to stimulate BALB/c mouse bone marrow-derived dendritic cells (BMDCs). The antigen-activated BMDCs were transferred into naïve BALB/c mice. Seven days after challenge of C. burnetii, the bacterial loads of mice receiving BMDCs activated with Com1 or Mip, but not GroEL, were significantly lower than that of mice receiving BMDCs pulsed with TrxA (Esherichia coli thioredoxin) in a quantitative polymerase chain reaction assay. After in vitro interaction with cognate antigen-pulsed BMDCs, the percentages of CD69-positive cells and TNF-α-positive cells in CD4(+) and CD8(+) T cells isolated from the spleens of mice receiving Com1-, Mip-, or GroEL-pulsed BMDCs were significantly higher than that of mice receiving mock-pulsed BMDCs in flow cytometric analysis. The percentages of IFN-γ-positive cells in CD4(+) and CD8(+) T cells from mice receiving Com1- or Mip-pulsed BMDCs were significantly greater than that of mice receiving GroEL-pulsed BMDCs. However, the percentage of IL-4-positive cells in CD4(+) T cells of mice receiving GroEL-pulsed BMDCs was obviously higher than that of mice receiving Com1- or Mip-pulsed BMDCs. Our results demonstrate that Com1 and Mip are protective antigens and strongly indicate that they favor to induce IFN-γ-producing Th1 and Tc1 cells, whereas the non-protective antigen GroEL is biased to induce a Th2 response. Therefore, Com1 and Mip are key antigens to induce a protective immune response against C. burnetii infection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Garlic induces a shift in cytokine pattern in Leishmania major-infected BALB/c mice.

PubMed

Ghazanfari, T; Hassan, Z M; Ebtekar, M; Ahmadiani, A; Naderi, G; Azar, A

2000-11-01

The regulation of T helper (Th)1- and Th2-type cytokine patterns is important in the final outcome of leishmaniasis in human and murine models. We examined the efficacy of garlic therapy or a combination of garlic and an antimonial drug (glucantime) in promoting healing and regulation of Th1/Th2 cytokine patterns in highly susceptible BALB/c mice infected with Leishmania major. Separate groups of infected mice received 20 mg/kg/day garlic, 60 mg/kg/day glucantime or a combination of the two, from day 30 after infection for 2 weeks. An enzyme-linked immunosorbant assay (ELISA) was performed on spleen cell culture supernatants for interferon(IFN)-gamma interleukin(IL)-2, IL-4 and IL-10. The results indicate that garlic therapy is more effective than the usual antileishmanial drug in curing the infection. Garlic-treated mice developed Th1-type cytokine responses. In contrast, glucantime therapy led to a Th2-type response in the control group with a lower level of IL-2. However, a combination of garlic and glucantime treatment was more effective than either treatment alone, and resulted in a Th1-type response similar to that which developed with garlic treatment. These results suggest that garlic extract in combination with an antimonial drug, may provide effective therapy against L. major. The immunomodulatory properties of garlic were elucidated in terms of shifting the cytokine response to a Th1-type pattern and therefore causing the protective response.

The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons.

PubMed

Carroll, Elizabeth C; Jin, Lei; Mori, Andres; Muñoz-Wolf, Natalia; Oleszycka, Ewa; Moran, Hannah B T; Mansouri, Samira; McEntee, Craig P; Lambe, Eimear; Agger, Else Marie; Andersen, Peter; Cunningham, Colm; Hertzog, Paul; Fitzgerald, Katherine A; Bowie, Andrew G; Lavelle, Ed C

2016-03-15

The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Additionally, this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and immunoglobulin G2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Early Peritoneal Immune Response during Echinococcus granulosus Establishment Displays a Biphasic Behavior

PubMed Central

Mourglia-Ettlin, Gustavo; Marqués, Juan Martín; Chabalgoity, José Alejandro; Dematteis, Sylvia

2011-01-01

Background Cystic echinococcosis is a worldwide distributed helminth zoonosis caused by the larval stage of Echinococcus granulosus. Human secondary cystic echinococcosis is caused by dissemination of protoscoleces after accidental rupture of fertile cysts and is due to protoscoleces ability to develop into new metacestodes. In the experimental model of secondary cystic echinococcosis mice react against protoscoleces producing inefficient immune responses, allowing parasites to develop into cysts. Although the chronic phase of infection has been analyzed in depth, early immune responses at the site of infection establishment, e.g., peritoneal cavity, have not been well studied. Because during early stages of infection parasites are thought to be more susceptible to immune attack, this work focused on the study of cellular and molecular events triggered early in the peritoneal cavity of infected mice. Principal Findings Data obtained showed disparate behaviors among subpopulations within the peritoneal lymphoid compartment. Regarding B cells, there is an active molecular process of plasma cell differentiation accompanied by significant local production of specific IgM and IgG2b antibodies. In addition, peritoneal NK cells showed a rapid increase with a significant percentage of activated cells. Peritoneal T cells showed a substantial increase, with predominance in CD4+ T lymphocytes. There was also a local increase in Treg cells. Finally, cytokine response showed local biphasic kinetics: an early predominant induction of Th1-type cytokines (IFN-γ, IL-2 and IL-15), followed by a shift toward a Th2-type profile (IL-4, IL-5, IL-6, IL-10 and IL-13). Conclusions Results reported here open new ways to investigate the involvement of immune effectors players in E. granulosus establishment, and also in the sequential promotion of Th1- toward Th2-type responses in experimental secondary cystic echinococcosis. These data would be relevant for designing rational therapies based on stimulation of effective responses and blockade of evasion mechanisms. PMID:21912714

Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

PubMed

Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

2016-06-01

TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Measuring T cell cytokines in allergic upper and lower airway inflammation: can we move to the clinic?

PubMed

Bullens, Dominique M A

2007-06-01

Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-gamma by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-gamma and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-gamma might cause severe airway inflammation. On the other hand, 'inflammatory T cells' or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation. We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Sun Hee; Choi, Dalwoong; Chun, Young-Jin

Keratinocytes are the major cellular components of human epidermis and play a key role in the modulating cutaneous inflammation and toxic responses. In human chronic skin diseases, the common skin inflammatory phenotypes like skin barrier disruption and epidermal hyperplasia are manifested in epidermal keratinocytes by interactions with T helper (Th) cells. To find a common gene expression signature of human keratinocytes in chronic skin diseases, we performed a whole genome microarray analysis on normal human epidermal keratinocytes (NHKs) treated with IFNγ, IL-4, IL-17A or IL-22, major cytokines from Th1, Th2, Th17 or Th22 cells, respectively. The microarray results showed thatmore » the four genes, IL-24, PDZK1IP1, H19 and filaggrin, had common expression profiles in NHKs exposed to Th cell cytokines. In addition, the acute phase pro-inflammatory cytokines, IL-1β, IL-6 and TNFα, also change the gene transcriptional profile of IL-24, PDZK1IP1, H19, and filaggrin in NHKs as those of Th cytokines. Therefore, the signature gene set, consisting of IL-24, PDZK1IP1, H19, and filaggrin, provides essential insights for understanding the process of cutaneous inflammation and toxic responses. We demonstrate that environmental toxic stressors, such as chemical irritants and ultraviolet irradiation stimulate the production of IL-24 in NHKs. IL-24 stimulates the JAK1-STAT3 and MAPK pathways in NHKs, and promotes the secretion of pro-inflammatory mediators IL-8, PGE2, and MMP-1. These results suggest that keratinocyte-derived IL-24 participates in the positive feedback regulation of epidermal inflammation in response to both endogenous and environmental toxic stressors. - Highlights: • Cutaneous inflammatory gene signature consists of PDZK1IP1, IL-24, H19 and filaggrin. • Pro-inflammatory cytokines increase IL-24 production in human keratinocytes. • Environmental toxic stressors increase IL-24 production in human keratinocytes. • IL-24 stimulates human keratinocytes to produce pro-inflammatory mediators. • IL-24 activates STAT3 and MAPK signaling pathways in human keratinocytes.« less

Adequate Th2-Type Response Associates with Restricted Bacterial Growth in Latent Mycobacterial Infection of Zebrafish

PubMed Central

Hammarén, Milka Marjut; Luukinen, Bruno Vincent; Pesu, Marko; Rämet, Mika; Parikka, Mataleena

2014-01-01

Tuberculosis is still a major health problem worldwide. Currently it is not known what kind of immune responses lead to successful control and clearance of Mycobacterium tuberculosis. This gap in knowledge is reflected by the inability to develop sufficient diagnostic and therapeutic tools to fight tuberculosis. We have used the Mycobacterium marinum infection model in the adult zebrafish and taken advantage of heterogeneity of zebrafish population to dissect the characteristics of adaptive immune responses, some of which are associated with well-controlled latency or bacterial clearance while others with progressive infection. Differences in T cell responses between subpopulations were measured at the transcriptional level. It was discovered that a high total T cell level was usually associated with lower bacterial loads alongside with a T helper 2 (Th2)-type gene expression signature. At late time points, spontaneous reactivation with apparent symptoms was characterized by a low Th2/Th1 marker ratio and a substantial induction of foxp3 reflecting the level of regulatory T cells. Characteristic gata3/tbx21 has potential as a biomarker for the status of mycobacterial disease. PMID:24968056

Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models.

PubMed

Portwood, Scott; Lal, Deepika; Hsu, Yung-Chun; Vargas, Rodrigo; Johnson, Megan K; Wetzler, Meir; Hart, Charles P; Wang, Eunice S

2013-12-01

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. ©2013 AACR.

Memory CD8+ T Cells Protect Dendritic Cells from CTL Killing1

PubMed Central

Watchmaker, Payal B.; Urban, Julie A.; Berk, Erik; Nakamura, Yutaro; Mailliard, Robbie B.; Watkins, Simon C.; van Ham, S. Marieke; Kalinski, Pawel

2010-01-01

CD8+ T cells have been shown to be capable of either suppressing or promoting immune responses. To reconcile these contrasting regulatory functions, we compared the ability of human effector and memory CD8+ T cells to regulate survival and functions of dendritic cells (DC). We report that, in sharp contrast to the effector cells (CTLs) that kill DCs in a granzyme B- and perforin-dependent mechanism, memory CD8+ T cells enhance the ability of DCs to produce IL-12 and to induce functional Th1 and CTL responses in naive CD4+ and CD8+ T cell populations. Moreover, memory CD8+ T cells that release the DC-activating factor TNF-α before the release of cytotoxic granules induce DC expression of an endogenous granzyme B inhibitor PI-9 and protect DCs from CTL killing with similar efficacy as CD4+ Th cells. The currently identified DC-protective function of memory CD8+ T cells helps to explain the phenomenon of CD8+ T cell memory, reduced dependence of recall responses on CD4+ T cell help, and the importance of delayed administration of booster doses of vaccines for the optimal outcome of immunization. PMID:18322193

The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans.

PubMed

Cheng, Shih-Chin; van de Veerdonk, Frank L; Lenardon, Megan; Stoffels, Monique; Plantinga, Theo; Smeekens, Sanne; Rizzetto, Lisa; Mukaremera, Liliane; Preechasuth, Kanya; Cavalieri, Duccio; Kanneganti, Thirumala Devi; van der Meer, Jos W M; Kullberg, Bart Jan; Joosten, Leo A B; Gow, Neil A R; Netea, Mihai G

2011-08-01

In the mucosa, the immune pathways discriminating between colonizing and invasive Candida, thus inducing tolerance or inflammation, are poorly understood. Th17 responses induced by Candida albicans hyphae are central for the activation of mucosal antifungal immunity. An essential step for the discrimination between yeasts and hyphae and induction of Th17 responses is the activation of the inflammasome by C. albicans hyphae and the subsequent release of active IL-1β in macrophages. Inflammasome activation in macrophages results from differences in cell-wall architecture between yeasts and hyphae and is partly mediated by the dectin-1/Syk pathway. These results define the dectin-1/inflammasome pathway as the mechanism that enables the host immune system to mount a protective Th17 response and distinguish between colonization and tissue invasion by C. albicans.

Blocking Junctional Adhesion Molecule C Enhances Dendritic Cell Migration and Boosts the Immune Responses against Leishmania major

PubMed Central

Ballet, Romain; Emre, Yalin; Jemelin, Stéphane; Charmoy, Mélanie; Tacchini-Cottier, Fabienne; Imhof, Beat A.

2014-01-01

The recruitment of dendritic cells to sites of infections and their migration to lymph nodes is fundamental for antigen processing and presentation to T cells. In the present study, we showed that antibody blockade of junctional adhesion molecule C (JAM-C) on endothelial cells removed JAM-C away from junctions and increased vascular permeability after L. major infection. This has multiple consequences on the output of the immune response. In resistant C57BL/6 and susceptible BALB/c mice, we found higher numbers of innate immune cells migrating from blood to the site of infection. The subsequent migration of dendritic cells (DCs) from the skin to the draining lymph node was also improved, thereby boosting the induction of the adaptive immune response. In C57BL/6 mice, JAM-C blockade after L. major injection led to an enhanced IFN-γ dominated T helper 1 (Th1) response with reduced skin lesions and parasite burden. Conversely, anti JAM-C treatment increased the IL-4-driven T helper 2 (Th2) response in BALB/c mice with disease exacerbation. Overall, our results show that JAM-C blockade can finely-tune the innate cell migration and accelerate the consequent immune response to L. major without changing the type of the T helper cell response. PMID:25474593

Immune-responsiveness of CD4+ T cells during Streptococcus suis serotype 2 infection

PubMed Central

Lecours, Marie-Pier; Letendre, Corinne; Clarke, Damian; Lemire, Paul; Galbas, Tristan; Benoit-Biancamano, Marie-Odile; Thibodeau, Jacques; Gottschalk, Marcelo; Segura, Mariela

2016-01-01

The pathogenesis of Streptococcus suis infection, a major swine and human pathogen, is only partially understood and knowledge on the host adaptive immune response is critically scarce. Yet, S. suis virulence factors, particularly its capsular polysaccharide (CPS), enable this bacterium to modulate dendritic cell (DC) functions and potentially impair the immune response. This study aimed to evaluate modulation of T cell activation during S. suis infection and the role of DCs in this response. S. suis-stimulated total mouse splenocytes readily produced TNF-α, IL-6, IFN-γ, CCL3, CXCL9, and IL-10. Ex vivo and in vivo analyses revealed the involvement of CD4+ T cells and a Th1 response. Nevertheless, during S. suis infection, levels of the Th1-derived cytokines TNF-α and IFN-γ were very low. A transient splenic depletion of CD4+ T cells and a poor memory response were also observed. Moreover, CD4+ T cells secreted IL-10 and failed to up-regulate optimal levels of CD40L and CD69 in coculture with DCs. The CPS hampered release of several T cell-derived cytokines in vitro. Finally, a correlation was established between severe clinical signs of S. suis disease and impaired antibody responses. Altogether, these results suggest S. suis interferes with the adaptive immune response. PMID:27905502

Sarcoidosis Th17 Cells are ESAT-6 Antigen Specific but Demonstrate Reduced IFN-γ Expression

PubMed Central

Richmond, Bradley W.; Ploetze, Kristen; Isom, Joan; Chambers-Harris, Isfahan; Braun, Nicole A.; Taylor, Thyneice; Abraham, Susamma; Mageto, Yolanda; Culver, Dan A.; Oswald-Richter, Kyra A.; Drake, Wonder P.

2013-01-01

Rationale Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells. Methods Flow cytometry was used to determine the numbers of Th-17 cells present in the peripheral blood and BALF of patients with sarcoidosis, the percentage of Th-17 cells that were specific to the mycobacterial virulence factor ESAT-6, and as well as to assess IFN-γ expression in Th-17 cells following polyclonal stimulation. Results Patients with sarcoidosis had greater numbers of Th-17 cells in the peripheral blood and BALF than controls and produced significantly more extracellular IL-17A (p=0.03 and p=0.02, respectively). ESAT-6 specific Th-17 cells were present in both peripheral blood and BALF of sarcoidosis patients (p<0.001 and p=0.03, respectively). After polyclonal stimulation, Th-17 cells from sarcoidosis patients produced less IFN-γ than healthy controls. Conclusions Patients with sarcoidosis have mycobacterial antigen-specific Th-17 cells peripherally and in sites of active sarcoidosis involvement. Despite the Th1 immunophenotype of sarcoidosis immunology, the Th-17 cells have reduced IFN-γ expression, compared to healthy controls. This reduction in immunity may contribute to sarcoidosis pathogenesis. PMID:23073617

Chronic Trichuris muris infection alters hematopoiesis and causes IFN-γ-expressing T-cell accumulation in the mouse bone marrow.

PubMed

Chenery, Alistair L; Antignano, Frann; Hughes, Michael R; Burrows, Kyle; McNagny, Kelly M; Zaph, Colby

2016-11-01

Proinflammatory cytokines produced during immune responses to infectious stimuli are well-characterized to have secondary effects on the function of hematopoietic progenitor cells in the BM. However, these effects on the BM are poorly characterized during chronic infection with intestinal helminth parasites. In this study, we use the Trichuris muris model of infection and show that Th1 cell-associated, but not acute Th2 cell-associated, responses to chronic T. muris infection cause a major, transient expansion of CD48 - CD150 - multipotent progenitor cells in the BM that is dependent on the presence of adaptive immune cells and IFN-γ signaling. Chronic T. muris infection also broadly stimulated proliferation of BM progenitor cells including CD48 - CD150 + hematopoietic stem cells. This shift in progenitor activity during chronic T. muris infection correlated with a functional increase in myeloid colony formation in vitro as well as neutrophilia in the BM and peripheral blood. In parallel, we observed an accumulation of CD4 + , CD8 + , and CD4 - CD8 - (double negative) T cells that expressed IFN-γ, displaying activated and central memory-type phenotypes in the bone marrow during chronic infection. Thus, these results demonstrate that Th1 cell-driven responses in the intestine during chronic helminth infection potently influence upstream hematopoietic processes in the BM via IFN-γ. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multiple host defense defects in failure of C57BL/6 ep/ep (pale ear) mice to resolve visceral Leishmania donovani infection.

PubMed Central

Murray, H W; Hariprashad, J; McDermott, D F; Stoeckle, M Y

1996-01-01

Euthymic C57BL/L ep/ep (pale ear [PE]) mice halt the visceral replication of intracellular Leishmania donovani but fail to properly resolve infection. A previous study identified an isolated defect in tissue granuloma formation in these mice; CD4+ and CD8+ cell number, gamma interferon (IFN-gamma) production, and macrophage antimicrobial activity in vitro were all intact. New in vivo results reported here suggest a considerably more complex immune defect, with evidence indicating (i) enhanced control over L. donovani after transfer of normal C57BL/6 spleen cells, (ii) a partially suppressive Th2 cell-associated response mediated by interleukin-4 (IL-4) but not reversed by CD4+ cell depletion, (iii) absent responses to endogenous Th1 cell lymphokines (IFN-gamma and IL-2) but preserved responsiveness to endogenous tumor necrosis factor alpha, (iv) absent responses to exogenous treatment with recognized antileishmanial cytokines (IFN-gamma, IL-2, IL-12, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) not corrected by transfer of C57BL/6 spleen cells, and (v) a deficient response to antimony chemotherapy. Defective hepatic granuloma formation was not corrected by transfer of C57BL/6 spleen cells or by anti-IL-4 administration. While treatment with IL-2 and GM-CSF modified the tissue reaction and induced selected effector cells to encase tissue macrophages, no antileishmanial activity resulted. Together, these observations suggest that the failure of PE mice to resolve visceral L. donovani infection likely represents expression of multiple suboptimal immune responses and/or partial defects, probably involving a combination of T-cell dysfunction, a Th2 cell response, and target cell (macrophage) hyporesponsiveness. PMID:8557335

Differentiation and Transmigration of CD4 T Cells in Neuroinflammation and Autoimmunity.

PubMed

Sonar, Sandip Ashok; Lal, Girdhari

2017-01-01

CD4 + T cells play a central role in orchestrating protective immunity and autoimmunity. The activation and differentiation of myelin-reactive CD4 + T cells into effector (Th1 and Th17) and regulatory (Tregs) subsets at the peripheral tissues, and their subsequent transmigration across the blood-brain barrier (BBB) into the central nervous system (CNS) parenchyma are decisive events in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. How the Th1, Th17, and regulatory Tregs transmigrate across the BBB into the CNS and cause CNS inflammation is not clearly understood. Studies with transgenic and gene knockout mice have unraveled that Th1, Th17, and Tregs play a critical role in the induction and resolution of neuroinflammation. However, the plasticity of these lineages and functional dichotomy of their cytokine products makes it difficult to understand what role CD4 + T cells in the peripheral lymphoid organs, endothelial BBB, and the CNS parenchyma play in the CNS autoimmune response. In this review, we describe some of the recent findings that shed light on the mechanisms behind the differentiation and transmigration of CD4 + T cells across the BBB into the CNS parenchyma and also highlight how these two processes are interconnected, which is crucial for the outcome of CNS inflammation and autoimmunity.

Differentiation and Transmigration of CD4 T Cells in Neuroinflammation and Autoimmunity

PubMed Central

Sonar, Sandip Ashok; Lal, Girdhari

2017-01-01

CD4+ T cells play a central role in orchestrating protective immunity and autoimmunity. The activation and differentiation of myelin-reactive CD4+ T cells into effector (Th1 and Th17) and regulatory (Tregs) subsets at the peripheral tissues, and their subsequent transmigration across the blood–brain barrier (BBB) into the central nervous system (CNS) parenchyma are decisive events in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. How the Th1, Th17, and regulatory Tregs transmigrate across the BBB into the CNS and cause CNS inflammation is not clearly understood. Studies with transgenic and gene knockout mice have unraveled that Th1, Th17, and Tregs play a critical role in the induction and resolution of neuroinflammation. However, the plasticity of these lineages and functional dichotomy of their cytokine products makes it difficult to understand what role CD4+ T cells in the peripheral lymphoid organs, endothelial BBB, and the CNS parenchyma play in the CNS autoimmune response. In this review, we describe some of the recent findings that shed light on the mechanisms behind the differentiation and transmigration of CD4+ T cells across the BBB into the CNS parenchyma and also highlight how these two processes are interconnected, which is crucial for the outcome of CNS inflammation and autoimmunity. PMID:29238350

Premalignant lesions skew spleen cell responses to immune modulation by adipocytes.

PubMed

Vielma, Silvana A; Klein, Richard L; Levingston, Corinne A; Young, M Rita I

2013-05-01

Obesity can promote a chronic inflammatory state and is associated with an increased risk for cancer. Since adipocytes can produce mediators that can regulate conventional immune cells, this study sought to determine if the presence of premalignant oral lesions would skew how immune cells respond to adipocyte-derived mediators to create an environment that may be more favorable for their progression toward cancer. While media conditioned by adipocytes stimulated normal spleen cell production of the T helper (Th) type-1 cytokines interleukin (IL)-2, interferon-γ (IFN-γ), IL-12 and granulocyte-monocyte colony-stimulating factor (GM CSF), media from premalignant lesion cells either blocked or had no added affect on the adipocyte-stimulated Th1 cytokine production. In contrast, media conditioned by premalignant lesion cells exacerbated adipocyte-stimulated spleen cell production of the Th2 cytokines IL-10 and IL-13, although it did not further enhance the adipocyte-stimulated spleen cell production of IL-4 and TGF-β. The premalignant lesion environment also heightened the adipocyte-stimulated spleen cell production of the inflammatory mediators IL 1α, IL-1β, IL-6 and IL-9, although it did not further increase the adipocyte-stimulated production of tumor necrosis factor-α (TNF-α). IL 17 production was unaffected by the adipocyte-derived mediators, but was synergistically triggered by adding media from premalignant lesion cells. These stimulatory effects on spleen cell production of Th2 and inflammatory mediators were not induced in the absence of media conditioned by adipocytes. In contrast, media conditioned by adipocytes did not stimulate production of predominantly monocyte-derived chemokine C-X-C motif ligand (CXCL)9, chemokine C-C motif ligand (CCL)3 or CCL4, although it stimulated production of CCL2 and the predominantly T cell-derived chemokine CCL5, which was the only chemokine whose production was further increased by media from premalignant lesions. These results suggest that the responsiveness of spleen cells to adipocyte-derived mediators is influenced by mediators from premalignant lesion cells to favor conventional immune cell production of a Th2 and inflammatory cytokines.

Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients.

PubMed

Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

2016-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161(+)Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161(+)Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase.

Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161+Th1 Cells) to CD161+Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients

PubMed Central

Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

2016-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161+Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161+Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase. PMID:27123445

The dual nature of retinoic acid in pemphigus and its therapeutic potential: Special focus on all-trans Retinoic Acid.

PubMed

Tavakolpour, Soheil; Daneshpazhooh, Maryam; Mahmoudi, Hamid Reza; Balighi, Kamran

2016-07-01

The efficient treatment of pemphigus with no certain side effect remained a controversial issue. Although there are various options for controlling disease severity, the majority of them may cause serious side effects. Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune functions. Effects of RA, especially all-trans-Retinoic Acid (ATRA) on different types of cells involved in immune responses were analyzed in vitro and in vivo. RAs could affect the differentiation of T helper (Th) cells, B cells responses, stabilization of both natural regulatory T cells (nTregs) and regulatory B cells (Bregs) populations, and regulating the expression of critical genes in immune responses. The role of RA, based on major immune cells involved in pemphigus has not been addressed so far. In this study, we sought to determine the possible effects of RA, with a special focus on ATRA in pemphigus. All the evidences of ATRA effects on the immune system were collected and their association with the pemphigus was analyzed. According to the previous results, ATRA causes a decline in Th17 populations; increase in CD4+ induced regulatory T cells (iTregs), stabilization of nTregs, and promotion of suppressive B cells, which are critical in the improvement of pemphigus. Nevertheless, it also causes shifting of the Th1:Th2 balance toward Th2 cells, which is not favorable for pemphigus patients. In conclusion, ATRA acts via different ways in pemphigus. Due to increase in the suppressive function via iTregs, nTregs, and Bregs, it is suggested that patients with pemphigus may benefit from systemic ATRA therapy. To clarify this issue, further studies, such as clinical trials are needed. Copyright © 2016 Elsevier B.V. All rights reserved.

Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma-homing CD4 T cells.

PubMed

Sakai, Shunsuke; Kauffman, Keith D; Schenkel, Jason M; McBerry, Cortez C; Mayer-Barber, Katrin D; Masopust, David; Barber, Daniel L

2014-04-01

Th1 cells are critical for containment of Mycobacterium tuberculosis infection, but little else is known about the properties of protective CD4 T cell responses. In this study, we show that the pulmonary Th1 response against M. tuberculosis is composed of two populations that are either CXCR3(hi) and localize to lung parenchyma or are CX3CR1(hi)KLRG1(hi) and are retained within lung blood vasculature. M. tuberculosis-specific parenchymal CD4 T cells migrate rapidly back into the lung parenchyma upon adoptive transfer, whereas the intravascular effectors produce the highest levels of IFN-γ in vivo. Importantly, parenchymal T cells displayed greater control of infection compared with the intravascular counterparts upon transfer into susceptible T cell-deficient hosts. Thus, we identified a subset of naturally generated M. tuberculosis-specific CD4 T cells with enhanced protective capacity and showed that control of M. tuberculosis correlates with the ability of CD4 T cells to efficiently enter the lung parenchyma rather than produce high levels of IFN-γ.

Efficient mucosal delivery of the HIV-1 Tat protein using the synthetic lipopeptide MALP-2 as adjuvant.

PubMed

Borsutzky, Stefan; Fiorelli, Valeria; Ebensen, Thomas; Tripiciano, Antonella; Rharbaoui, Faiza; Scoglio, Arianna; Link, Claudia; Nappi, Filomena; Morr, Michael; Buttó, Stefano; Cafaro, Aurelio; Mühlradt, Peter F; Ensoli, Barbara; Guzmán, Carlos A

2003-06-01

A major requirement for HIV/AIDS research is the development of a mucosal vaccine that stimulates humoral and cell-mediated immune responses at systemic and mucosal levels, thereby blocking virus replication at the entry port. Thus, a vaccine prototype based on biologically active HIV-1 Tat protein as antigen and the synthetic lipopeptide, macrophage-activating lipopeptide-2 (MALP-2), asa mucosal adjuvant was developed. Intranasal administration to mice stimulated systemic and mucosal anti-Tat antibody responses, and Tat-specific T cell responses, that were more efficient than those observed after i.p. immunization with Tat plus incomplete Freund's adjuvant. Major linear B cell epitopes mapped within aa 1-20 and 46-60, whereas T cell epitopes were identified within aa 36-50 and 56-70. These epitopes have also been described in vaccinated primates and in HIV-1-infected individuals with better prognosis. Analysis of the anti-Tat IgG isotypes in serum, and the cytokine profile of spleen cells indicated that a dominant Th1 helper response was stimulated by Tat plus MALP-2, as opposed to the Th2 response observed with Tat plus incomplete Freund's adjuvant. Tat-specific IFN-gamma-producing cells were significantly increased only in response to Tat plus MALP-2. These data suggest that Malp-2 may represent an optimal mucosal adjuvant for candidate HIV vaccines based on Tat alone or in combination with other HIV antigens.

Humoral and Cell-Mediated Immune Responses to Alternate Booster Schedules of Anthrax Vaccine Adsorbed in Humans

PubMed Central

Sabourin, Carol L.; Schiffer, Jarad M.; Niemuth, Nancy A.; Semenova, Vera A.; Li, Han; Rudge, Thomas L.; Brys, April M.; Mittler, Robert S.; Ibegbu, Chris C.; Wrammert, Jens; Ahmed, Rafi; Parker, Scott D.; Babcock, Janiine; Keitel, Wendy; Poland, Gregory A.; Keyserling, Harry L.; El Sahly, Hana; Jacobson, Robert M.; Marano, Nina; Plikaytis, Brian D.; Wright, Jennifer G.

2016-01-01

Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r2 = 0.86, P < 0.0001, log10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.) PMID:26865594

IL-10R Blockade during Chronic Schistosomiasis Mansoni Results in the Loss of B Cells from the Liver and the Development of Severe Pulmonary Disease

PubMed Central

Fairfax, Keke C.; Amiel, Eyal; King, Irah L.; Freitas, Tori C.; Mohrs, Markus; Pearce, Edward J.

2012-01-01

In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection. PMID:22291593

Immunomodulatory and Immunosuppressive Roles of 1α,25(OH)2D3 in Autoimmune Diseases.

PubMed

Alhassan Mohammed, H; Saboor-Yaraghi, A A; Mirshafiey, A; Vahedi, H; Shiri-Shahsavar, M R; Mousavi Nasl Khameneh, A

2017-02-01

Autoimmune diseases are pathological conditions characterized by abnormal responses, accompanied by autoantibodies to self-molecules. The role of vitamin D in autoimmune diseases has increased significantly in the recent past from its functions in calcium and phosphate homoeostasis, and it is now involved in the regulations and proliferations of Th1 and Th17 lymphocyte. 1α,25(OH)2D3 is very important in ameliorations of inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is performed is still a bone of contentions. This review aimed to highlight the existing facts about the roles of Vitamin D in the treatment and management of autoimmune diseases. An extensive online literature search was conducted using PubMed, MEDLINE and Scopus. Accumulated bodies of research evidence are available which demonstrates that Vitamin D has a very important part to play in the regulation of immune responses in autoimmune diseases. Some of the authors suggested that Vitamin D3 carry-out its immunosuppressive and immune modulatory action, through its actions on antigen-presenting cells and activated T and B cells with the help of Vitamin D receptors present on the each of these cells. Vitamin D supplementation assists in autoimmune disorders by making qualitative and quantitative changes in the immune system (downregulation of Th1 and upregulations of Th2 cells). This resulted in the body to be more tolerant of self and less likely to mount autoimmune responses. © 2016 The Foundation for the Scandinavian Journal of Immunology.

Anti-inflammatory potential of a heat-killed Lactobacillus strain isolated from Kimchi on house dust mite-induced atopic dermatitis in NC/Nga mice.

PubMed

Choi, C-Y; Kim, Y-H; Oh, S; Lee, H J; Kim, J H; Park, S H; Kim, H J; Lee, S J; Chun, T

2017-08-01

Atopic dermatitis (AD) is an allergic skin disease driven by the Th2-prone immune response. Therefore, a fundamental approach to restoring the Th1/Th2 balance is needed to treat AD. Eighteen different Lactobacillus strains isolated from Kimchi were screened to identify those that stimulated immune cells to secret Th1-type or Th2-type cytokines. Lactobacillus brevis NS1401 induced the greatest IFN-γ and IL-12 secretion and the least IL-4 production among the tested Lactobacillus strains. Furthermore, oral administration of heat-killed NS1401 ameliorated the symptoms of dust mite-induced AD in NC/Nga mice by decreasing the serum IgE level and reducing the number of mast cells and eosinophils in lesions. Also, the size and number of cells in the draining lymph nodes of NS1401-administered mice were significantly reduced. In agreement with these results, secretion of a Th1-type cytokine (IFN-γ) and allergen-specific IgG2a were increased, whereas secretion of Th2-type cytokines (IL-4, IL-5, and IL-10) and allergen-specific IgG1 were decreased upon administration of NS1401 in mice. Lactobacillus brevis NS1401 alleviates the symptoms of AD by restoring the Th1/Th2 balance through enhancing Th1-prone immunity. The immunomodulatory function of L. brevis NS1401 may provide effective new therapeutics against AD. © 2017 The Society for Applied Microbiology.

Altered balance between self-reactive T helper (Th)17 cells and Th10 cells and between full-length forkhead box protein 3 (FoxP3) and FoxP3 splice variants in Hashimoto's thyroiditis.

PubMed

Kristensen, B; Hegedüs, L; Madsen, H O; Smith, T J; Nielsen, C H

2015-04-01

T helper type 17 (Th17) cells play a pathogenic role in autoimmune disease, while interleukin (IL)-10-producing Th10 cells serve a protective role. The balance between the two subsets is regulated by the local cytokine milieu and by the relative expression of intact forkhead box protein 3 (FoxP3) compared to FoxP3Δ2, missing exon 2. Th17 and Th10 cell differentiation has usually been studied using polyclonal stimuli, and little is known about the ability of physiologically relevant self-antigens to induce Th17 or Th10 cell differentiation in autoimmune thyroid disease. We subjected mononuclear cells from healthy donors and patients with Hashimoto's thyroiditis (HT) or Graves' disease (GD) to polyclonal stimulation, or stimulation with human thyroglobulin (TG), human thyroid peroxidase (TPO), or Esherichia coli lipopolysaccharide (LPS). TPO and LPS induced increased differentiation of naive CD4(+) CD45RA(+) CD45R0(-) T cells from HT patients into Th17 cells. Th10 cell proportions were decreased in HT after polyclonal stimulation, but were comparable to those of healthy donors after antigen-specific stimulation. Taken together, our data show that an increased Th17 : Th10 ratio was found in HT patients after stimulation with thyroid-specific self-antigens. We also observed an elevated baseline production of IL-6 and transforming growth factor (TGF)-β1 and of mRNA encoding FoxP3Δ2 rather than intact FoxP3. This may contribute to the skewing towards Th17 cell responses in HT. © 2014 British Society for Immunology.

HLA-DR4-associated T and B cell responses to specific determinants on the IA-2 autoantigen in type 1 diabetes.

PubMed

McLaughlin, Kerry A; Gulati, Kavita; Richardson, Carolyn C; Morgan, Diana; Bodansky, H Jonathan; Feltbower, Richard G; Christie, Michael R

2014-11-01

Autoantibodies to IA-2 in type 1 diabetes are associated with HLA-DR4, suggesting influences of HLA-DR4-restricted T cells on IA-2-specific B cell responses. The aim of this study was to investigate possible T-B cell collaboration by determining whether autoantibodies to IA-2 epitopes are associated with T cell responses to IA-2 peptides presented by DR4. T cells secreting the cytokines IFN-γ and IL-10 in response to seven peptides known to elicit T cell responses in type 1 diabetes were quantified by cytokine ELISPOT in HLA-typed patients characterized for Abs to IA-2 epitopes. T cell responses were detected to all peptides tested, but only IL-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45RO(hi) T cells secreting IL-10 in response to these two peptides indicated that these expressed GATA-3 or T-bet, but not FOXP3, consistent with these being Th2 or Th1 memory T cells rather than of regulatory phenotype. T cell responses to the same two peptides were also associated with specific Abs: those to 841-860 peptide with Abs to juxtamembrane epitopes, which appear early in prediabetes, and those to peptide 853-872 with Abs to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Abs to juxtamembrane and central region constructs were both DR4 associated. This study identifies a region of focus for B and T cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA associations of IA-2 autoantibodies, and this region may provide a target for future immune intervention to prevent disease. Copyright © 2014 by The American Association of Immunologists, Inc.

Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.

PubMed

Hammer, Leslie A; Waldner, Hanspeter; Zagon, Ian S; McLaughlin, Patricia J

2016-01-01

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by infiltrating myelin-reactive T lymphocytes and demyelinating lesions. Experimental autoimmune encephalomyelitis (EAE) is the animal model widely utilized to study MS. EAE is mediated by CD4(+) T cells and can be induced in EAE-susceptible mice through immunization with a myelin antigen, such as proteolipid protein 139-151 (PLP139-151) in SJL mice. In this PLP-induced EAE model, autoreactive CD4(+) T cells migrate from peripheral tissues into the CNS where they are reactivated resulting in CNS damage. Th1 and Th17 cells produce the pro-inflammatory cytokines IFNγ and IL-17, respectively, that have been shown to have pathogenic roles in EAE and MS. Anti-inflammatory Th2, IL-4 secreting cells, have been indicated to inhibit EAE exacerbation. However, given the inflammatory environment of EAE, Th2 effector cells are outnumbered by Th1/Th17 cells. Regulatory CD4(+) T cells suppress immune reactions and have been demonstrated to be dysfunctional in MS patients. Opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, is a negative growth factor that interacts with the OGF receptor. The OGF-OGFr axis can be activated through exogenous administration of OGF or a low dosage of naltrexone (LDN), an opioid antagonist. We have previously demonstrated that modulation of the OGF-OGFr axis results in alleviation from relapse-remitting EAE, and that CNS-infiltrating CD3(+) T cells are diminished with exogenous OGF or intermittent blockade with LDN administration. In this paper, we aimed to determine whether OGF or LDN alter the Th effector responses of CD4(+) T lymphocytes within the CNS in established EAE. We report in these studies that the numbers of CD4(+) T lymphocytes in the CNS of EAE mice are decreased following treatment with OGF for five days but not LDN. However, modulation of the OGF-OGFr axis did not result in changes to CD4(+) Th effector cell responses in the CNS of EAE mice. © 2016 by the Society for Experimental Biology and Medicine.

Interaction between allergic asthma and atherosclerosis

PubMed Central

Liu, Conglin; Zhang, Jingying; Shi, Guo-Ping

2015-01-01

Prior studies have established an essential role of mast cells in allergic asthma and atherosclerosis. Mast cell deficiency or inactivation protects mice from allergen-induced airway hyper-responsiveness and diet-induced atherosclerosis, suggesting that mast cells share pathologic activities in both diseases. Allergic asthma and atherosclerosis are inflammatory diseases that contain similar sets of elevated numbers of inflammatory cells in addition to mast cells in the airway and arterial wall, such as macrophages, monocytes, T cells, eosinophils, and smooth muscle cells. Emerging evidence from experimental models and human studies points to a potential interaction between the two seemingly unrelated diseases. Patients or mice with allergic asthma have a high risk of developing atherosclerosis or vice versa, despite the fact that asthma is a Th2-oriented disease, whereas Th1 immunity promotes atherosclerosis. In addition to the preferred Th1/Th2 responses that may differentiate the two diseases, mast cells and many other inflammatory cells also contribute to their pathogenesis by much more than just T cell immunity. Here we summarize the different roles of airway and arterial wall inflammatory cells and vascular cells in asthma and atherosclerosis, and propose an interaction between the two diseases, although limited investigations are available to delineate the molecular and cellular mechanisms by which one disease increases the risk of the other. Results from mouse allergic asthma and atherosclerosis models and from human population studies lead to the hypothesis that patients with atherosclerosis may benefit from anti-asthmatic medications, or that the therapeutic regimens targeting atherosclerosis may also alleviate allergic asthma. PMID:26608212

Low-molecular-weight polysaccharides from Agaricus blazei Murrill modulate the Th1 response in cancer immunity.

PubMed

Jiang, Liyan; Yu, Zhipu; Lin, Yu; Cui, Liran; Yao, Shujuan; Lv, Liyan; Liu, Jicheng

2018-03-01

To assess the effect of low-molecular-weight polysaccharides from Agaricus blazei Murrill (ABP-AW1) as an immunoadjuvant therapy for type 1 T-helper (Th1) responses in tumorigenesis, C57BL/6 mice were inoculated subcutaneously with ovalbumin (E.G7-OVA). After 3, 10 and 17 days, the mice were immunized with PBS, OVA alone, or OVA and ABP-AW1, at low (50 µg), intermediate (100 µg) or high (200 µg) doses. Tumor growth was examined and compared among the groups, as were the following parameters: Splenocyte viability/proliferation, peripheral blood CD4 + /CD8 + T cell ratio, serum OVA-specific IgG1 and IgG2b, secretion of interleukin (IL)-2 and interferon (IFN)-γ, and IFN-γ production on a single cell level from cultured splenocytes. Tumor growth in mice treated with OVA and ABP-AW1 (100 or 200 µg) was significantly slower, compared with in the other groups at the same time-points. OVA with 100 or 200 µg ABP-AW1 was associated with a higher number of total splenocytes, a higher ratio of peripheral blood CD4 + /CD8 + T-lymphocytes, higher serum levels of OVA-specific Th1-type antibody IgG2b and greater secretion of the Th1 cytokines IL-1 and IFN-γ from splenocytes. ABP-AW1 is a promising immunoadjuvant therapy candidate, due to its ability to boost the Th1 immune response when co-administered with a cancer vaccine intended to inhibit cancer progression.

Low-molecular-weight polysaccharides from Agaricus blazei Murrill modulate the Th1 response in cancer immunity

PubMed Central

Jiang, Liyan; Yu, Zhipu; Lin, Yu; Cui, Liran; Yao, Shujuan; Lv, Liyan; Liu, Jicheng

2018-01-01

To assess the effect of low-molecular-weight polysaccharides from Agaricus blazei Murrill (ABP-AW1) as an immunoadjuvant therapy for type 1 T-helper (Th1) responses in tumorigenesis, C57BL/6 mice were inoculated subcutaneously with ovalbumin (E.G7-OVA). After 3, 10 and 17 days, the mice were immunized with PBS, OVA alone, or OVA and ABP-AW1, at low (50 µg), intermediate (100 µg) or high (200 µg) doses. Tumor growth was examined and compared among the groups, as were the following parameters: Splenocyte viability/proliferation, peripheral blood CD4+/CD8+ T cell ratio, serum OVA-specific IgG1 and IgG2b, secretion of interleukin (IL)-2 and interferon (IFN)-γ, and IFN-γ production on a single cell level from cultured splenocytes. Tumor growth in mice treated with OVA and ABP-AW1 (100 or 200 µg) was significantly slower, compared with in the other groups at the same time-points. OVA with 100 or 200 µg ABP-AW1 was associated with a higher number of total splenocytes, a higher ratio of peripheral blood CD4+/CD8+ T-lymphocytes, higher serum levels of OVA-specific Th1-type antibody IgG2b and greater secretion of the Th1 cytokines IL-1 and IFN-γ from splenocytes. ABP-AW1 is a promising immunoadjuvant therapy candidate, due to its ability to boost the Th1 immune response when co-administered with a cancer vaccine intended to inhibit cancer progression. PMID:29467867

Innate Immune Cytokines, Fibroblast Phenotypes, and Regulation of Extracellular Matrix in Lung.

PubMed

Richards, Carl D

2017-02-01

Chronic inflammation can be caused by adaptive immune responses in autoimmune and allergic conditions, driven by a T lymphocyte subset balance (TH1, TH2, Th17, Th22, and/or Treg) and skewed cellular profiles in an antigen-specific manner. However, several chronic inflammatory diseases have no clearly defined adaptive immune mechanisms that drive chronicity. These conditions include those that affect the lung such as nonatopic asthma or idiopathic pulmonary fibrosis comprising significant health problems. The remodeling of extracellular matrix (ECM) causes organ dysfunction, and it is largely generated by fibroblasts as the major cell controlling net ECM. As such, these are potential targets of treatment approaches in the context of ECM pathology. Fibroblast phenotypes contribute to ECM and inflammatory cell accumulation, and they are integrated into chronic disease mechanisms including cancer. Evidence suggests that innate cytokine responses may be critical in nonallergic/nonautoimmune disease, and they enable environmental agent exposure mechanisms that are independent of adaptive immunity. Innate immune cytokines derived from macrophage subsets (M1/M2) and innate lymphoid cell (ILC) subsets can directly regulate fibroblast function. We also suggest that STAT3-activating gp130 cytokines can sensitize fibroblasts to the innate cytokine milieu to drive phenotypes and exacerbate existing adaptive responses. Here, we review evidence exploring innate cytokine regulation of fibroblast behavior.

Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes

PubMed Central

Ghazy, Amany A.; Abu El-Nazar, Salma Y.; Ghoneim, Hossam E.; Taha, Abdul-Rahman M.; Abouelella, Amira M.

2015-01-01

Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays. PMID:25914644