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.

Helper T Cell Responses to Respiratory Viruses in the Lung: Development, Virus Suppression, and Pathogenesis.

PubMed

Miyauchi, Kosuke

The lung is an important line of defense that is exposed to respiratory infectious pathogens, including viruses. Lung epithelial cells and/or alveolar macrophages are initially targeted by respiratory viruses. Once respiratory viruses invade the cells of the lung, innate immunity is activated to inhibit viral replication. Innate immune signaling also activates virus-specific adaptive immune responses. The helper T cells play pivotal roles in the humoral and cellular adaptive immune responses. Helper T cells are categorized into several distinct subsets (e.g., T H 1, T H 2, T FH , T H 17, and Treg), differentiated by their corresponding signature cytokine production profiles. Helper T cells migrate into the airways and the lung after respiratory virus infections. The behavior of the helper T cells differs with each respiratory virus-in some cases, the response is beneficial; in other cases, it is harmful. Here, the general mechanisms underlying helper T cell responses to viral infections are summarized, and functions and reactions of the helper T cells against some respiratory viral infections are discussed. In influenza virus infections, T H 1 cells, which regulate the cytotoxic T lymphocytes and IgG2 responses, are efficiently activated. T FH cells required for highly specific and memory humoral responses are also activated on influenza infections. In infections with respiratory syncytial virus and rhinovirus, T H 2 cells develop in the lung and contribute to pathogenesis. In many cases, Treg cells inhibit excessive virus-specific T cell responses that can contribute to viral pathogenicity.

Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus.

PubMed

Donnarumma, Tiziano; Young, George R; Merkenschlager, Julia; Eksmond, Urszula; Bongard, Nadine; Nutt, Stephen L; Boyer, Claude; Dittmer, Ulf; Le-Trilling, Vu Thuy Khanh; Trilling, Mirko; Bayer, Wibke; Kassiotis, George

2016-11-01

CD4 + T cells develop distinct and often contrasting helper, regulatory, or cytotoxic activities. Typically a property of CD8 + T cells, granzyme-mediated cytotoxic T cell (CTL) potential is also exerted by CD4 + T cells. However, the conditions that induce CD4 + CTLs are not entirely understood. Using single-cell transcriptional profiling, we uncover a unique signature of Granzyme B (GzmB) + CD4 + CTLs, which distinguishes them from other CD4 + T helper (Th) cells, including Th1 cells, and strongly contrasts with the follicular helper T (Tfh) cell signature. The balance between CD4 + CTL and Tfh differentiation heavily depends on the class of infecting virus and is jointly regulated by the Tfh-related transcription factors Bcl6 and Tcf7 (encoding TCF-1) and by the expression of the inhibitory receptors PD-1 and LAG3. This unique profile of CD4 + CTLs offers targets for their study, and its antagonism by the Tfh program separates CD4 + T cells with either helper or killer functions. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Important role of phosphoramido linkage in imidazole-based dioleyl helper lipids for liposome stability and primary cell transfection.

PubMed

Mével, Mathieu; Haudebourg, Thomas; Colombani, Thibault; Peuziat, Pauline; Dallet, Laurence; Chatin, Benoît; Lambert, Olivier; Berchel, Mathieu; Montier, Tristan; Jaffrès, Paul-Alain; Lehn, Pierre; Pitard, Bruno

2016-01-01

To optimize synthetic gene delivery systems, there is a need to develop more efficient lipid formulations. Most cationic lipid formulations contain 'helper' neutral lipids because of their ability to increase DNA delivery, in particular by improving endosomal escape of DNA molecules via the pH-buffering effect of protonatable groups and/or fusion with the lipid bilayer of endosomes. We evaluated the influence of the linker structure between the two oleyl chains in the helper lipid on transfection efficiency in cell lines, as well as in primary cells (hepatocytes/cardiomyocytes). We reported the synthesis of two new pH-buffering imidazole helper lipids characterized by a polar headgroup containing one (compound 6) or two (compound 5) imidazole groups and two oleyl chains linked by an amide group. We studied their association with the aminoglycoside lipidic derivative dioleylsuccinylparomomycin (DOSP), which contains two oleyl chains linked to the aminoglycoside polar headgroup via an amide function. We compared the morphology and transfection properties of such binary liposomes of DOSP/5 and DOSP/6 with those of liposomes combining DOSP with another imidazole-based dioleyl helper lipid (MM27) in which a phosphoramido group acts as a linker between the two oleyl chains and imidazole function. The phosphoramido linker in the helper lipid induces a major difference in terms of morphology and resistance to decomplexation at physical pH for DOSP/helper lipid complexes. This hybrid dioleyl linker composition of DOSP/MM27 led to higher transfection efficiency in cell lines and in primary cells compared to complexes with homogeneous dioleyl linker. Copyright © 2015 John Wiley & Sons, Ltd.

Emerging concepts in T follicular helper cell responses to malaria.

PubMed

Hansen, Diana S; Obeng-Adjei, Nyamekye; Ly, Ann; Ioannidis, Lisa J; Crompton, Peter D

2017-02-01

Antibody responses to malaria and candidate malaria vaccines are short-lived in children, leaving them susceptible to repeated malaria episodes. Because T follicular helper (T FH ) cells provide critical help to B cells to generate long-lived antibody responses, they have become the focus of recent studies of Plasmodium-infected mice and humans. The emerging data converge on common themes, namely, that malaria-induced T H1 cytokines are associated with the activation of (i) T-like memory T FH cells with impaired B cell helper function, and (ii) pre-T FH cells that acquire Th1-like features (T-bet expression, IFN-γ production), which impede their differentiation into fully functional T FH cells, thus resulting in germinal center dysfunction and suboptimal antibody responses. Deeper knowledge of T FH cells in malaria could illuminate strategies to improve vaccines through modulating T FH cell responses. This review summarizes emerging concepts in T FH cell responses to malaria. Copyright © 2016. Published by Elsevier Ltd.

Th9 cells: differentiation and disease

PubMed Central

Kaplan, Mark H.

2014-01-01

Summary CD4+ T-helper cells regulate immunity and inflammation through the acquisition of potential to secrete specific cytokines. The acquisition of cytokine-secreting potential, in a process termed T-helper cell differentiation, is a response to multiple environmental signals including the cytokine milieu. The most recently defined subset of T-helper cells are termed Th9 and are identified by the potent production of interleukin-9 (IL-9). Given the pleiotropic functions of IL-9, Th9 cells might be involved in pathogen immunity and immune-mediated disease. In this review, I focus on recent developments in understanding the signals that promote Th9 differentiation, the transcription factors that regulate IL-9 expression, and finally the potential roles for Th9 cells in immunity in vivo. PMID:23405898

T-cell help permits memory CD8(+) T-cell inflation during cytomegalovirus latency.

PubMed

Walton, Senta M; Torti, Nicole; Mandaric, Sanja; Oxenius, Annette

2011-08-01

CD4(+) T cells are implied to sustain CD8(+) T-cell responses during persistent infections. As CD4(+) T cells are often themselves antiviral effectors, they might shape CD8(+) T-cell responses via help or via controlling antigen load. We used persistent murine CMV (MCMV) infection to dissect the impact of CD4(+) T cells on virus-specific CD8(+) T cells, distinguishing between increased viral load in the absence of CD4(+) T cells and CD4(+) T-cell-mediated helper mechanisms. Absence of T-helper cells was associated with sustained lytic MCMV replication and led to a slow and gradual reduction of the size and function of the MCMV-specific CD8(+) T-cell pool. However, when virus replication was controlled in the absence of CD4(+) T cells, CD8(+) T-cell function was comparably impaired, but in addition CD8(+) T-cell inflation, a hallmark of CMV infection, was completely abolished. Thus, CD8(+) T-cell inflation during latent CMV infection is strongly dependent on CD4(+) T-cell helper functions, which can partially be compensated by ongoing lytic viral replication in the absence of CD4(+) T cells. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

T Helper1/T Helper2 Cells and Resistance/Susceptibility to Leishmania Infection: Is This Paradigm Still Relevant?

PubMed Central

Alexander, James; Brombacher, Frank

2012-01-01

Work in large part on Leishmania major in the 1980s identified two distinct apparently counter-regulatory CD4+ T cell populations, T helper (h)1 and Th2, that controlled resistance/susceptibility to infection respectively. However, the generation of IL-4−/− mice in the 1990s questioned the paramount role of this Th2 archetypal cytokine in the non-healing response to Leishmania infection. The more recent characterization of CD4+ T cell regulatory populations and further effector CD4+ T helper populations, Th17, Th9, and T follicular (f)h cells as well as the acknowledged plasticity in T helper cell function has further added to the complexity of host pathogen interactions. These interactions are complicated by the multiplicity of cells that respond to CD4+ T cell subset signatory cytokines, as well as the diversity of Leishmania species that are often subject to significantly different immune-regulatory controls. In this article we review current knowledge with regard to the role of CD4+ T cells and their products during Leishmania infection. In particular we update on our studies using conditional IL-4Rα gene-deficient mice that have allowed dissection of the cell interplay dictating the disease outcomes of the major Leishmania species infecting humans. PMID:22566961

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.

An inherently bi-functional subset of Foxp3+ T helper cells is controlled by the transcription factor Eos

PubMed Central

Sharma, Madhav D.; Huang, Lei; Choi, Jeong-Hyeon; Lee, Eun-Joon; Wilson, James M.; Lemos, Henrique; Pan, Fan; Blazar, Bruce R.; Pardoll, Drew M.; Mellor, Andrew L; Shi, Huidong; Munn, David H.

2013-01-01

SUMMARY At sites of inflammation, certain regulatory T cells (Treg cells) can undergo rapid reprogramming into helper-like cells, without loss of the transcription factor Foxp3. We show that reprogramming is controlled by down-regulation of the transcription factor Eos (Ikzf4), an obligate co-repressor for Foxp3. Reprogramming was restricted to a specific subset of “Eoslabile” Treg cells which were present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive T cells. Down-regulation of Eos required the pro-inflammatory cytokine IL-6, and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eos, and prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3+ lineage contains a committed subset of Treg cells capable of rapid conversion into biologically important helper cells. PMID:23684987

BCL6 interacting corepressor contributes to germinal center T follicular helper cell formation and B cell helper function

PubMed Central

Yang, Jessica A.; Tubo, Noah J.; Gearhart, Micah D.; Bardwell, Vivian J.; Jenkins, Marc K.

2015-01-01

CD4+ germinal center (GC) T follicular helper (GC-Tfh) cells help B cells become long-lived plasma cells and memory cells. The transcriptional repressor BCL6 plays a key role in GC-Tfh formation by inhibiting the expression of genes that promote differentiation into other lineages. We determined whether BCOR, a component of a Polycomb repressive complex that interacts with the BCL6 BTB domain, influences GC-Tfh differentiation. T cell-targeted BCOR deficiency led to a substantial loss of peptide:MHCII-specific GC-Tfh cells following Listeria monocytogenes infection and a 2-fold decrease following immunization with a peptide in CFA. The reduction in GC-Tfh cells was associated with diminished plasma cell and GC B cell formation. Thus, T cell-expressed BCOR is critical for optimal GC-Tfh differentiation and humoral immunity. PMID:25964495

Multicolor flow-cytometric analysis of milk allergen-specific T-helper type 2 cells revealed coexpression of interleukin-4 with Foxp3.

PubMed

Yamawaki, Kazuo; Inuo, Chisato; Nomura, Takayasu; Tanaka, Kenichi; Nakajima, Yoichi; Kondo, Yasuto; Yoshikawa, Tetsushi; Urisu, Atsuo; Tsuge, Ikuya

2015-12-01

Allergen-specific T-helper type 2 (TH2) cells play an important role in the development of allergic inflammation; however, investigations of the properties of allergen-specific T cells have been challenging in humans. Despite clear evidence that forkhead box p3 (Foxp3) is expressed in conventional effector T cells, its function has remained unknown. To characterize allergen-specific TH2 cells in milk allergy, with particular focus on the expression of Foxp3. Twenty-one children with milk allergy and 11 children without milk allergy were studied. Peripheral blood mononuclear cells from subjects were stimulated with milk allergen for 6 hours and analyzed using multicolor flow cytometry to identify CD154(+) allergen-specific T-helper cells. Simultaneously, the expression of intracellular cytokines and Foxp3 was analyzed. The milk allergy group had significantly larger numbers of milk allergen-specific interleukin (IL)-4- and IL-5-producing CD4(+) T cells than the control group. Subjects in the milk allergy group had significantly more CD154(+)CD4(+) IL-10-producing cells and CD154(+)Foxp3(+)CD4(+) cells than those in the control group. In addition, the number of milk allergen-specific CD154(+)Foxp3(+)CD4(+) cells strongly correlated with that of CD154(+)IL4(+)CD4(+) cells. Bcl-2 expression in CD154(+)IL-4(+)Foxp3(+) T-helper cells was significantly lower compared with that in total CD4 cells. Increased numbers of IL-4-producing allergen-specific T-helper cells were found in patients with milk allergy. In addition, Foxp3 was coexpressed with IL-4 in allergen-specific TH2 cells from patients. This coexpression was associated with lower Bcl-2 levels and could contribute to the phenotype and function of TH2 cells. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

In vitro generation of helper T cells and suppressor T cells that regulate the cytolytic T lymphocyte response to trinitrophenyl-modified syngeneic cells.

PubMed

Gualde, N; Weinberger, O; Ratnofsky, S; Benacerraf, B; Burakoff, S J

1982-04-01

Helper T cells and suppressor T cells have been generated in vitro that regulate the cytolytic T lymphocyte (CTL) response to trinitrophenyl (TNP)-modified syngeneic cells. B6D2F1 helper cells generated to TNP-modified parental (P1) cells augment the CTL response to those P1-TNP-modified antigens but not to P2-TNP-modified antigens. The generation of these helper T cells requires the presence of splenic adherent cells and these helper T cells are radioresistant. A soluble factor can be obtained from the helper T cell cultures that can also augment the CTL response. The suppressor T cells generated in culture do not demonstrate the specificity observed with the helper T cells; however, they are antigen-dependent in their induction. Whether helper or suppressor activity is obtained depends upon the length of time cells are cultured in vitro.

In vitro generation of helper T cells and suppressor T cells that regulate the cytolytic T lymphocyte response to trinitrophenyl-modified syngeneic cells

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

Gualde, N.; Weinberger, O.; Ratnofsky, S.

1982-04-01

Helper T cells and suppressor T cells have been generated in vitro that regulate the cytolytic T lymphocyte (CTL) response to trinitrophenyl (TNP)-modified syngeneic cells. B6D2F1 helper cells generated to TNP-modified parental (P1) cells augment the CTL response to those P1-TNP-modified antigens but not to P2-TNP-modified antigens. The generation of these helper T cells requires the presence of splenic adherent cells and these helper T cells are radioresistant. A soluble factor can be obtained from the helper T cell cultures that can also augment the CTL response. The suppressor T cells generated in culture do not demonstrate the specificity observedmore » with the helper T cells; however, they are antigen-dependent in their induction. Whether helper or suppressor activity is obtained depends upon the length of time cells are cultured in vitro.« less

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.

JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells.

PubMed

Keohane, Clodagh; Kordasti, Shahram; Seidl, Thomas; Perez Abellan, Pilar; Thomas, Nicholas S B; Harrison, Claire N; McLornan, Donal P; Mufti, Ghulam J

2015-10-01

CD4(+) T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4(+) T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4(+)  CD127(low)  CD25(high)  FOXP3(+) T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional 'silencing' of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs. © 2015 John Wiley & Sons Ltd.

Lymphocyte function in experimental endemic syphilis of Syrian hamsters.

PubMed Central

Bagasra, O; Kushner, H; Hashemi, S

1985-01-01

We have studied the changes in the lymph nodes, spleen and thymus that occur in inbred LSH Syrian hamsters infected with Treponema pallidum Bosnia A, the causative agent of endemic syphilis, as well as the B-cell responses of these infected animals to helper T-cell independent and dependent antigens. The lymph nodes increased significantly in weight up to 6 weeks after infection, and contained viable treponemes. No significant changes in the spleen weight were observed, and no viable treponemes could be recovered from the spleen. However, the size of the thymus decreased steadily during the course of the disease. The relative number of Ig+ cells (B cells) increased in the spleen and regional lymph nodes, whereas the relative number of T cells decreased during the course of infection. In both the spleen and lymph nodes, the relative number of macrophages increased initially and decreased thereafter in the form of a bell-shaped curve showing a peak at 4-6 weeks of infection. The ability of splenic lymphocytes from infected hamsters to mount a primary PFC response to pneumococcal polysaccharide type III (SIII), a helper T-cell independent antigen, was elevated throughout the course of infection. However, the splenic PFC response to sheep erythrocytes (SRBC), a helper T-cell dependent antigen, was increased only during the first 4 weeks of infection and progressively decreased thereafter. The PFC responses of infected lymph node lymphocytes to both SIII and SRBC were increased during the first 4 weeks and decreased thereafter. These data suggested that atrophy of the thymus seen in syphilitic infection is accompanied by the complex losses of subsets of T cells and altered B-cell functions. An early loss of suppressor T cells in both the lymph nodes and spleen occurs concomitantly with a loss of T helper cells and heterologous (treponema-unrelated) B-cell functions in the lymph nodes. Helper T cells are lost from the spleen only in the later stages of infection, whereas splenic B-cell functions remain intact throughout the course of the disease. These findings were further tested by in vitro methods where splenic and lymph node lymphocytes from infected hamsters were examined for their ability to respond to Con A in terms of the induction of antigen non-specific suppressor T cells. The mixing of Con A stimulated splenic or lymph node lymphocytes from infected hamsters was unable to inhibit the primary antibody responses of SRBC as compared to the normal control.(ABSTRACT TRUNCATED AT 400 WORDS) Images Figure 1 PMID:2931353

The Effects of TLR Activation on T-Cell Development and Differentiation

PubMed Central

Jin, Bo; Sun, Tao; Yu, Xiao-Hong; Yang, Ying-Xiang; Yeo, Anthony E. T.

2012-01-01

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed. PMID:22737174

Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated through distinct biochemical mechanisms

PubMed Central

Huang, Chuanxin; Hatzi, Katerina; Melnick, Ari

2013-01-01

The transcription factor Bcl-6 orchestrates the germinal center reaction through its actions in B and T cells, and regulates inflammatory signaling in macrophages. We report that genetic replacement by mutant Bcl-6, which cannot bind corepressors to its BTB domain, disrupted germinal center formation and immunoglobulin affinity maturation, due to a defect in B cell proliferation and survival. In contrast, BTB loss of function had no effect on T follicular helper cell differentiation and function, nor other T helper subsets. Bcl6 null mice displayed a lethal inflammatory phenotype, whereas BTB mutant mice experienced normal healthy lives with no inflammation. Bcl-6 repression of inflammatory responses in macrophages was accordingly independent of the BTB domain repressor function. Bcl-6 thus mediates its actions through lineage-specific biochemical functions. PMID:23455674

T follicular helper cell differentiation, function, and roles in disease

PubMed Central

Crotty, Shane

2014-01-01

Summary Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high affinity antibodies and memory B cells. Tfh cell differentiation is a multi-stage, multi-factorial process involving B cell lymphoma 6 (Bcl6) and other transcription factors. This article reviews understanding of Tfh cell biology, including their differentiation, migration, transcriptional regulation, and B cell help functions. Tfh cells are critical components of many protective immune responses against pathogens. As such, there is strong interest in harnessing Tfh cells to improve vaccination strategies. Tfh cells also have roles in a range of other diseases, particularly autoimmune diseases. Overall, there have been dramatic advances in this young field, but there is much to be learned about Tfh cell biology in the interest of applying that knowledge to biomedical needs. PMID:25367570

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

cAMP is an essential signal in the induction of antibody production by B cells but inhibits helper function of T cells.

PubMed

Gilbert, K M; Hoffmann, M K

1985-09-01

Dibutyryl cAMP and IL 1 were found to stimulate antigen-specific and polyclonal antibody production when added together to cultures of highly purified B cells. We propose that IL 1 and an elevation in cytoplasmic cAMP represent minimal signal requirements for B cell activation. In contrast to its effect on B cells, dibutyryl cAMP inhibited helper T cell activity. Cyclic AMP suppressed the production of IL 2 and T cell replacing factor (TRF) by T cells and thus abrogated the ability of helper T cells to enhance SRBC-specific antibody production by B cells. Cyclic AMP did not inhibit the generation by T cells of B cell growth factor (BCGF). BCGF, not normally detected in Con A supernatant, was found in the culture supernatant of spleen cells that were stimulated with Con A in the presence of cAMP. Our findings indicate that cAMP blocks the production of an inhibitor of BCGF activity. cAMP had no effect on the production by macrophages of IL 1.

Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer.

PubMed

Wagner, Philipp; Koch, Moritz; Nummer, Daniel; Palm, Sylvia; Galindo, Luis; Autenrieth, Daniel; Rahbari, Nuh; Schmitz-Winnenthal, Friedrich H; Schirrmacher, Volker; Büchler, Markus W; Beckhove, Philipp; Weitz, Jürgen

2008-08-01

Tumor-infiltrating T lymphocytes (TIL) play an important role in primary colorectal cancer, but their activity in liver metastases has not yet been investigated. The aim of this study was to examine whether tumor-selective infiltration, activation, and cytotoxic activity of TIL can be demonstrated in situ in colorectal liver metastases. TIL were obtained from liver metastases and corresponding normal liver tissue of 16 patients with colorectal liver metastases. Characterization of TIL in situ was performed by multicolor flowcytometric analysis. Presence of tumor antigen-reactive T cells was evaluated by interferon gamma Elispot analysis. TIL in colorectal liver metastases responding against tumor antigens were present in most patients. Although the proportions of CD3(+) T cells were comparable in liver metastasis and normal liver tissue, metastases contained significantly enhanced proportions of CD4(+) cells (49% vs. 22%, P < .001). Among all CD4(+) T helper cells, the proportion of activated (CD4(+)CD25(+)) effector cells was significantly increased in liver metastases (15.0% vs. 7.8%, P = .003). Metastases showed significantly higher proportions of activated (CD69(+) [70.1% vs. 49.8%, P = .02] and CD25(+) [4.1% vs. .6%, P = .06]) and cytotoxically active (CD107a(+)) CD8(+) TIL (3.2% vs. 1.3%, P = .03). Importantly, the presence of activated T helper cells correlated with the frequencies of cytotoxic T lymphocytes that exerted cytotoxic activity in situ (P = .02). CD4(+) and CD8(+) TIL are selectively activated in liver metastases, and cytotoxic T lymphocytes exert tumor-selective cytotoxic activity in situ in the presence of activated T helper cells, suggesting the requirement of in-situ-activated T helper cells for efficient cytotoxic T lymphocytes effector function.

Lectins and substitution for helper function in anti-hapten responses in Xenopus laevis.

PubMed

Clothier, R H; James, H S; Ruben, L N; Balls, M

1984-08-01

Substitution by lectins for the carrier-priming requirement in thymus-dependent, antigen-binding responses in Xenopus laevis has been examined. Concanavalin A (Con A) was found to substitute for carrier priming in control, early-thymectomized and adult-thymectomized animals, but not in animals given a single, high dose of N-methyl-N-nitrosourea, which has a permanent effect on certain thymus-dependent functions in this species. Lipopolysaccharide and other lectins, such as peanut agglutinin and wheat germ agglutinin, were unable to substitute for carrier priming. These effects of Con A are discussed in terms of substitution via amplifier T cells or a helper T cell subset.

Genetics Home Reference: ZAP70-related severe combined immunodeficiency

MedlinePlus

... involved in the activation of helper T cells (CD4+ T cells). These cells direct and assist the functions of ... CD8+ T cells and an excess of inactive CD4+ T cells. The resulting shortage of active T cells causes ...

T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention.

PubMed

van Langelaar, Jamie; van der Vuurst de Vries, Roos M; Janssen, Malou; Wierenga-Wolf, Annet F; Spilt, Isis M; Siepman, Theodora A; Dankers, Wendy; Verjans, Georges M G M; de Vries, Helga E; Lubberts, Erik; Hintzen, Rogier Q; van Luijn, Marvin M

2018-05-01

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

The differentiation and protective function of cytolytic CD4 T cells in influenza infection

USDA-ARS?s Scientific Manuscript database

CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity play a role in chronic, as well as, acute infections...

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

Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development.

PubMed

Taniuchi, Ichiro; Osato, Motomi; Egawa, Takeshi; Sunshine, Mary Jean; Bae, Suk Chul; Komori, Toshihisa; Ito, Yoshiaki; Littman, Dan R

2002-11-27

T lymphocytes differentiate in discrete stages within the thymus. Immature thymocytes lacking CD4 and CD8 coreceptors differentiate into double-positive cells (CD4(+)CD8(+)), which are selected to become either CD4(+)CD8(-)helper cells or CD4(-)CD8(+) cytotoxic cells. A stage-specific transcriptional silencer regulates expression of CD4 in both immature and CD4(-)CD8(+) thymocytes. We show here that binding sites for Runt domain transcription factors are essential for CD4 silencer function at both stages, and that different Runx family members are required to fulfill unique functions at each stage. Runx1 is required for active repression in CD4(-)CD8(-) thymocytes whereas Runx3 is required for establishing epigenetic silencing in cytotoxic lineage thymocytes. Runx3-deficient cytotoxic T cells, but not helper cells, have defective responses to antigen, suggesting that Runx proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes.

B cells in T Follicular Helper Cell Development and Function: Separable Roles in Delivery of ICOS Ligand and Antigen

PubMed Central

Weinstein, Jason S.; Bertino, Sarah A.; Hernandez, Sairy G.; Poholek, Amanda C.; Teplitzky, Taylor B.; Nowyhed, Heba N.; Craft, Joe

2014-01-01

B cells are required for follicular helper T (Tfh) cell development, as is the ligand for ICOS (ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B cells to Tfh-cell development and function are unknown. We find that Tfh-cell and germinal center differentiation are dependent upon cognate B-cell display of ICOS-L, but only when Ag presentation by the latter is limiting, with the requirement for B-cell expression of ICOS-L overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells provide different, yet compensatory signals for Tfh-cell differentiation, while reconciling conflicting data indicating a requirement for ICOS-L expression on cognate B cells for Tfh-cell development with those demonstrating this requirement could be bypassed in lieu of that tendered by non-cognate B cells. Our findings clarify the separable roles of delivery of Ag and ICOS-L by cognate B cells for Tfh-cell maturation and function, and have implications for using therapeutic ICOS blockade in settings of abundantly available Ag, such as in systemic autoimmunity. PMID:24610013

PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity.

PubMed

Pinchuk, Irina V; Saada, Jamal I; Beswick, Ellen J; Boya, Gushyalatha; Qiu, Sumin M; Mifflin, Randy C; Raju, Gottumukkala S; Reyes, Victor E; Powell, Don W

2008-10-01

A prominent role for inhibitory molecules PD-L1 and PD-L2 in peripheral tolerance has been proposed. However, the phenotype and function of PD-L-expressing cells in human gut remains unclear. Recent studies suggest that colonic myofibroblasts (CMFs) and fibroblasts are important in the switch from acute inflammation to adaptive immunity. In the normal human colon, CMFs represent a distinct population of major histocompatibility complex class II(+) cells involved in the regulation of mucosal CD4(+) T-cell responses. PD-L1 and PD-L2 expression on human CMFs was determined using Western blot, fluorescence-activated cell sorter analysis and confocal microscopy. Lymphoproliferation assays and cytokine enzyme-linked immunosorbent assays were used to evaluate the role of B7 costimulators expressed by CMFs with regard to the regulation of preactivated T-helper cell responses. We demonstrate here the expression of PD-L1/2 molecules by normal human CMF and fibroblasts in situ and in culture. Both molecules support suppressive functions of CMFs in the regulation of activated CD4(+) T-helper cell proliferative responses; blocking this interaction reverses the suppressive effect of CMFs on T-cell proliferation and leads to increased production of the major T-cell growth factor, interleukin (IL)-2. PD-L1/2-mediated CMF suppressive functions are mainly due to the inhibition of IL-2 production, because supplementation of the coculture media with exogenous IL-2 led to partial recovery of activated T-cell proliferation. Our data suggest that stromal myofibroblasts and fibroblasts may limit T-helper cell proliferative activity in the gut and, thus, might play a prominent role in mucosal intestinal tolerance.

Functional characterization of a regulatory human T-cell subpopulation increasing during autologous MLR.

PubMed Central

Cosulich, M E; Risso, A; Canonica, G W; Bargellesi, A

1986-01-01

The present study was undertaken to investigate the heterogeneity of helper T cells in humans using two different monoclonal antibodies: 5/9 and MLR4. The former identifies 15-20% of resting T lymphocytes from peripheral blood and corresponds to an anti-helper/inducer T cell. The second antibody, MLR4, recognizes 5% of total T lymphocytes and partially overlaps with the 5/9+ T cells. In order to investigate functional differences within the 5/9+ cells, we separated two different subsets (5/9+ MLR+ and 5/9+ MLR4-) by a rosetting technique. Although both subsets provide help for Ig synthesis in a PWM-stimulated culture, only the 5/9+ MLR4- fraction gave a proliferative response in both autologous and allogeneic MLR and to soluble protein antigens. The effect of radiation on the ability of the two subsets to provide help for Ig synthesis showed that the 5/9+ MLR4+ subset is highly radiation-sensitive, while 5/9+ MLR- is relatively radiation-resistant. In a further series of experiments, 5/9+ MLR4+ cells isolated after activation in an autologous MLR but not by Con A, were no longer able to induce T-cell differentiation but now showed a strong suppressor effect. The 5/9+ MLR4- subset separated from the same cultures did not display any suppressor function. These data demonstrate in fresh PBL the existence of a radiation-sensitive regulatory subset exerting a helper activity, and which acquires suppressor activity after activation in autologous MLR. PMID:2936679

Identification of transcription coactivator OCA-B-dependent genes involved in antigen-dependent B cell differentiation by cDNA array analyses.

PubMed

Kim, Unkyu; Siegel, Rachael; Ren, Xiaodi; Gunther, Cary S; Gaasterland, Terry; Roeder, Robert G

2003-07-22

The tissue-specific transcriptional coactivator OCA-B is required for antigen-dependent B cell differentiation events, including germinal center formation. However, the identity of OCA-B target genes involved in this process is unknown. This study has used large-scale cDNA arrays to monitor changes in gene expression patterns that accompany mature B cell differentiation. B cell receptor ligation alone induces many genes involved in B cell expansion, whereas B cell receptor and helper T cell costimulation induce genes associated with B cell effector function. OCA-B expression is induced by both B cell receptor ligation alone and helper T cell costimulation, suggesting that OCA-B is involved in B cell expansion as well as B cell function. Accordingly, several genes involved in cell proliferation and signaling, such as Lck, Kcnn4, Cdc37, cyclin D3, B4galt1, and Ms4a11, have been identified as OCA-B-dependent genes. Further studies on the roles played by these genes in B cells will contribute to an understanding of B cell differentiation.

Intertriginous mycosis fungoides: a distinct presentation of cutaneous T-cell lymphoma that may be caused by malignant follicular helper T cells.

PubMed

Gammon, Bryan; Guitart, Joan

2012-09-01

Follicular helper T cells are a subset of helper T cells that facilitate B-cell recruitment and maturation. Rare cases of cutaneous T-cell lymphoma manifesting as de novo tumor lesions in intertriginous skin contain an infiltrate rich in B cells. These cases may represent malignant counterparts of skin-homing follicular helper T cells. Two men and 1 woman (age range, 35-58 years) were seen with predominantly intertriginous tumor-stage cutaneous T-cell lymphoma lesions characterized by the absence of epidermotropism and the presence of a mixed infiltrate rich in B cells. Two of the patients died of the disease less than 3 years from the initial diagnosis. The surviving patient has aggressive disease and underwent hematopoietic stem cell transplantation. Two of the patients had a prominent CXCL13+, Bcl6/CD3+, and programmed death protein 1-positive follicular helper T-cell population. The intertriginous tumor variant of cutaneous T-cell lymphoma is heterogeneous but may be associated in some cases with a follicular helper T-cell immunophenotype. These patients may follow an aggressive clinical course. Tumor progression in sanctuary sites on patients receiving phototherapy may manifest as a similar clinical phenotype. Further characterization of the disease process is needed to confirm this observation.

The Absence of Interleukin 1 Receptor–Related T1/St2 Does Not Affect T Helper Cell Type 2 Development and Its Effector Function

PubMed Central

Hoshino, Katsuaki; Kashiwamura, Shin-ichiro; Kuribayashi, Kozo; Kodama, Taku; Tsujimura, Tohru; Nakanishi, Kenji; Matsuyama, Tomohiro; Takeda, Kiyoshi; Akira, Shizuo

1999-01-01

T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is expressed constitutively and stably on the surface of T helper type 2 (Th2) cells, but not on Th1 cells. T1/ST2 is also expressed on mast cells, which are critical for Th2-mediated effector responses. To evaluate whether T1/ST2 is required for Th2 responses and mast cell function, we have generated T1/ST2-deficient (T1/ST2−/−) mice and examined the roles of T1/ST2. Naive CD4+ T cells isolated from T1/ST2−/− mice developed to Th2 cells in response to IL-4 in vitro. T1/ST2−/− mice showed normal Th2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis as well as in the mouse model of allergen-induced airway inflammation. In addition, differentiation and function of bone marrow–derived cultured mast cells were unaffected. These findings demonstrate that T1/ST2 does not play an essential role in development and function of Th2 cells and mast cells. PMID:10562328

Developmental acquisition of regulomes underlies innate lymphoid cell functionality

USDA-ARS?s Scientific Manuscript database

Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and ·transcription factors. To better understand ILC subsets and their relationship with Th cells, we measur...

Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150)

PubMed Central

Yusuf, Isharat; Kageyama, Robin; Monticelli, Laurel; Johnston, Robert J.; DiToro, Daniel; Hansen, Kyle; Barnett, Burton; Crotty, Shane

2010-01-01

CD4 T cell help is critical for the generation and maintenance of germinal centers (GCs), and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP [SH2D1A]) expression in CD4 T cells is essential for GC development. However, SAP-deficient mice have only a moderate defect in TFH differentiation, as defined by common TFH surface markers. CXCR5+ TFH cells are found within the GC, as well as along the boundary regions of T/B cell zones. In this study, we show that GC-associated T follicular helper (GC TFH) cells can be identified by their coexpression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. GC TFH cells are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH cell subset and SAP− TFH cells are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that uses SAP signaling, is specifically required for IL-4 production by GC TFH cells. GC TFH cells require IL-4 and -21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by GC CD4 T cells but not in TFH cell and GC TFH cell differentiation. PMID:20525889

T follicular helper and T follicular regulatory cells have different TCR specificity

PubMed Central

Maceiras, Ana Raquel; Almeida, Silvia Cristina Paiva; Mariotti-Ferrandiz, Encarnita; Chaara, Wahiba; Jebbawi, Fadi; Six, Adrien; Hori, Shohei; Klatzmann, David; Faro, Jose; Graca, Luis

2017-01-01

Immunization leads to the formation of germinal centres (GCs) that contain both T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Whether T-cell receptor (TCR) specificity defines the differential functions of Tfh and Tfr cells is unclear. Here we show that antigen-specific T cells after immunization are preferentially recruited to the GC to become Tfh cells, but not Tfr cells. Tfh cells, but not Tfr cells, also proliferate efficiently on restimulation with the same immunizing antigen in vitro. Ex vivo TCR repertoire analysis shows that immunization induces oligoclonal expansion of Tfh cells. By contrast, the Tfr pool has a TCR repertoire that more closely resembles that of regulatory T (Treg) cells. Our data thus indicate that the GC Tfh and Tfr pools are generated from distinct TCR repertoires, with Tfh cells expressing antigen-responsive TCRs to promote antibody responses, and Tfr cells expressing potentially autoreactive TCRs to suppress autoimmunity. PMID:28429709

Shifted T Helper Cell Polarization in a Murine Staphylococcus aureus Mastitis Model.

PubMed

Zhao, Yanqing; Zhou, Ming; Gao, Yang; Liu, Heyuan; Yang, Wenyu; Yue, Jinhua; Chen, Dekun

2015-01-01

Mastitis, one of the most costly diseases in dairy ruminants, is an inflammation of the mammary gland caused by pathogenic infection. The mechanisms of adaptive immunity against pathogens in mastitis have not been fully elucidated. To investigate T helper cell-mediated adaptive immune responses, we established a mastitis model by challenge with an inoculum of 4 × 106 colony-forming units of Staphylococcus aureus in the mammary gland of lactating mice, followed by quantification of bacterial burden and histological analysis. The development of mastitis was accompanied by a significant increase in both Th17 and Th1 cells in the mammary gland. Moreover, the relative expression of genes encoding cytokines and transcription factors involved in the differentiation and function of these T helper cells, including Il17, Rorc, Tgfb, Il1b, Il23, Ifng, Tbx21, and Il12, was greatly elevated in the infected mammary gland. IL-17 is essential for neutrophil recruitment to infected mammary gland via CXC chemokines, whereas the excessive IL-17 production contributes to tissue damage in mastitis. In addition, a shift in T helper cell polarization toward Th2 and Treg cells was observed 5 days post-infection, and the mRNA expression of the anti-inflammatory cytokine Il10 was markedly increased at day 7 post-infection. These results indicate that immune clearance of Staphylococcus aureus in mastitis is facilitated by the enrichment of Th17, Th1 and Th2 cells in the mammary gland mediated by pro-inflammatory cytokine production, which is tightly regulated by Treg cells and the anti-inflammatory cytokine IL-10.

Shifted T Helper Cell Polarization in a Murine Staphylococcus aureus Mastitis Model

PubMed Central

Zhao, Yanqing; Zhou, Ming; Gao, Yang; Liu, Heyuan; Yang, Wenyu; Yue, Jinhua; Chen, Dekun

2015-01-01

Mastitis, one of the most costly diseases in dairy ruminants, is an inflammation of the mammary gland caused by pathogenic infection. The mechanisms of adaptive immunity against pathogens in mastitis have not been fully elucidated. To investigate T helper cell-mediated adaptive immune responses, we established a mastitis model by challenge with an inoculum of 4 × 106 colony-forming units of Staphylococcus aureus in the mammary gland of lactating mice, followed by quantification of bacterial burden and histological analysis. The development of mastitis was accompanied by a significant increase in both Th17 and Th1 cells in the mammary gland. Moreover, the relative expression of genes encoding cytokines and transcription factors involved in the differentiation and function of these T helper cells, including Il17, Rorc, Tgfb, Il1b, Il23, Ifng, Tbx21, and Il12, was greatly elevated in the infected mammary gland. IL-17 is essential for neutrophil recruitment to infected mammary gland via CXC chemokines, whereas the excessive IL-17 production contributes to tissue damage in mastitis. In addition, a shift in T helper cell polarization toward Th2 and Treg cells was observed 5 days post-infection, and the mRNA expression of the anti-inflammatory cytokine Il10 was markedly increased at day 7 post-infection. These results indicate that immune clearance of Staphylococcus aureus in mastitis is facilitated by the enrichment of Th17, Th1 and Th2 cells in the mammary gland mediated by pro-inflammatory cytokine production, which is tightly regulated by Treg cells and the anti-inflammatory cytokine IL-10. PMID:26230498

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.

Defective immunoregulatory T-cell function in chronic lymphocytic leukemia

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

Han, T.; Ozer, H.; Henderson, E.S.

Chronic lymphocytic leukemia (CLL) of B-cell origin results in the malignant proliferation of small immunoglobulin-bearing lymphocytes. There is currently a controversy in the literature regarding both the ability of this leukemic population to differentiate into mature plasma cells, as well as the ability of apparently normal T cells from these patients to regulate allogeneic B-cell differentiation. In the present study we have examined the lymphocytes of CLL patients in various clinical stages of their disease and with different surface phenotypes of their leukemic B-cell population. Our results show that leukemic CLL B cells from all 20 patients (including one patientmore » with a monoclonal IgM paraprotein and another with a monoclonal IgG paraprotein) are incapable of further differentiation even in the absence of suppressor T cells and the presence of helper T lymphocytes. This lack of capacity to differentiate is unaffected by clinical stage, by therapy, or by the phenotype of the malignant population. Since the leukemic B population did not suppress normal allogeneic B-cell differentiation, the maturation deficit is evidently intrinsic to the leukemic clone rather than a result of activity of non-T suppressor cells. T helper function was also variably depressed in the blood of some patients with CLL, and this depression did not correlate with clinical stage, with therapy, or with the degree of lymphocytosis. Dysfunction of radiosensitive T suppressor cells was found to be the most consistent regulatory deficit of CLL T cells. Each of 11 patients whose leukemic cell population was of the ..mu..delta, ..mu cap alpha.., or ..mu.. phenotype had both helper and suppressor cell defects.« less

In vitro Peptide Immunization ofTargetTax Protein HumanT-Cell Leukemia Virus Type 1 – Specific CD4+ Helper T Lymphocytes

PubMed Central

Kobayashi, Hiroya; Ngato, Toshihiro; Sato, Keisuke; Aoki, Naoko; Kimura, Shoji; Tanaka, Yuetsu; Aizawa, Hitoshi; Tateno, Masatoshi; Celis, Esteban

2006-01-01

Purpose Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1Tax is the most dominant antigen for HTLV-1-specific CD8+ CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4+ helper T lymphocytes in HTLV-1Tax protein have been described.The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II – restricted epitopes that could be used for vaccine development. Experimental Design An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4+ T lymphocytes. Results Peptides Tax191–205 and Tax305–319 were effective in inducingT-helper-cell responses. Although Tax191–205 was restricted by the HLA-DR1 and DR9 alleles, responses to Tax305–319 were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1+ T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1Tax+ tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide – based vaccine capable of inducing simultaneous CTL andT-helper responses. Conclusion Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4+ helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1. PMID:16778109

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

B cell helper factors. II. Synergy among three helper factors in the response of T cell- and macrophage-depleted B cells.

PubMed

Liebson, H J; Marrack, P; Kappler, J

1982-10-01

The concanavalin A- (Con A) stimulated supernatant of normal spleen cells (normal Con A SN) was shown to contain a set of helper factors sufficient to allow T cell- and macrophage- (M phi) depleted murine splenic B cells to produce a plaque-forming cell response to the antigen sheep red blood cells (SRBC). The activity of normal Con A SN could be reconstituted by a mixture of three helper factor preparations. The first was the interleukin 2- (IL 2) containing Con A SN of the T cell hybridoma, FS6-14.13. The second was a normal Con A SN depleted of IL 2 by extended culture with T cell blasts from which the 30,000 to 50,000 m.w. factors were isolated (interleukin X, IL X). The third was a SN either from the M phi tumor cell line P388D1 or from normal M phi taken from Corynebacterium parvum-immune mice. The combination of all three helper factor preparations was required to equal the activity of normal Con A SN; however, the M phi SN had the least overall effect. The M phi SN and IL 2 had to be added at the initiation of the culture period for a maximal effect, but the IL X preparation was most effective when added 24 hr after the initiation of culture. These results indicate that at least three nonspecific helper factors contribute to the helper activity in normal Con A SN.

Induction of Mucosal and Systemic Immunity to a Recombinant Simian Immunodeficiency Viral Protein

NASA Astrophysics Data System (ADS)

Lehner, T.; Bergmeier, L. A.; Panagiotidi, C.; Tao, L.; Brookes, R.; Klavinskis, L. S.; Walker, P.; Walker, J.; Ward, R. G.; Hussain, L.; Gearing, A. J. H.; Adams, S. E.

1992-11-01

Heterosexual transmission through the cervico-vaginal mucosa is the principal route of human immunodeficiency virus (HIV) infection in Africa and is increasing in the United States and Europe. Vaginal immunization with simian immunodeficiency virus (SIV) had not yet been studied in nonhuman primates. Immune responses in macaques were investigated by stimulation of the genital and gut-associated lymphoid tissue with a recombinant, particulate SIV antigen. Vaginal, followed by oral, administration of the vaccine elicited three types of immunity: (i) gag protein p27-specific, secretory immunoglobulin A (IgA) and immunoglobulin G (IgG) in the vaginal fluid, (ii) specific CD4^+ T cell proliferation and helper function in B cell p27-specific IgA synthesis in the genital lymph nodes, and (iii) specific serum IgA and IgG, with CD4^+ T cell proliferative and helper functions in the circulating blood.

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

Polyclonal activation of human lymphocytes in vitro-II. Reappraisal of T and B cell-specific mitogens.

PubMed

Dosch, H M; Schuurman, R K; Gelfand, E W

1980-08-01

The capacity of the T cell mitogens phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), and Staphylococcus protein A (SpA) to induce B cell proliferation and differentiation was compared with the B cell mitogen, formalinized Staphylococcus aureus (STA). Lymphocyte subpopulations from normal donors and patients with various immunodeficiency diseases were studied. In the presence of the T cell mitogens, irradiated T cells were capable of providing a helper cell activity that enabled co-cultured B lymphocytes to proliferate in response to these mitogens and to differentiate into IgM-secreting (direct) hemolytic plaque-forming cells (PFC). In the PFC response, radioresistant T-helper and radiosensitive T-suppressor cell activities could be demonstrated. T-suppressor cell activity outweighed helper activity only in nonirradiated co-cultures stimulated with Con A. Patients with severe combined immunodeficiency lacked mitogen-induced helper T cells, whereas patients with various forms of humoral immune deficiency were normal in this respect. These findings and the tissue distribution of the helper activity is aquired early in post-thymic T cell differentiation. The data suggest that experiments with cell lineage-specific lymphocyte mitogens should be considered in the context of more complex cell-cell interactions.

T Helper 17 Cells Interplay with CD4+CD25highFoxp3+ Tregs in Regulation of Inflammations and Autoimmune Diseases

PubMed Central

Mai, Jietang; Wang, Hong; Yang#, Xiao-Feng

2010-01-01

Interleukin-17 (IL-17)-secreting T helper 17 cells (Th17) are a recently identified CD4+ T helper subset that has been implicated in various inflammatory and autoimmune diseases. Th17, along with CD4+CD25high Foxp3+ regulatory T cells (Tregs) and other newly emergent T helper subsets, Th9 and Tfh, have expanded the Th1-Th2 paradigm. Although this newly proposed six-subset paradigm significantly improved our understanding on the differentiation of CD4+ T helper cell subsets and the regulation of T helper cells in inflammation and autoimmunity, many questions remain to be answered. In this overview, we will briefly review the following issues: a) Old Th1-Th2 paradigm versus new multi-subset paradigm; b) Structural features of IL-17 family cytokines; c) Th17 cells; d) Effects of IL-17 on various cell types and tissues; e) IL-17 receptor and signaling pathways; f) Th17-mediated inflammations; and g) Protective mechanisms of IL-17 in infections. Lastly, we will look into the interaction of Th17 and Treg in autoimmune diseases and inflammation: Th17 cells interplay with Tregs. Regulation of autoimmunity and inflammation lies in the interplays of the different T helper subsets, therefore, better understanding of these subsets’ interactions with one another would greatly improve our approaches in developing therapy to combat inflammatory and autoimmune diseases. PMID:20515737

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.

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.

Regulation of type 17 helper T-cell function by nitric oxide during inflammation

PubMed Central

Niedbala, Wanda; Alves-Filho, Jose C.; Fukada, Sandra Y.; Vieira, Silvio Manfredo; Mitani, Akio; Sonego, Fabiane; Mirchandani, Ananda; Nascimento, Daniele C.; Cunha, Fernando Q.; Liew, Foo Y.

2011-01-01

Type 17 helper T (Th17) cells are implicated in the pathogenesis many of human autoimmune diseases. Development of Th17 can be enhanced by the activation of aryl hydrocarbon receptor (AHR) whose ligands include the environmental pollutant dioxin, potentially linking environmental factors to the increased prevalence of autoimmune disease. We report here that nitric oxide (NO) can suppress the proliferation and function of polarized murine and human Th17 cells. NO also inhibits AHR expression in Th17 cells and the downstream events of AHR activation, including IL-22, IL-23 receptor, and Cyp1a1. Conversely, NO did not affect the polarization of Th17 cells from mice deficient in AHR. Furthermore, mice lacking inducible nitric oxide synthase (Nos2−/−) developed more severe experimental autoimmune encephalomyelitis than WT mice, with elevated AHR expression, increased IL-17A, and IL-22 synthesis. NO may therefore represent an important endogenous regulator to prevent overexpansion of Th17 cells and control of autoimmune diseases caused by environmental pollutants. PMID:21576463

Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity.

PubMed

Zander, Ryan A; Vijay, Rahul; Pack, Angela D; Guthmiller, Jenna J; Graham, Amy C; Lindner, Scott E; Vaughan, Ashley M; Kappe, Stefan H I; Butler, Noah S

2017-11-14

Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Metabolic pathways in T cell activation and lineage differentiation.

PubMed

Almeida, Luís; Lochner, Matthias; Berod, Luciana; Sparwasser, Tim

2016-10-01

Recent advances in the field of immunometabolism support the concept that fundamental processes in T cell biology, such as TCR-mediated activation and T helper lineage differentiation, are closely linked to changes in the cellular metabolic programs. Although the major task of the intermediate metabolism is to provide the cell with a constant supply of energy and molecular precursors for the production of biomolecules, the dynamic regulation of metabolic pathways also plays an active role in shaping T cell responses. Key metabolic processes such as glycolysis, fatty acid and mitochondrial metabolism are now recognized as crucial players in T cell activation and differentiation, and their modulation can differentially affect the development of T helper cell lineages. In this review, we describe the diverse metabolic processes that T cells engage during their life cycle from naïve towards effector and memory T cells. We consider in particular how the cellular metabolism may actively support the function of T cells in their different states. Moreover, we discuss how molecular regulators such as mTOR or AMPK link environmental changes to adaptations in the cellular metabolism and elucidate the consequences on T cell differentiation and function. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Experiment K-7-23: Effect of Spaceflight on Level and Function of Immune Cells. Part 1; Immunology Studies

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Mandel, A.; Konstantinova, I. V.; Berry, W. D.; Taylor, G. R.; Lesnyak, A. T.; Fuchs, B. B.; Rakhmilevich, A. L.

1994-01-01

Two different experiments were carried out in this segment of the immunology protocol for samples received from rats flown on Cosmos 2044. Control groups included vivarium, synchronous and antiorthostatically suspended rats. In the first experiment, rat bone marrow cells were examined in Moscow for their response to recombinant murine colony stimulating factor-granulocyte / monocyte (CSF-GM). In the second experiment, rat spleen and bone marrow cells were stained in Moscow with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and shipped to the United States for analysis on a flow cytometer. The results of the studies indicated that bone marrow cells from flown and suspended rats showed a decreased response to CSF-GM as compared to bone marrow cells from control rats. Spleen cells from flown rats showed increased percentages of suppressor-cytotoxic-T and helper-T cells amongst the entire cell population. Bone marrow cells showed an increase in the percentage of helper-T cells in the myelogenous population and increased percentages of anti-asialo GM-1 bearing, interleukin-2 receptor bearing, pan-T and helper-T cells in the lymphocytic population. Cell populations from rats suspended antiorthostatically did not follow the same pattern of distribution of leukocytes as cell populations for flown rats. These results are similar, but not identical to, earlier results from Cosmos 1887, and confirm that space flight can have profound effects on immune system components and activities.

Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets.

PubMed

Gross, Catharina C; Schulte-Mecklenbeck, Andreas; Hanning, Uta; Posevitz-Fejfár, Anita; Korsukewitz, Catharina; Schwab, Nicholas; Meuth, Sven G; Wiendl, Heinz; Klotz, Luisa

2017-06-01

Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS). To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts. Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation. Patients with exclusively cerebral or preferential spinal lesion manifestation were associated with increased proportions of circulating granulocyte-macrophage colony-stimulating factor (GM-CSF) producing T H 1 cells or interleukin (IL)-17-producing T H 17 cells, respectively. In contrast, proportions of peripheral IL-17/IL-22-producing lymphoid tissue inducer (LTi), the innate counterpart of T H 17 cells, were enhanced in RRMS patients with exclusively cerebral lesion topography. Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS.

Adeno-associated virus vectors can be efficiently produced without helper virus.

PubMed

Matsushita, T; Elliger, S; Elliger, C; Podsakoff, G; Villarreal, L; Kurtzman, G J; Iwaki, Y; Colosi, P

1998-07-01

The purpose of this work was to develop an efficient method for the production of adeno-associated virus (AAV) vectors in the absence of helper virus. The adenovirus regions that mediate AAV vector replication were identified and assembled into a helper plasmid. These included the VA, E2A and E4 regions. When this helper plasmid was cotransfected into 293 cells, along with plasmids encoding the AAV vector, and rep and cap genes, AAV vector was produced as efficiently as when using adenovirus infection as a source of help. CMV-driven constructs expressing the E4orf6 and the 72-M(r), E2A proteins were able to functionally replace the E4 and E2A regions, respectively. Therefore the minimum set of genes required to produce AAV helper activity equivalent to that provided by adenovirus infection consists of, or is a subset of, the following genes: the E4orf6 gene, the 72-M(r), E2A protein gene, the VA RNA genes and the E1 region. AAV vector preparations made with adenovirus and by the helper virus-free method were essentially indistinguishable with respect to particle density, particle to infectivity ratio, capsimer ratio and efficiency of muscle transduction in vivo. Only AAV vector preparations made by the helper virus-free method were not reactive with anti-adenovirus sera.

Effects of alcohols and ciclopirox alamine, an anti-fungal agent, on the peripheral blood lymphocyte functions in vitro

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

Prabhala, R.H.; Maxey, V.; Hicks, M.J.

1986-03-01

Effects of ethanol (1%), propanol (1%) and ciclopirox alamine, an anti-fungal agent, (4 ..mu..g/well), on the peripheral blood lymphocyte functions, including response to T- (Concanavalin A, ConA) and B-cell (Lipopolysaccharide, LPS) mitogens, and presence of functional T-lymphocyte subsets were determined in vitro. Purified human lymphocytes were incubated at 37/sup 0/C for 48 hours with or without test compounds in presence or absence of ConA and LPS. All three compounds suppress the response to T- or B-cell mitogens. The percentage of T-lymphocytes with T-helper characteristics in the presence of ethanol and ciclopirox alamine was increased. All three compounds suppressed the percentagemore » of T-lymphocytes with E-resetting characteristics. Alcohols enhanced the number of natural killer cells, whereas, ciclopirox alamine exhibited the reverse action. Although the alcohols and the anti-fungal agent enhanced the T-helper subpopulation, their response to mitogens was suppressed. This may be due to the suppression of T-cell activating lymphokines. Alcohol metabolite such as acetaldehyde also suppress the number of T-cells and their functions at 0.01% so may also be part of the explanation for immunoalteration.« less

New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function.

PubMed

Fu, Shin-Huei; Yeh, Li-Tzu; Chu, Chin-Chen; Yen, B Lin-Ju; Sytwu, Huey-Kang

2017-07-21

B lymphocyte-induced maturation protein-1 (Blimp-1) serves as a master regulator of the development and function of antibody-producing B cells. Given that its function in T lymphocytes has been identified within the past decade, we review recent findings with emphasis on its role in coordinated control of gene expression during the development, differentiation, and function of T cells. Expression of Blimp-1 is mainly confined to activated T cells and is essential for the production of interleukin (IL)-10 by a subset of forkhead box (Fox)p3 + regulatory T cells with an effector phenotype. Blimp-1 is also required to induce cell elimination in the thymus and critically modulates peripheral T cell activation and proliferation. In addition, Blimp-1 promotes T helper (Th) 2 lineage commitment and limits Th1, Th17 and follicular helper T cell differentiation. Furthermore, Blimp-1 coordinates with other transcription factors to regulate expression of IL-2, IL-21 and IL-10 in effector T lymphocytes. In CD8 + T cells, Blimp-1 expression is distinct in heterogeneous populations at the stages of clonal expansion, differentiation, contraction and memory formation when they encounter antigens. Moreover, Blimp-1 plays a fundamental role in coordinating cytokine receptor signaling networks and transcriptional programs to regulate diverse aspects of the formation and function of effector and memory CD8 + T cells and their exhaustion. Blimp-1 also functions as a gatekeeper of T cell activation and suppression to prevent or dampen autoimmune disease, antiviral responses and antitumor immunity. In this review, we discuss the emerging roles of Blimp-1 in the complex regulation of gene networks that regulate the destiny and effector function of T cells and provide a Blimp-1-dominated transcriptional framework for T lymphocyte homeostasis.

Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation

PubMed Central

Gerami-Nejad, Maryam; Kumamoto, Yosuke; Mohammed, Javed A.; Jarrett, Elizabeth; Drummond, Rebecca A.; Zurawski, Sandra M.; Zurawski, Gerard; Berman, Judith; Iwasaki, Akiko; Brown, Gordon D.; Kaplan, Daniel H.

2015-01-01

Summary Candida albicans is a dimorphic fungus responsible for chronic mucocutaneous and systemic infections. Mucocutaneous immunity to C. albicans requires T helper-17 (Th17) cell differentiation that is thought to depend on recognition of filamentous C. albicans. Systemic immunity is considered T cell independent. Using a murine skin infection model, we compared T helper cell responses to yeast and filamentous C. albicans, We found that only yeast induced Th17 cell responses through a mechanism that required Dectin-1 mediated expression of interleukin-6 (IL-6) by Langerhans cells. Filamentous forms induced Th1 without Th17 cell responses due to the absence of Dectin-1 ligation. Notably, Th17 cell responses provided protection against cutaneous infection while Th1 cell responses provided protection against systemic infection. Thus, C. albicans morphology drives distinct T helper cell responses that provide tissue specific protection. These findings provide insight into compartmentalization of Th responses, C. albicans pathogenesis and have critical implications for vaccine strategies. PMID:25680275

Impact of Chronic Viral Infection on T-Cell Dependent Humoral Immune Response.

PubMed

Rodriguez, Stéphane; Roussel, Mikaël; Tarte, Karin; Amé-Thomas, Patricia

2017-01-01

During the last decades, considerable efforts have been done to decipher mechanisms supported by microorganisms or viruses involved in the development, differentiation, and function of immune cells. Pathogens and their associated secretome as well as the continuous inflammation observed in chronic infection are shaping both innate and adaptive immunity. Secondary lymphoid organs are functional structures ensuring the mounting of adaptive immune response against microorganisms and viruses. Inside these organs, germinal centers (GCs) are the specialized sites where mature B-cell differentiation occurs leading to the release of high-affinity immunoglobulin (Ig)-secreting cells. Different steps are critical to complete B-cell differentiation process, including proliferation, somatic hypermutations in Ig variable genes, affinity-based selection, and class switch recombination. All these steps require intense interactions with cognate CD4 + helper T cells belonging to follicular helper lineage. Interestingly, pathogens can disturb this subtle machinery affecting the classical adaptive immune response. In this review, we describe how viruses could act directly on GC B cells, either through B-cell infection or by their contribution to B-cell cancer development and maintenance. In addition, we depict the indirect impact of viruses on B-cell response through infection of GC T cells and stromal cells, leading to immune response modulation.

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.

Beyond Helper Phage: Using "Helper Cells" to Select Peptide Affinity Ligands.

PubMed

Phipps, M Lisa; Lillo, Antoinetta M; Shou, Yulin; Schmidt, Emily N; Paavola, Chad D; Naranjo, Leslie; Bemdich, Sara; Swanson, Basil I; Bradbury, Andrew R M; Martinez, Jennifer S

2016-01-01

Peptides are important affinity ligands for microscopy, biosensing, and targeted delivery. However, because they can have low affinity for their targets, their selection from large naïve libraries can be challenging. When selecting peptidic ligands from display libraries, it is important to: 1) ensure efficient display; 2) maximize the ability to select high affinity ligands; and 3) minimize the effect of the display context on binding. The "helper cell" packaging system has been described as a tool to produce filamentous phage particles based on phagemid constructs with varying display levels, while remaining free of helper phage contamination. Here we report on the first use of this system for peptide display, including the systematic characterization and optimization of helper cells, their inefficient use in antibody display and their use in creating and selecting from a set of phage display peptide libraries. Our libraries were analyzed with unprecedented precision by standard or deep sequencing, and shown to be superior in quality than commercial gold standards. Using our helper cell libraries, we have obtained ligands recognizing Yersinia pestis surface antigen F1V and L-glutamine-binding periplasmic protein QBP. In the latter case, unlike any of the peptide library selections described so far, we used a combination of phage and yeast display to select intriguing peptide ligands. Based on the success of our selections we believe that peptide libraries obtained with helper cells are not only suitable, but preferable to traditional phage display libraries for selection of peptidic ligands.

[Effect of chronic sensorineural hearing loss on several indicators of immune and endocrine systems of 7-11 year-old children].

PubMed

Beschasnyĭ, S P

2013-01-01

We investigated the effects of chronic bilateral sensorineural hearing loss of III-IV degree on the performance of interleukins, immunoglobulins serum and saliva, the functional activity of granulocyte-monocyte cell immunity, evaluated the activity of the hypothalamic-pituitary-adrenal system in children aged 7-11 years. It was found that due to stress activation of the sympathetic-adrenal system the function of granulocytes and monocytes is suppressed, with a predominance of production of anti-inflammatory interleukins. This leads to the dominance of T-helper type 2. Products granulocytes and T-helper type-2 anti-inflammatory interleukins IL-4, IL-5, IL-10, IL-13 leads to the activation of B-cells. Thus, in children 7-11 years of age with congenital bilateral sensorineural hearing loss is a decrease of non-specific humoral immunity dominated type of immune response to increased levels of IgG.

The Transcription Factor STAT3 and Type I Interferons Are Mutually Repressive Insulators for Differentiation of Follicular Helper and T Helper_1 Cells

PubMed Central

Ray, John P.; Marshall, Heather D.; Laidlaw, Brian J.; Staron, Matthew M.; Kaech, Susan M.; Craft, Joe

2014-01-01

Summary Follicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4+ T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of interferoninducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper-1 (Th1) cell-like effector phenotype. Conversely, IFNαβ receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4+ T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection. PMID:24631156

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

Bradbury, Andrew M.

The invention relates to a novel phagemid display system for packaging phagemid DNA into phagemid particles which completely avoids the use of helper phage. The system of the invention incorporates the use of bacterial packaging cell lines which have been transformed with helper plasmids containing all required phage proteins but not the packaging signals. The absence of packaging signals in these helper plasmids prevents their DNA from being packaged in the bacterial cell, which provides a number of significant advantages over the use of both standard and modified helper phage. Packaged phagemids expressing a protein or peptide of interest, inmore » fusion with a phage coat protein such as g3p, are generated simply by transfecting phagemid into the packaging cell line.« less

Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer.

PubMed

Song, Yang; Yang, Jian Ming

2017-11-04

Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, is reported to be significantly generated by a distinct subset of CD4 + T-cells, upgrading cancer-elicited inflammation and preventing cancer cells from immune surveillance. T-helper (Th)17 cells produced from naive CD4 + T cells have recently been renowned and generally accepted, gaining eminence in cancer studies and playing the effective role in context of cancer. Th17 cells are the main source of IL-17-secreting cells, It was found that other cell types produced this cytokine as well, including Group 3 innate lymphoid cells (ILC3), δγT cells, invariant natural killer T (iNKT) cells, lymphoid-tissue inducer (LTi)-like cells and Natural killer (NK) cells. Th17-associated cytokines give impetus to tumor progression, or inducing angiogenesis and metastasis. This review demonstrates an understanding on how the pro- or antitumor function of Th17 cells and IL-17 may change cancer progression, leading to the appearance of complex and pivotal biologic activities in tumor. Copyright © 2017 Elsevier Inc. All rights reserved.

HIV skews the lineage-defining transcriptional profile of Mycobacterium tuberculosis-specific CD4+ T cells

PubMed Central

Riou, Catherine; Strickland, Natalie; Soares, Andreia P.; Corleis, Bjorn; Kwon, Douglas; Wherry, E. John; Wilkinson, Robert J.; Burgers, Wendy A.

2016-01-01

HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4+T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis likely relies on the development of a balanced CD4 response, where distinct CD4+T helper subsets act in synergy to control the infection. To define the diversity of Mtb-specific CD4+Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt and Foxp3 was measured in Mtb-specific CD4+T cells in HIV-uninfected (n=20) and HIV-infected individuals (n=20) with latent TB infection. Our results show that upon 5 day restimulation in vitro, Mtb-specific CD4+T cells from healthy individuals have the ability to exhibit a broad spectrum of T helper subsets, defined by specific patterns of transcription factor co-expression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bethighFoxp3+ Mtb-specific CD4+T cells was significantly decreased (p=0.002) compared to HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p=0.0007) and plasma TNF-α (p=0.027). Our data demonstrate an important balance in T helper subset diversity defined by lineage-defining transcription factor co-expression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of Mtb-specific CD4+T helper subsets. PMID:26927799

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection

PubMed Central

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh–B cell interactions. PMID:29109730

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection.

PubMed

Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

2017-01-01

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions.

The lupus susceptibility gene Pbx1 regulates the balance between follicular helper T cell and regulatory T cell differentiation

PubMed Central

Choi, Seung-Chul; Hutchinson, Tarun E.; Titov, Anton A.; Seay, Howard R.; Li, Shiwu; Brusko, Todd M.; Croker, Byron P.; Salek-Ardakani, Shahram; Morel, Laurence

2016-01-01

Pbx1 controls chromatin accessibility to a large number of genes and is entirely conserved between mice and humans. The Pbx1-d dominant negative isoform is more frequent in the CD4+ T cells from lupus patients than from healthy controls. Pbx1-d is associated with the production of autoreactive T cells in mice carrying the Sle1a1 lupus susceptibility locus. Transgenic expression of Pbx1-d in CD4+ T cells reproduced the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4+ T cells and impaired regulatory T cell homeostasis. Pbx1-d Tg also expanded the number of follicular helper T cells in a cell-intrinsic and antigen-specific manner that was enhanced in recall responses, and resulted in TH1-biased antibodies. Moreover, Pbx1-d Tg CD4+ T cells upregulated the expression of miR-10a, miR-21 and miR-155, which have been implicated in Treg and TFH cell homeostasis. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation and promoting TFH cells at the expense of Treg cells. In addition, our results identify Pbx1 as a novel regulator of CD4+ T cell effector function. PMID:27296664

Helper T Cell Identity and Evolution of Differential Transcriptomes and Epigenomes

PubMed Central

Vahedi, Golnaz; Poholek, Amanda; Hand, Timothy W.; Laurence, Arian; Kann, Yuka; O’Shea, John J.; Hirahara, Kiyoshi

2013-01-01

Summary CD4+ T cells are critical for the elimination of an immense array of microbial pathogens. Among the ways they accomplish this task is to generate progeny with specialized, characteristic patterns of gene expression. From this perspective, helper cells can be viewed as pluripotent precursors that adopt distinct cell fates. Although there are aspects of helper cell differentiation that can be modeled as a classic cell fate commitment, CD4+ T cells also maintain considerable flexibility in their transcriptional program. This makes sense in terms of host defense but raises the question of how these remarkable cells balance both these requirements, a high degree of specific gene expression and the capacity for plasticity. In this review, we discuss recent advances in our understanding of CD4+ T-cell specification, focusing on how genomic perspectives have influenced our views of these processes. The relative contributions of sensors of the cytokine milieu, especially the signal transducer and activator of transcription (STAT) family transcription factors, ‘master regulators’, and other transcription factors are considered as they relate to the helper cell transcriptome and epigenome. PMID:23405893

Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells

PubMed Central

Xu, Huanbin; Wang, Xiaolei; Malam, Naomi; Aye, Pyone P.; Alvarez, Xavier; Lackner, Andrew A.

2015-01-01

ABSTRACT CD4+ follicular T helper (Tfh) cells play a prominent role in humoral immune responses, but the mechanisms of their accumulation and infection in AIDS remain unclear. Here we found that germinal center (GC) Tfh cells, defined here as CXCR5+ PD-1HIGH CD4+ T cells, do not express the HIV coreceptor CCR5 yet serve as a latent reservoir in GCs. With disease progression, an expansion of GC Tfh cells is accompanied by increases in dysfunctional CD8+ T cells. In contrast, Tfh precursor (CXCR5− CD4+ T) cells in lymph nodes do express CCR5 and differentiate into GC Tfh cells following interleukin-6 (IL-6) and IL-21 stimulation, and viral DNA is detectable in fully differentiated GC Tfh cells ex vivo. This suggests that SIV-infected GC Tfh cells may be derived from Tfh precursor cell subsets that become infected in marginal zones and then migrate into GCs as fully mature GC Tfh cells that serve as persistent virus reservoirs. These findings suggest that viral persistence in lymph nodes drives compensatory differentiation, aberrant accumulation, and latent infection of GC Tfh cells, resulting in marked impairment of humoral immune responses. IMPORTANCE Generation of antibodies that can effectively eliminate viruses requires interactions of B cells with highly specialized T cells in GCs of lymphoid tissues called follicular T helper cells. Here we show that in simian immunodeficiency virus infection, these cells are initially infected in a precursor stage that leads to alterations in their homing, accumulation, and function that may be responsible for the inability of human immunodeficiency virus-infected patients to generate effective antibody responses. PMID:26608323

Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells.

PubMed

Xu, Huanbin; Wang, Xiaolei; Malam, Naomi; Aye, Pyone P; Alvarez, Xavier; Lackner, Andrew A; Veazey, Ronald S

2016-02-01

CD4(+) follicular T helper (Tfh) cells play a prominent role in humoral immune responses, but the mechanisms of their accumulation and infection in AIDS remain unclear. Here we found that germinal center (GC) Tfh cells, defined here as CXCR5(+) PD-1(HIGH) CD4(+) T cells, do not express the HIV coreceptor CCR5 yet serve as a latent reservoir in GCs. With disease progression, an expansion of GC Tfh cells is accompanied by increases in dysfunctional CD8(+) T cells. In contrast, Tfh precursor (CXCR5(-) CD4(+) T) cells in lymph nodes do express CCR5 and differentiate into GC Tfh cells following interleukin-6 (IL-6) and IL-21 stimulation, and viral DNA is detectable in fully differentiated GC Tfh cells ex vivo. This suggests that SIV-infected GC Tfh cells may be derived from Tfh precursor cell subsets that become infected in marginal zones and then migrate into GCs as fully mature GC Tfh cells that serve as persistent virus reservoirs. These findings suggest that viral persistence in lymph nodes drives compensatory differentiation, aberrant accumulation, and latent infection of GC Tfh cells, resulting in marked impairment of humoral immune responses. Generation of antibodies that can effectively eliminate viruses requires interactions of B cells with highly specialized T cells in GCs of lymphoid tissues called follicular T helper cells. Here we show that in simian immunodeficiency virus infection, these cells are initially infected in a precursor stage that leads to alterations in their homing, accumulation, and function that may be responsible for the inability of human immunodeficiency virus-infected patients to generate effective antibody responses. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

In vivo regulation of Bcl6 and T follicular helper cell development1

PubMed Central

Poholek, Amanda C.; Hansen, Kyle; Hernandez, Sairy G.; Eto, Danelle; Chandele, Anmol; Weinstein, Jason S.; Dong, Xuemei; Odegard, Jared M.; Kaech, Susan M.; Dent, Alexander L.; Crotty, Shane; Craft, Joe

2010-01-01

Follicular helper T (TFH) cells, defined by expression of the surface markers CXCR5 and PD-1 and synthesis of IL-21, require upregulation of the transcriptional repressor Bcl6 for their development and function in B cell maturation in germinal centers. We have explored the role of B cells, and the cytokines IL-6 and IL-21, in the in vivo regulation of Bcl6 expression and TFH cell development. We found that TFH cells are characterized by a Bcl6-dependent downregulation of P-selectin glycoprotein ligand-1 (PSGL1, a CCL19- and CCL21-binding protein), indicating that, like CXCR5 and PD-1 upregulation, modulation of PSGL1 expression is part of the TFH cell program of differentiation. B cells were neither required for initial upregulation of Bcl6 nor PSGL1 downregulation, suggesting these events preceded T-B cell interactions, although they were required for full development of the TFH cell phenotype, including CXCR5 and PD-1 upregulation, and IL-21 synthesis. Bcl6 upregulation and TFH cell differentiation were independent of IL-6 and IL-21, revealing that either cytokine is not absolutely required for development of Bcl6+ TFH cells in vivo. These data increase our understanding of Bcl6 regulation in TFH cells and their differentiation in vivo, and identifies a new surface marker that may be functionally relevant in this subset. PMID:20519643

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.

PubMed

Racke, M K; Bonomo, A; Scott, D E; Cannella, B; Levine, A; Raine, C S; Shevach, E M; Röcken, M

1994-11-01

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy.

PubMed

Kyte, Jon Amund; Gaudernack, Gustav; Faane, Anne; Lislerud, Kari; Inderberg, Else Marit; Brunsvig, Paal; Aamdal, Steinar; Kvalheim, Gunnar; Wälchli, Sébastien; Pule, Martin

2016-01-01

We herein report retargeting of T-helper (Th) cells against the universal cancer antigen telomerase for use in adoptive cell therapy. The redirected Th cells may counter tumor tolerance, transform the inflammatory milieu, and induce epitope spreading and cancer senescence. We have previously conducted a series of trials evaluating vaccination with telomerase peptides. From long-term survivors, we isolated >100 CD4 + Th-cell clones recognizing telomerase epitopes. The clones were characterized with regard to HLA restriction, functional avidity, fine specificity, proliferative capacity, cytokine profile, and recognition of naturally processed epitopes. DP4 is the most prevalent HLA molecule worldwide. Two DP4-restricted T-cell clones with different functional avidity, C13 and D71, were selected for molecular T-cell receptor (TCR) cloning. Both clones showed a high proliferative capacity, recognition of naturally processed telomerase epitopes, and a polyfunctional and Th1-weighted cytokine profile. TCR C13 and D71 were cloned into the retroviral vector MP71 together with the compact and GMP-applicable marker/suicide gene RQR8. Both TCRs were expressed well in recipient T cells after PBMC transduction. The transduced T cells co-expressed RQR8 and acquired the desired telomerase specificity, with a polyfunctional response including production of TNFa, IFNγ, and CD107a. Interestingly, the DP4-restricted TCRs were expressed and functional both in CD4 + and CD8 + T cells. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired hTERT-specificity and functionality. We hypothesize that adoptive therapy with Th cells may offer a powerful novel approach for overcoming tumor tolerance and synergize with other forms of immunotherapy.

ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings.

PubMed

Weiss, Jonathan M; Chen, Wei; Nyuydzefe, Melanie S; Trzeciak, Alissa; Flynn, Ryan; Tonra, James R; Marusic, Suzana; Blazar, Bruce R; Waksal, Samuel D; Zanin-Zhorov, Alexandra

2016-07-19

Rho-associated kinase 2 (ROCK2) determines the balance between human T helper 17 (TH17) cells and regulatory T (Treg) cells. We investigated its role in the generation of T follicular helper (TFH) cells, which help to generate antibody-producing B cells under normal and autoimmune conditions. Inhibiting ROCK2 in normal human T cells or peripheral blood mononuclear cells from patients with active systemic lupus erythematosus (SLE) decreased the number and function of TFH cells induced by activation ex vivo. Moreover, inhibition of ROCK2 activity decreased the abundance of the transcriptional regulator Bcl6 (B cell lymphoma 6) and increased that of Blimp1 by reducing the binding of signal transducer and activator of transcription 3 (STAT3) and increasing that of STAT5 to the promoters of the genes Bcl6 and PRDM1, respectively. In the MRL/lpr murine model of SLE, oral administration of the selective ROCK2 inhibitor KD025 resulted in a twofold reduction in the numbers of TFH cells and antibody-producing plasma cells in the spleen, as well as a decrease in the size of splenic germinal centers, which are the sites of interaction between TFH cells and B cells. KD025-treated mice showed a substantial improvement in both histological and clinical scores compared to those of untreated mice and had reduced amounts of Bcl6 and phosphorylated STAT3, as well as increased STAT5 phosphorylation. Together, these data suggest that ROCK2 signaling plays a critical role in controlling the development of TFH cells induced by autoimmune conditions through reciprocal regulation of STAT3 and STAT5 activation. Copyright © 2016, American Association for the Advancement of Science.

Differential induction of CD94 and NKG2 in CD4 helper T cells. A consequence of influenza virus infection and interferon-γ?

PubMed Central

Graham, Christine M; Christensen, Jillian R; Thomas, D Brian

2007-01-01

Influenza A virus causes worldwide epidemics and pandemics and the investigation of memory T helper (Th) cells that help maintain serological memory following infection is important for vaccine design. In this study we investigated CD94 and NKG2 gene expression in memory CD4 T-cell clones established from the spleens of C57BL/10 (H-2b) and BALB/c (H-2d) mice infected with influenza A virus (H3N2). CD94 and NKG2A/C/E proteins form heterodimeric membrane receptors that are involved in virus recognition. CD94 and NKG2 expression have been well characterized in natural killer (NK) and cytotoxic T cells. Despite CD94 being potentially an important marker for Th1 cells involved in virus infection, however, there has been little investigation of its expression or function in the CD4 T-cell lineage and no studies have looked at in-vivo-generated Th cells or memory cells. We show in this study that in-vivo-generated CD4 Th1 cells, but not Th2 cells, exhibited full-length CD94 and NKG2A gene expression following activation with viral peptide. For NKG2A, a novel ‘short’ (possibly redundant) truncated isoform was detectable in a Th2 cell clone. Another member of the NK receptor family, NKG2D, but not NKG2C or E, was also differentially expressed in Th1 cells. We show here that CD94 and NKG2A may exist as multiple isoforms with the potential to distinguish helper T-cell subsets. PMID:17462078

Loss of Proliferation and Antigen Presentation Activity following Internalization of Polydispersed Carbon Nanotubes by Primary Lung Epithelial Cells

PubMed Central

Kumari, Mandavi; Sachar, Sumedha; Saxena, Rajiv K.

2012-01-01

Interactions between poly-dispersed acid functionalized single walled carbon nanotubes (AF-SWCNTs) and primary lung epithelial (PLE) cells were studied. Peritoneal macrophages (PMs, known phagocytic cells) were used as positive controls in this study. Recovery of live cells from cultures of PLE cells and PMs was significantly reduced in the presence of AF-SWCNTs, in a time and dose dependent manner. Both PLE cells as well as PMs could take up fluorescence tagged AF-SWCNTs in a time dependent manner and this uptake was significantly blocked by cytochalasin D, an agent that blocks the activity of acto-myosin fibers and therefore the phagocytic activity of cells. Confocal microscopic studies confirmed that AF-SWCNTs were internalized by both PLE cells and PMs. Intra-trachially instilled AF-SWCNTs could also be taken up by lung epithelial cells as well as alveolar macrophages. Freshly isolated PLE cells had significant cell division activity and cell cycling studies indicated that treatment with AF-SWCNTs resulted in a marked reduction in S-phase of the cell cycle. In a previously standardized system to study BCG antigen presentation by PLE cells and PMs to sensitized T helper cells, AF-SWCNTs could significantly lower the antigen presentation ability of both cell types. These results show that mouse primary lung epithelial cells can efficiently internalize AF-SWCNTs and the uptake of nanotubes interfered with biological functions of PLE cells including their ability to present BCG antigens to sensitized T helper cells. PMID:22384094

Beyond helper phage: Using "helper cells" to select peptide affinity ligands

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

Phipps, Mary Lisa; Lillo, Antoinetta M.; Shou, Yulin

Peptides are important affinity ligands for microscopy, biosensing, and targeted delivery. However, because they can have low affinity for their targets, their selection from large naïve libraries can be challenging. When selecting peptidic ligands from display libraries, it is important to: 1) ensure efficient display; 2) maximize the ability to select high affinity ligands; and 3) minimize the effect of the display context on binding. The “helper cell” packaging system has been described as a tool to produce filamentous phage particles based on phagemid constructs with varying display levels, while remaining free of helper phage contamination. Here we report onmore » the first use of this system for peptide display, including the systematic characterization and optimization of helper cells, their inefficient use in antibody display and their use in creating and selecting from a set of phage display peptide libraries. Our libraries were analyzed with unprecedented precision by standard or deep sequencing, and shown to be superior in quality than commercial gold standards. Using our helper cell libraries, we have obtained ligands recognizing Yersinia pestis surface antigen F1V and L-glutamine-binding periplasmic protein QBP. In the latter case, unlike any of the peptide library selections described so far, we used a combination of phage and yeast display to select intriguing peptide ligands. Here, based on the success of our selections we believe that peptide libraries obtained with helper cells are not only suitable, but preferable to traditional phage display libraries for selection of peptidic ligands.« less

Beyond helper phage: Using "helper cells" to select peptide affinity ligands

DOE PAGES

Phipps, Mary Lisa; Lillo, Antoinetta M.; Shou, Yulin; ...

2016-09-14

Peptides are important affinity ligands for microscopy, biosensing, and targeted delivery. However, because they can have low affinity for their targets, their selection from large naïve libraries can be challenging. When selecting peptidic ligands from display libraries, it is important to: 1) ensure efficient display; 2) maximize the ability to select high affinity ligands; and 3) minimize the effect of the display context on binding. The “helper cell” packaging system has been described as a tool to produce filamentous phage particles based on phagemid constructs with varying display levels, while remaining free of helper phage contamination. Here we report onmore » the first use of this system for peptide display, including the systematic characterization and optimization of helper cells, their inefficient use in antibody display and their use in creating and selecting from a set of phage display peptide libraries. Our libraries were analyzed with unprecedented precision by standard or deep sequencing, and shown to be superior in quality than commercial gold standards. Using our helper cell libraries, we have obtained ligands recognizing Yersinia pestis surface antigen F1V and L-glutamine-binding periplasmic protein QBP. In the latter case, unlike any of the peptide library selections described so far, we used a combination of phage and yeast display to select intriguing peptide ligands. Here, based on the success of our selections we believe that peptide libraries obtained with helper cells are not only suitable, but preferable to traditional phage display libraries for selection of peptidic ligands.« less

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...

Separation of concanavalin A-induced human suppressor and helper T cells by the autologous erythrocyte rosette technique.

PubMed

Sakane, T; Honda, M; Taniguchi, Y; Kotani, H

1981-08-01

Very few normal human peripheral blood T cells are capable of binding autologous erythrocytes to form rosettes, whereas in the T cell population activated by concanavalin A (Con A) the autorosette levels are markedly enhanced. Fractionation of the Con A-activated T cells with autologous erythrocytes into autorosetting and nonrosetting cells demonstrates that suppressor, but not helper, activity resides in the autorosetting population, whereas the reverse is true of the nonrosetting population. Both these activities are found to be Con A dependent. The Con A-induced human suppressor cells can be identified and separated from the Con A-induced human helper cells by the autorosette technique. Studies on the surface properties of autorosetting and nonrosetting T cells indicate that there is little correlation between the activated suppressor and helper T cell subsets defined by autorosette technique and either those defined by monoclonal antibodies (which are able to distinguish these subsets in the resting but not activated T cells) or those defined by Fc receptors. Since the autorosetting T cell population (which acts as suppressor cells) bears receptors for peanut agglutinin, the nature of Con A-induced human suppressor cells appears to be analogous to that of Con A-induced murine suppressor cells.

Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection

PubMed Central

Cubas, Rafael; van Grevenynghe, Julien; Wills, Saintedym; Kardava, Lela; Santich, Brian H.; Buckner, Clarisa M.; Muir, Roshell; Tardif, Virginie; Nichols, Carmen; Procopio, Francesco; He, Zhong; Metcalf, Talibah; Ghneim, Khader; Locci, Michela; Ancuta, Petronella; Routy, Jean-Pierre; Trautmann, Lydie; Li, Yuxing; McDermott, Adrian B.; Koup, Rick A.; Petrovas, Constantinos; Migueles, Steven A.; Connors, Mark; Tomaras, Georgia D.; Moir, Susan; Crotty, Shane

2015-01-01

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2–responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART. PMID:26546609

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.

Variation of Neisseria gonorrhoeae Lipooligosaccharide Directs Dendritic Cell–Induced T Helper Responses

PubMed Central

van Vliet, Sandra J.; Steeghs, Liana; Bruijns, Sven C. M.; Vaezirad, Medi M.; Snijders Blok, Christian; Arenas Busto, Jésus A.; Deken, Marcel; van Putten, Jos P. M.; van Kooyk, Yvette

2009-01-01

Gonorrhea is one of the most prevalent sexually transmitted diseases in the world. A naturally occurring variation of the terminal carbohydrates on the lipooligosaccharide (LOS) molecule correlates with altered disease states. Here, we investigated the interaction of different stable gonoccocal LOS phenotypes with human dendritic cells and demonstrate that each variant targets a different set of receptors on the dendritic cell, including the C-type lectins MGL and DC-SIGN. Neisseria gonorrhoeae LOS phenotype C constitutes the first bacterial ligand to be described for the human C-type lectin receptor MGL. Both MGL and DC-SIGN are locally expressed at the male and female genital area, the primary site of N. gonorrhoeae infection. We show that targeting of different C-type lectins with the N. gonorrhoeae LOS variants results in alterations in dendritic cell cytokine secretion profiles and the induction of distinct adaptive CD4+ T helper responses. Whereas N. gonorrhoeae variant A with a terminal N-acetylglucosamine on its LOS was recognized by DC-SIGN and induced significantly more IL-10 production, phenotype C, carrying a terminal N-acetylgalactosamine, primarily interacted with MGL and skewed immunity towards the T helper 2 lineage. Together, our results indicate that N. gonorrhoeae LOS variation allows for selective manipulation of dendritic cell function, thereby shifting subsequent immune responses in favor of bacterial survival. PMID:19834553

Evidence that Singlet Oxygen-induced Human T Helper Cell Apoptosis Is the Basic Mechanism of Ultraviolet-A Radiation Phototherapy

PubMed Central

Morita, Akimichi; Werfel, Thomas; Stege, Helger; Ahrens, Constanze; Karmann, Karin; Grewe, Markus; Grether-Beck, Susanne; Ruzicka, Thomas; Kapp, Alexander; Klotz, Lars-Oliver; Sies, Helmut; Krutmann, Jean

1997-01-01

Ultraviolet A (UVA) irradiation is effectively used to treat patients with atopic dermatitis and other T cell mediated, inflammatory skin diseases. In the present study, successful phototherapy of atopic dermatitis was found to result from UVA radiation-induced apoptosis in skin-infiltrating T helper cells, leading to T cell depletion from eczematous skin. In vitro, UVA radiation-induced human T helper cell apoptosis was mediated through the FAS/FAS-ligand system, which was activated in irradiated T cells as a consequence of singlet oxygen generation. These studies demonstrate that singlet oxygen is a potent trigger for the induction of human T cell apoptosis. They also identify singlet oxygen generation as a fundamental mechanism of action operative in phototherapy. PMID:9362536

Effect of ginseng polysaccharides and dendritic cells on the balance of Th1/Th2 T helper cells in patients with non-small cell lung cancer.

PubMed

Ma, Junjie; Liu, Huiping; Wang, Xiaolong

2014-12-01

To investigate the effect of thorascopic administration.of ginseng polysaccharides (GPS) plus dendritic cells (DC) on T helper cell type 1/T helper cell type 2 (Th1/Th2) balance in patients with non-small cell lung cancer (NSCLC). A total of 96 NSCLC patients were divided evenly into two groups. The control group was treated with DCs alone and the treatment group was treated with DCs plus GPS. After DCs and GPS were administered thoracoscopically, once a week, 4 times for 30 days, the patients' quality of life was measured with the Functional Assessment of Cancer Treatment-Lung (FACT-L) questionnaire before and after treatment. Serum interferon-γ (INF-γ), interleukin-4 (IL-4), IL-2 and IL-5 were examined before and after treatments. The level of Th1 cytokines (INF-γ, IL-2) and the ratio of Th1/Th2 cytokines (INF-γ/IL-4, IL-2/ IL-5) increased in both treatment groups, while Th2 cytokines (IL-4, IL-5) and FACT-L scores decreased (P < 0.01). Furthermore, after treatment Th1 cytokines (INF-γ, IL-2) and the ratio of Th1/Th2 cytokines (INF-γ/IL-4, IL-2/IL-5) were higher in the DCs + GPS group than in the control group (P < 0.05). Conversely, FACT-L scores and Th2 cytokines (IL-4, IL-5) were higher in the control group than in the DCs + GPS group (P < 0.05). The treatment regime of DCs plus GPS had a greater effect on NSCLC patients' immune function as compared with DCs alone. This was evident by increased expression of Th1 cytokines (INF-γ, IL-2) and the ratio of Th1/Th2 (INF-γ/IL-4, IL-2/IL-5), as well as by decreased FACT-L scores and the expression of Th2 cytokines (IL-4, IL-5).

Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells.

PubMed

Sadtler, Kaitlyn; Estrellas, Kenneth; Allen, Brian W; Wolf, Matthew T; Fan, Hongni; Tam, Ada J; Patel, Chirag H; Luber, Brandon S; Wang, Hao; Wagner, Kathryn R; Powell, Jonathan D; Housseau, Franck; Pardoll, Drew M; Elisseeff, Jennifer H

2016-04-15

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair. Copyright © 2016, American Association for the Advancement of Science.

Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells

PubMed Central

Sadtler, Kaitlyn; Estrellas, Kenneth; Allen, Brian W.; Wolf, Matthew T.; Fan, Hongni; Tam, Ada J.; Patel, Chirag H.; Luber, Brandon S.; Wang, Hao; Wagner, Kathryn R.; Powell, Jonathan D.; Housseau, Franck; Pardoll, Drew M.

2016-01-01

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4–dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair. PMID:27081073

Analysis of T cell-replacing factor-like activity: potent induction of T helper activity for human B cells by residual concanavalin A and interleukin 2.

PubMed

Sauerwein, R W; Van der Meer, W G; Aarden, L A

1987-08-01

At least two factors with the capacity to induce IgM synthesis in human B cells were found to be present in the 15-20-kDa fraction of the supernatant of mononuclear cells activated with concanavalin A (Con A) and phorbol ester. Previously, it has been shown (Sauerwein, R. W. et al., Eur. J. Immunol. 1985. 15: 611) that interleukin 2 (IL2) in this material is able to induce T cell-dependent IgM secretion in normal B cells. Evidence was obtained for the presence of another factor distinct from IL2 that could replace T cells in the induction of B cell differentiation. We have analyzed this factor with the use of a neoplastic B cell population of prolymphocytic origin that was functionally nonresponsive to IL2. T cell-replacing factor (TRF)-like activity and IL2 could be separated by ion-exchange chromatography, although a small amount of IL2 was recovered in the TRF fractions. This small amount of IL2 was found to be crucial for the observed TRF activity. Moreover, a substantial amount of monomeric Con A was detected in the TRF preparation. Our studies show that Con A in the presence of IL2 can act as a potent inducer of helper function in lower numbers of T cells for normal and neoplastic B cells. Functional assays for T cell contamination in B cell suspensions are therefore of limited value because they are determined by the efficiency of the stimulating signal. Particularly in those B cell factor preparations, obtained from mitogen-activated T cells with an obligatory or unidentified role of IL2, the possible effect of a contaminating mitogen must be considered.

Transcription factor RBP-J-mediated signalling regulates basophil immunoregulatory function in mouse asthma model.

PubMed

Qu, Shuo-Yao; He, Ya-Long; Zhang, Jian; Wu, Chang-Gui

2017-09-01

Basophils (BA) play an important role in the promotion of aberrant T helper type 2 (Th2) immune responses in asthma. It is not only the effective cell, but also modulates the initiation of Th2 immune responses. We earlier demonstrated that Notch signalling regulates the biological function of BAin vitro. However, whether this pathway plays the same role in vivo is not clear. The purpose of the present study was to investigate the effect of Notch signalling on BA function in the regulation of allergic airway inflammation in a murine model of asthma. Bone marrow BA were prepared by bone marrow cell culture in the presence of recombinant interleukin-3 (rIL-3; 300 pg/ml) for 7 days, followed by isolation of the CD49b + microbeads. The recombination signal binding protein J (RBP-J -/- ) BA were co-cultured with T cells, and the supernatant and the T-cell subtypes were examined. The results indicated disruption of the capacity of BA for antigen presentation alongside an up-regulation of the immunoregulatory function. This was possibly due to the low expression of OX40L in the RBP-J -/- BA. Basophils were adoptively transferred to ovalbumin-sensitized recipient mice, to establish an asthma model. Lung pathology, cytokine profiles of brobchoalveolar fluid, airway hyperactivity and the absolute number of Th1/Th2 cells in lungs were determined. Overall, our results indicate that the RBP-J-mediated Notch signalling is critical for BA-dependent immunoregulation. Deficiency of RBP-J influences the immunoregulatory functions of BA, which include activation of T cells and their differentiation into T helper cell subtypes. The Notch signalling pathway is a potential therapeutic target for BA-based immunotherapy against asthma. © 2017 John Wiley & Sons Ltd.

IMMUNOLOGIC MEMORY CELLS OF BONE MARROW ORIGIN

PubMed Central

Miller, Harold C.; Cudkowicz, Gustavo

1972-01-01

Individual immunocompetent precursor cells of (C57BL/10 x C3H)F1 mouse marrow generate, on transplantation, three to five times more antibody-forming cells localized in recipient spleens during secondary than during primary immune responses. The increased burst size is immunologically specific since antigens of horse and chicken erythrocytes and of Salmonella typhimurium do not cause this effect in marrow cells responsive to sheep red blood cells. Both sensitized and nonsensitized precursors require the helper function of thymus-derived cells and antigen for the final steps of differentiation and maturation. The burst size of primed precursor cells is the same after cooperative interactions with virgin or educated helper cells of thymic origin. The greater potential of these marrow precursors may be attributable to self-replication and migration before differentiation into antibody-forming descendants. In fact, the progeny cells of primed precursor units are distributed among a multiplicity of foci, whereas those of nonimmune precursors are clustered into one focus. The described properties of specifically primed marrow precursors are those underlying immunologic memory. It remains to be established whether memory cells are induced or selected by antigens and whether the thymus plays a role in this process. PMID:4553850

Characterization of a human antigen specific helper factor

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

Richardson, B.

1986-03-01

While antigen (Ag) specific helper factors have been characterized in mice, similar molecules have not been identified in humans. To characterize human antigen specific helper molecules, an IL-2 dependent tetanus toxoid (T.T.) reactive T cell line was fused with a 6-thioguanine resistant CEM line, and hybrids selected in medium containing hypoxanthine and azaserine. Hybrids were screened by culturing the cells with /sup 35/S-Met then reacting the supernatants with T.T. or hepatitis vaccine immobilized on nitrocellulose. One hybrid, TT6BA-O, was identified which secreted a Met-containing molecule which bound T.T. but not hepatitis vaccine. Supernatants from TT6BA-O, but not the parent CEMmore » line, when added to autologous peripheral blood mononuclear cells (PBMC's) stimulated secretion of T.T. specific antibodies (Abs). Specificity controls demonstrated that TT6BA-O supernatant did not induce antibodies to diphtheria toxoid, hepatitis vaccine or pneumococcal polysaccharide, and total immunoglobulin (lg) synthesis was minimally increased. In contrast, pokeweed mitogen stimulated significant lg synthesis as well as Ab's to pneumococcal polysaccharide and T.T. TT6BA-O supernatant induced anti-T.T.Ab's in autologous PBMC's but not PBMC's from 3 unrelated donors, suggesting that the activity of the helper factor is restricted, possibly by the MHC. The molecular weight of the helper factor was estimated at 100,000-150,000 by Sephacryl S-300 chromatography. Finally, the helper factor could be demonstrated to bind and elute from sephorose-immobilized T.T. and anti-DR antisera, but not anti-lg antisera or the T40/25 monoclonal antibody, which binds a nonpolymorphic determinant on the human T cell receptor. These results demonstrate that human Ag specific helper factors exist, bind antigen and bear class II MHC determinants.« less

Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation.

PubMed

Sehra, Sarita; Serezani, Ana P M; Ocaña, Jesus A; Travers, Jeffrey B; Kaplan, Mark H

2016-07-01

Atopic dermatitis is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells, and mast cells. The role of mast cells in atopic dermatitis is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of epidermal differentiation complex and other skin genes. Decreased epidermal differentiation complex gene expression in mice that genetically lack mast cells (Kit(W-sh/W-sh) mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells (DCs) compared with similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens. To test this further, we crossed Kit(W-sh/W-sh) mice with signal transducer and activator of transcription 6 (i.e., Stat6) VT transgenic mice that develop spontaneous atopic dermatitis-like disease that is dependent on T helper cell 2 cytokines and is associated with high serum concentrations of IgE. We observed that Stat6VT × Kit(W-sh/W-sh) mice developed more frequent and more severe allergic skin inflammation than Stat6VT transgenic mice that had mast cells. Together, these studies suggest that mast cells regulate epidermal barrier function and have a potential protective role in the development of atopic dermatitis-like disease. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Lactobacilli Activate Human Dendritic Cells that Skew T Cells Toward T Helper 1 Polarization

DTIC Science & Technology

2005-01-06

Species Modulate the Phenotype and Function of MDCs. Previous studies have shown that Lactobacillus plantarum and Lactobacillus rhamnosus can induce...cell immune responses at both systemic and mucosal sites. Many Lactobacillus species are normal members of the human gut microflora and most are regarded...several well defined strains, representing three species of Lactobacillus on human myeloid DCs (MDCs) and found that they modulated the phenotype and

Reduced Memory CD4+ T-Cell Generation in the Circulation of Young Children May Contribute to the Otitis-Prone Condition

PubMed Central

Sharma, Sharad K.; Casey, Janet R.

2011-01-01

Background. An explanation for the immunologic dysfunction that causes children to be prone to repeated episodes of acute otitis media (AOM) has long been sought. Poor antibody response has been associated with the otitis-prone condition; however, there is no precise mechanistic explanation for this condition. Methods. Non–otitis-prone and otitis-prone children with AOM or nasopharyngeal (NP) colonization caused by either Streptococcus pneumoniae or Haemophilus influenzae were compared for pathogen-specific CD4+ T-helper memory responses by stimulating peripheral blood mononuclear cells using 6 vaccine candidate S. pneumoniae and 3 H. influenzae protein antigens. Samples were analyzed by multi-parameter flow cytometry. Results. Significantly reduced percentages of functional CD45RALow memory CD4+ T cells producing specific cytokines (interferon γ, interleukin [IL]–2, IL-4 and IL-17a) were observed in otitis-prone children following AOM and NP colonization with either S. pneumoniae or H. influenzae. Immunoglobulin (Ig) G responses to the studied protein antigens were reduced, which suggests that antigen-specific B-cell function may be compromised as a result of poor T-cell help. Staphylococcal enterotoxin B stimulated similar cytokine patterns in memory CD4+T cells in both groups of children. Conclusions. Otitis-prone children have suboptimal circulating functional T-helper memory and reduced IgG responses to S. pneumoniae or H. influenzae after colonization and after AOM; this immune dysfunction causes susceptibility to recurrent AOM infections. PMID:21791667

The role of helper lipids in the intracellular disposition and transfection efficiency of niosome formulations for gene delivery to retinal pigment epithelial cells.

PubMed

Ojeda, Edilberto; Puras, Gustavo; Agirre, Mireia; Zarate, Jon; Grijalvo, Santiago; Eritja, Ramon; DiGiacomo, Luca; Caracciolo, Giulio; Pedraz, Jose-Luis

2016-04-30

In this work, we carried out a comparative study of four different niosome formulations based on the same cationic lipid and non-ionic tensoactive. The niosomes prepared by oil-in-water emulsion technique (o/w) only differed in the helper lipid composition: squalene, cholesterol, squalane or no helper lipid. Niosomes and nioplexes elaborated upon the addition of pCMS-EGFP reporter plasmid were characterized in terms of size, zeta potential and polydispersity index. The capacity of the niosomes to condense, release and protect the DNA against enzymatic degradation was evaluated by agarose gel electrophoresis. In vitro experiments were carried out to evaluate transfection efficiency and cell viability in retinal pigment epithelial cells. Moreover, uptake and intracellular trafficking studies were performed to further understand the role of the helper lipids in the transfection process. Interestingly, among all tested formulations, niosomes elaborated with squalene as helper lipid were the most efficient transfecting cells. Such transfection efficiency could be attributed to their higher cellular uptake and the particular entry pathways used, where macropinocytosis pathway and lysosomal release played an important role. Therefore, these results suggest that helper lipid composition is a crucial step to be considered in the design of niosome formulation for retinal gene delivery applications since clearly modulates the cellular uptake, internalization mechanism and consequently, the final transfection efficiency. Copyright © 2016 Elsevier B.V. All rights reserved.

Activation of human T-helper/inducer cell, T-cytotoxic/suppressor cell, B-cell, and natural killer (NK)-cells and induction of NK cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin

USDA-ARS?s Scientific Manuscript database

Background Modified citrus pectin (MCP) is known for its anti-cancer effects and its ability to be absorbed and circulated in the human body. In this report we tested the ability of MCP to induce the activation of human blood lymphocyte subsets including T-helper/inducer cell, Tcytotoxic/suppres...

Curcumin up regulates T helper 1 cells in patients with colon cancer.

PubMed

Xu, Bin; Yu, Lin; Zhao, Li-Zhong

2017-01-01

The therapy for the advanced colon cancer (Cca) is unsatisfactory currently. To regulate the immune effector cell function has shown a positive effect on the treatment of advanced cancers. This study tests a hypothesis that administration with curcumin converts the Cca patient-derived regulatory T cells (Treg) to T helper (Th) 1 cells. In this study, a group of patients with advanced Cca was recruited into this study. The patients were treated with curcumin. The peripheral Tregs and Th1 cells were assessed by flow cytometry. The results showed that, after the curcumin therapy, the forkhead box protein (Foxp) 3 positive Treg frequency was markedly reduced, the frequency of Th1 cells was significantly increased in Cca patients. Treating with curcumin repressed the Foxp3 gene transcription in Tregs; the Tregs were then converted into Th1 cells. The results also revealed that Foxp3 bound T-bet to prevent IFN-γ expression in CD4 + T cells, which was abolished by treating with curcumin. In conclusion, the administration of curcumin can convert Tregs to Th1 cells via repressing Foxp3 expression and enhancing IFN-γ production.

Synergistic effect of concanavalin A and Bu-WSA on DNA synthesis in human peripheral blood lymphocytes.

PubMed

Nitta, T; Okumura, S; Nakano, M

1985-02-01

Butanol-extracted water soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii was not mitogenic for human peripheral blood mononuclear cells (PBM) but was capable of enhancing (3H) thymidine uptake of T cells stimulated by concanavalin A (Con A) in the presence of B cells or macrophages (M phi) in vitro. The mechanisms of the synergy of Con A and Bu-WSA were studied by using separated cell populations from PBM. Both subfractioned OKT4+ and OKT8+ cells were responsive to co-stimulation by Con A and Bu-WSA in the presence of an accessory cell population. Allogeneic B cells and M phi as well as autologous cells had helper function as accessory cells. Heavy irradiation with gamma-rays did not affect the function of the accessory cells, but previous treatment of B cells with anti-Ig serum plus complement (C) or treatment of M phi with anti-M phi serum plus C deprived them of their function. The treatment of accessory cells with anti-HLA-DR serum, regardless of the presence or absence of C, resulted in loss of their helper function. Cultures in Marbrook-type vessels showed that a mixed cell population of T cells and accessory cells in the lower chamber produced some active factor(s) after co-stimulation with Con A and Bu-WSA, and by passing through the membrane filter separating the chambers, the factor(s) enhanced the proliferation of the Con A-activated T cell population in the upper chamber. The factor(s) was presumed to be interleukin 2 (IL 2), because it supported the growth of IL 2-dependent CTLL cells. These results indicate that the synergy of Con A and Bu-WSA on the proliferative response of human PBM is due to the elevation of growth factor production from T cells stimulated by those mitogens.

Inflammatory T helper 17 cells promote depression-like behavior in mice.

PubMed

Beurel, Eléonore; Harrington, Laurie E; Jope, Richard S

2013-04-01

Recognition of substantial immune-neural interactions is revising dogmas about their insular actions and revealing that immune-neural interactions can substantially impact central nervous system functions. The inflammatory cytokine interleukin-6 promotes susceptibility to depression and drives production of inflammatory T helper 17 (Th17) T cells, raising the hypothesis that in mouse models, Th17 cells promote susceptibility to depression-like behaviors. Behavioral characteristics were measured in male mice administered Th17 cells, CD4(+) cells, or vehicle and in retinoid-related orphan receptor-γT (RORγT)(+/GFP) mice or male mice treated with RORγT inhibitor or anti-interleukin-17A antibodies. Mouse brain Th17 cells were elevated by learned helplessness and chronic restraint stress, two common depression-like models. Th17 cell administration promoted learned helplessness in 89% of mice in a paradigm where no vehicle-treated mice developed learned helplessness, and impaired novelty suppressed feeding and social interaction behaviors. Mice deficient in the RORγT transcription factor necessary for Th17 cell production exhibited resistance to learned helplessness, identifying modulation of RORγT as a potential intervention. Treatment with the RORγT inhibitor SR1001, or anti-interleukin-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness. These findings indicate that Th17 cells are increased in the brain during depression-like states, promote depression-like behaviors in mice, and specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior, suggesting antidepressant effects may be attained by targeting Th17 cells. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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.

Mitomycin C-treated or irradiated concanavalin A-activated T cells augment the activation of cytotoxic T cells in vivo.

PubMed

Moyers, C; Pottmeyer-Gerber, C; Gerber, M; Buszello, H; Dröge, W

1984-10-01

The activation of cytotoxic T lymphocytes (CTL) in vivo after immunization of normal or cyclophosphamide-treated mice with allogeneic cells was strongly augmented by the administration of mitomycin C-treated or irradiated concanavalin A-activated spleen cells (Con A-spl). This effect of the Con A-spl was abrogated by treatment with Anti-Thy 1 antibody plus complement, and was therefore presumably mediated by activated "helper" T cells. (The term "helper" cell is only operationally defined in this context and indicates that the augmenting irradiation resistant T cells are obviously not CTL precursor cells). These observations indicated (i) that even the cytotoxic response against allogeneic stimulator cells suffers in vivo from insufficient "helper" T cell activity, and (ii) that the injection of Con A-spl may serve as a simple procedure to apply this "helper" activity in vivo. This procedure was at least as effective as the repeated injection of interleukin 2 (IL-2)-containing cell supernatants with up to four 30-unit doses of IL-2 per mouse. IL-2-containing cell supernatants were found to mediate similar effects only if injected into the footpads but not intravenously. This was in line with the reported observation that IL-2 has an extremely short half-life in vivo. The injection of Con A-spl was also found to augment the proliferative response in the regional lymph nodes.

Increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ T follicular helper cells in adult patients with minimal change disease.

PubMed

Li, Tao; Shi, Yunpeng; Sun, Weixia; Wang, Haifeng; Wang, Quan; Jiang, Yanfang

2018-02-01

T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD-1) + Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD-1 + Tfh cells and their functional effects in adult patients with minimal change disease (MCD). The frequencies of circulating PD-1 + , PD-1 + CD154 + , and PD-1 + interleukin (IL)-21 + Tfh cells, and CD38 + CD19 + and CD38 + CD19 + CD40 + B cells, as well as serum IL-2, IL-4, IL-17A, IL-6, IL-21, and interferon (IFN)-γ were significantly increased in the MCD patients compared with the healthy controls (HCs) (P < 0.05). However, no significant difference was found in PD-1 + BCL-6 + or PD-1 + ICOS + Tfh cells. Furthermore, the percentages of PD-1 + Tfh and PD-1 + CD154 + Tfh cells were negatively correlated with the estimated glomerular filtration rate (eGFR), but positively correlated with the 24-h urinary protein concentration and serum IL-21 level. The percentages of PD-1 + Tfh and PD-1 + CD154 + Tfh cells were positively correlated with the percentages of CD38 + plasma cells and active CD38 + CD40 + plasma cells, respectively. After an 8-12-week treatment with prednisolone, the percentages of PD-1 + , PD-1 + CD154 + , and PD-1 + IL-21 + Tfh cells as well as the serum level of IL-21 were significantly reduced; in contrast, the serum levels of IL-4 and IL-10 were increased (P < 0.05). We conclude that increased PD-1 + CD154 + Tfh cells are possibly the most important functional subset of PD-1 + Tfh cells and may contribute towards the pathogenesis of MCD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Search for biomarkers of asbestos exposure and asbestos-induced cancers in investigations of the immunological effects of asbestos.

PubMed

Matsuzaki, Hidenori; Kumagai-Takei, Naoko; Lee, Suni; Maeda, Megumi; Sada, Nagisa; Hatayama, Tamayo; Yamamoto, Shoko; Ikeda, Miho; Yoshitome, Kei; Min, Yu; Nishimura, Yasumitsu; Otsuki, Takemi

2017-06-09

The immunological effects of asbestos exposure on various lymphocytes such as the regulatory T cell (Treg), responder CD4+ T helper cell (Tresp), CD8+ cytotoxic T lymphocytes (CTL), and natural killer (NK) cells were investigated. Results show that asbestos exposure impairs antitumor immunity through enhancement of regulatory T cell function and volume, reduction of CXCR3 chemokine receptor in responder CD4+ T helper cells, and impairment of the killing activities of CD8+ cytotoxic T lymphocytes (CTL) and NK cells. These findings were used to explore biological markers associated with asbestos exposure and asbestos-induced cancers and suggested the usefulness of serum/plasma IL-10 and TGF-β, surface CXCR3 expression in Tresp, the secreting potential of IFN-γ in Tresp, intracellular perforin level in CTL, and surface expression NKp46 in NK cells. Although other unexplored cytokines in serum/plasma and molecules in these immunological cells, including Th17, should be investigated by experimental procedures in addition to a comprehensive analysis of screening methods, biomarkers based on immunological alterations may be helpful in clinical situations to screen the high-risk population exposed to asbestos and susceptible to asbestos-related cancers such as mesothelioma.

Innate lymphoid cells in secondary lymphoid organs.

PubMed

Bar-Ephraïm, Yotam E; Mebius, Reina E

2016-05-01

The family of innate lymphoid cells (ILCs) has attracted attention in recent years as its members are important regulators of immunity, while they can also cause pathology. In both mouse and man, ILCs were initially discovered in developing lymph nodes as lymphoid tissue inducer (LTi) cells. These cells form the prototypic members of the ILC family and play a central role in the formation of secondary lymphoid organs (SLOs). In the absence of LTi cells, lymph nodes (LN) and Peyer's Patches (PP) fail to form in mice, although the splenic white pulp can develop normally. Besides LTi cells, the ILC family encompasses helper-like ILCs with functional distinctions as seen by T-helper cells, as well as cytotoxic natural killer (NK) cells. ILCs are still present in adult SLOs where they have been shown to play a role in lymphoid tissue regeneration. Furthermore, ILCs were implicated to interact with adaptive lymphocytes and influence the adaptive immune response. Here, we review the recent literature on the role of ILCs in secondary lymphoid tissue from the formation of SLOs to mature SLOs in adults, during homeostasis and pathology. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epitope mapping and evaluation of specificity of T-helper sites in four major antigenic peptides of chicken riboflavin carrier protein in outbred rats.

PubMed

Subramanian, Sarada; Andal, S; Karande, Anjali A; Radhakantha Adiga, P

2003-11-07

This paper reviews our studies on synthetic peptides spanning the major antigenic determinants of the chicken riboflavin carrier protein (RCP; 219 AA). These determinants are composed of residues 4-24 (YGC), 64-83 (CED), 130-147 (GEN), and 200-219 (HAC) and function as minivaccines in terms of eliciting anti-peptide antibodies which recognize the native protein and are particularly promising contraceptive vaccine candidates. We have used 15-residue synthetic peptides to define short sequences involved in interaction with antibody and with T-cells. We have mapped the boundaries of T-cell epitopes of these peptides in outbred rats by immunizing the animals with each peptide and assaying the popliteal lymph node cell proliferation against a series of overlapping synthetic 15-mers covering the entire length of the individual peptides. The peptides YGC, GEN, and HAC harboured a single T-cell epitope each whereas the peptide CED exhibited bimodal response possessing two epitopes, one at N-terminus and the other at the C-terminus. These studies provide insight into the way in which an immunogen is viewed by the immune system. In addition, preferential T-cell helper function for B cells recognizing unique determinants on the same molecule was demonstrated. This information helps in exploiting synthetic peptides in the construction of designer immunogens which have potential as candidate vaccines.

Cell Cycle-Dependent Expression of Adeno-Associated Virus 2 (AAV2) Rep in Coinfections with Herpes Simplex Virus 1 (HSV-1) Gives Rise to a Mosaic of Cells Replicating either AAV2 or HSV-1

PubMed Central

Franzoso, Francesca D.; Seyffert, Michael; Vogel, Rebecca; Yakimovich, Artur; de Andrade Pereira, Bruna; Meier, Anita F.; Sutter, Sereina O.; Tobler, Kurt; Vogt, Bernd; Greber, Urs F.; Büning, Hildegard; Ackermann, Mathias

2017-01-01

ABSTRACT Adeno-associated virus 2 (AAV2) depends on the simultaneous presence of a helper virus such as herpes simplex virus 1 (HSV-1) for productive replication. At the same time, AAV2 efficiently blocks the replication of HSV-1, which would eventually limit its own replication by diminishing the helper virus reservoir. This discrepancy begs the question of how AAV2 and HSV-1 can coexist in a cell population. Here we show that in coinfected cultures, AAV2 DNA replication takes place almost exclusively in S/G2-phase cells, while HSV-1 DNA replication is restricted to G1 phase. Live microscopy revealed that not only wild-type AAV2 (wtAAV2) replication but also reporter gene expression from both single-stranded and double-stranded (self-complementary) recombinant AAV2 vectors preferentially occurs in S/G2-phase cells, suggesting that the preference for S/G2 phase is independent of the nature of the viral genome. Interestingly, however, a substantial proportion of S/G2-phase cells transduced by the double-stranded but not the single-stranded recombinant AAV2 vectors progressed through mitosis in the absence of the helper virus. We conclude that cell cycle-dependent AAV2 rep expression facilitates cell cycle-dependent AAV2 DNA replication and inhibits HSV-1 DNA replication. This may limit competition for cellular and viral helper factors and, hence, creates a biological niche for either virus to replicate. IMPORTANCE Adeno-associated virus 2 (AAV2) differs from most other viruses, as it requires not only a host cell for replication but also a helper virus such as an adenovirus or a herpesvirus. This situation inevitably leads to competition for cellular resources. AAV2 has been shown to efficiently inhibit the replication of helper viruses. Here we present a new facet of the interaction between AAV2 and one of its helper viruses, herpes simplex virus 1 (HSV-1). We observed that AAV2 rep gene expression is cell cycle dependent and gives rise to distinct time-controlled windows for HSV-1 replication. High Rep protein levels in S/G2 phase support AAV2 replication and inhibit HSV-1 replication. Conversely, low Rep protein levels in G1 phase permit HSV-1 replication but are insufficient for AAV2 replication. This allows both viruses to productively replicate in distinct sets of dividing cells. PMID:28515305

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.

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

CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer

PubMed Central

Wang, Weiwei; Yuan, Xiangliang; Chen, Hui; Xie, Guohua; Ma, Yanhui; Zheng, Yingxia; Zhou, Yunlan; Shen, Lisong

2015-01-01

Regulatory B cells (Bregs) play a critical role in inflammation and autoimmune disease. We characterized the role of Bregs in the progression of gastric cancer. We detected an increase in Bregs producing IL-10 both in peripheral blood mononuclear cells (PBMCs) and in gastric tumors. Multicolor flow cytometry analysis revealed that a subset of CD19+CD24hiCD38hi B cells produces IL-10. Functional studies indicated that increased Bregs do not inhibit the proliferation of CD3+T cells or CD4+ helper T cells (Th cells). However, Bregs do suppress the secretion of IFN-γ and TNF-α by CD4+Th cells. CD19+CD24hiCD38hiBregs were also found to correlate positively with CD4+FoxP3+ regulatory T cells (Tregs). Neutralization experiments showed that Bregs convert CD4+CD25− effector T cells to CD4+FoxP3+Tregs via TGF-β1. Collectively, these findings demonstrate that increased Bregs play a immunosuppressive role in gastric cancer by inhibiting T cells cytokines as well as conversion to Tregs. These results may provide new clues about the underlying mechanisms of immune escape in gastric cancer. PMID:26378021

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

Specific Schistosoma mansoni rat T cell clones. I. Generation and functional analysis in vitro and in vivo.

PubMed

Pestel, J; Dissous, C; Dessaint, J P; Louis, J; Engers, H; Capron, A

1985-06-01

In an attempt to determine the role of schistosome-specific T cells in the immune mechanisms developed during schistosomiasis, Schistosoma mansoni-specific T cells and clones were generated in vitro and some of their functions analyzed in vitro and in vivo in the fischer rat model. The data presented here can be summarized as follows: a) Lymph node cells (LNC) from rats primed with the excretory/secretory antigens-incubation products (IPSm) of adult worms proliferate in vitro only in response to the homologous schistosome antigens and not to unrelated antigens (Ag) such as ovalbumin (OVA) or Dipetalonema viteae and Fasciola hepatica parasite extracts. b) After in vitro restimulation of the primed LNC population with IPSm in the presence of antigen-presenting cells (APC) and maintenance in IL 2-containing medium, the frequency of IPSm-specific T cells is increased and the T cells can be restimulated only in the presence of APC possessing the same major histocompatibility complex (MHC) antigens. c) Following appropriate limiting dilution assays (LDA) (1 cell/well), 10 IPSm-specific T cell clones were obtained, and two of four maintained in culture were tested for their helper activity because they expressed only the W3/13+ W3/25+ surface phenotypes. d) The two highly proliferating IPSm-specific T cell clones (G5 and E23) exhibit an IPSm-dependent helper activity, as shown by the increase in IgG production by IPSm-primed B cells. e) IPSm-T cell clone (G5) as well as IPSm-T cell lines when injected in S. mansoni-infested rats can exert an in vivo helper activity, which is characterized by an accelerated production of IgG antibodies specific for the previously identified 30 to 40 kilodaltons (kd) schistosomula surface antigens (Ag). As recent studies have demonstrated that rat monoclonal antibodies recognize some incubation products of adult S. mansoni as well as one of the 30 to 40 kd schistosomula surface antigens, and taking into account the fact that the T cell clones here studied were restimulated either with IPSm or with schistosomulum Ag, it appears that such IPSm-specific T cell clones could be involved in the concomitant immunity mechanisms.

Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine.

PubMed

Hu, Yinin; Petroni, Gina R; Olson, Walter C; Czarkowski, Andrea; Smolkin, Mark E; Grosh, William W; Chianese-Bullock, Kimberly A; Slingluff, Craig L

2014-08-01

Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4(+) and CD8(+) T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-γ ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4(+) T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE-A3281-295 (49 %) and tyrosinase386-406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8(+) T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4(+) and CD8(+) T cell responses against melanoma antigens. CD4(+) T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8(+) T cell responses suggests epitope spreading and systemic activity mediated at the tumor site.

What on "irf" is this gene 4? Irf4 transcription-factor-dependent dendritic cells are required for T helper 2 cell responses in murine skin.

PubMed

Flutter, Barry; Nestle, Frank O

2013-10-17

Interferon regulatory factors play an important role in the transcriptional regulation of immunity. In this issue of Immunity, Kumamoto et al. (2013) and Gao et al. (2013) identify an Irf4-dependent migratory dendritic cell subset required for T helper 2 cell polarization following cutaneous challenge. Copyright © 2013 Elsevier Inc. All rights reserved.

Tracking by flow cytometry antigen-specific follicular helper T cells in wild-type animals after protein vaccination.

PubMed

Chakarov, Svetoslav; Fazilleau, Nicolas

2015-01-01

Flow cytometry is a valuable technology used in immunology to characterize and enumerate the different cell subpopulations specific for a nonself-antigen in the context of an ongoing immune response. Among them, follicular helper T cells are the cognate regulators of B cells in secondary lymphoid tissues. Thus, tracking them is of high interest especially in the context of protein vaccination. For this purpose, transgenic antigen-receptor mouse models have been largely used. It is now clear that transgenic models are not always the best means to study the dynamics of the immune response since they can modify the response. In this chapter, we describe how to track endogenous antigen-specific follicular helper T cells by flow cytometry after protein vaccination in nonmodified wild-type animals, which ultimately provides a comprehensive way to enumerate, characterize, and isolate these particular cells in vivo.

Impaired function of CD4+/CD25+ T regulatory lymphocytes characterizes the self-limited hepatitis A virus infection.

PubMed

Perrella, Alessandro; Vitiello, Laura; Atripaldi, Luigi; Sbreglia, Costanza; Grattacaso, Stella; Bellopede, Pasquale; Patarino, Tommaso; Morelli, Giuseppe; Altamura, Simona; Racioppi, Luigi; Perrella, Oreste

2008-07-01

Hepatitis A virus (HAV) causes a transient illness leaving permanent protection against reinfection. Few data are available on the regulatory mechanisms involved in the CD4+ T helper activation. We aimed to investigate the frequency and function of CD3+/CD4+/CD25+ T cells with regulatory function (Tregs) during acute HAV infection. We enrolled 35 consecutive patients and 15 healthy donors, enumerated Tregs by flow cytometry assay and evaluated, after immunomagnetical sorting with magnetic beads, their ability to inhibit the proliferation of CD4+/CD25- T lymphocytes at different ratios (1:1, 1:10, 1:20). All patients had the usual course of infection. Our immunological analysis showed Tregs frequency in these patients (6.5% [range, 5-8.8%]; 36 [range, 10-87] cells) did not have any statistical difference compared with healthy donors (6% [range, 5-8%]; 48 (range, 23-71) cells), while their ability to suppress CD4+/CD25- was drastically reduced at different ratios (Mann-Whitney U-test; ratio 1:1, 93% vs 72%, z = -3.34, P < 0.0001; ratio 1:10, 86% vs 51%, z = -4.04, P < 0.001; ratio 1:20, 56% vs 30%, z = -3.43, P < 0.0001). After the seroconversion, CD4+/CD25+ frequency and function in HAV-infected patients did not differ from healthy individuals. CD4+/CD25+ T cells seem to be impaired in their function during the HAV acute infection. This evidence might help to determine an optimal T helper cell immune network that is a predisposing factor for a self-limiting disease.

HIV and T follicular helper cells: a dangerous relationship

PubMed Central

Vinuesa, Carola G.

2012-01-01

HIV infection leads to progressive destruction of infected CD4 T cells, hypergammaglobulinemia, and loss of memory B cells. Germinal centers, which are key to memory B cell formation and protective antibody responses, are major HIV reservoirs in which the virus replicates within T follicular helper (TFH) cells. In this issue of the JCI, the Koup and Streeck groups report that chronic SIV/HIV infection promotes TFH cell accumulation, which may drive B cell dysregulation. Their discoveries suggest that HIV harnesses TFH cells to evade the antibody response. PMID:22922252

Human germinal center CD4+CD57+ T cells act differently on B cells than do classical T-helper cells.

PubMed

Bouzahzah, F; Bosseloir, A; Heinen, E; Simar, L J

1995-01-01

We have isolated two subtypes of helper T cells from human tonsils: CD4+CD57+ cells, mostly located in the germinal center (GC), and CD4+CD57- cells, distributed through the interfollicular areas but also present in the GC. In a functional study, we have compared the capacities of these T-cell subtypes to stimulate B cells in cocultures. In order to block T-cell proliferation while maintaining their activation level, we pretreated isolated T cells with mitomycin C prior to culture in the presence of B cells and added polyclonal activators such as PHA and Con A, combined or not with IL-2. Contrary to CD4+ CD57- cells, CD4+CD57+ cells did not markedly enhance B-cell proliferation. Even when sIgD.B cells typical of germinal center cells were tested, the CD4+CD57+ cells had no significant effect. This is in accordance with the location of these cells: They mainly occupy the light zones of the GC where few B cells divide. Even when added to preactivated, actively proliferating cells, CD4+CD57 cells failed to modulate B-cell multiplication. On the supernatants of B-cell-T-cell cocultures, we examined by the ELISA technique the effect of T cells on Ig synthesis. Contrary to CD57+ T cells, whose effect was strong, CD57- T cells weakly stimulated Ig synthesis. More IgM than IgG was generally found. Because CD57 antigen is a typical marker of natural killer cells, we tested the cytolytic activity of tonsillar CD4+CD57+ cells on K562 target cells. Unlike NK cells, neither CD4+CD57+ nor CD4+CD57- cells exhibit any cytotoxicity. Thus, germinal center CD4+CD57+ cells are not cytolytic and do not strongly stimulate either B-cell proliferation or Ig secretion. CD4+CD57- cells, however, enhance B-cell proliferation and differentiation, thus acting like the classical helper cells of the T-dependent areas.

Monoclonal antibodies expression improvement in CHO cells by PiggyBac transposition regarding vectors ratios and design.

PubMed

Ahmadi, Samira; Davami, Fatemeh; Davoudi, Noushin; Nematpour, Fatemeh; Ahmadi, Maryam; Ebadat, Saeedeh; Azadmanesh, Kayhan; Barkhordari, Farzaneh; Mahboudi, Fereidoun

2017-01-01

Establishing stable Chinese Hamster Ovary (CHO) cells producing monoclonal antibodies (mAbs) usually pass through the random integration of vectors to the cell genome, which is sensitive to gene silencing. One approach to overcome this issue is to target a highly transcribed region in the genome. Transposons are useful devices to target active parts of genomes, and PiggyBac (PB) transposon can be considered as a good option. In the present study, three PB transposon donor vectors containing both heavy and light chains were constructed, one contained independent expression cassettes while the others utilized either an Internal Ribosome Entry Site (IRES) or 2A element to express mAb. Conventional cell pools were created by transferring donor vectors into the CHO cells, whereas transposon-based cells were generated by transfecting the cells with donor vectors with a companion of a transposase-encoding helper vector, with 1:2.5 helper/donor vectors ratio. To evaluate the influence of helper/donor vectors ratio on expression, the second transposon-based cell pools were generated with 1:5 helper/donor ratio. Expression levels in the transposon-based cells were two to five -folds more than those created by conventional method except for the IRES-mediated ones, in which the observed difference increased more than 100-fold. The results were dependent on both donor vector design and vectors ratios.

Monoclonal antibodies expression improvement in CHO cells by PiggyBac transposition regarding vectors ratios and design

PubMed Central

Ahmadi, Samira; Davami, Fatemeh; Davoudi, Noushin; Nematpour, Fatemeh; Ahmadi, Maryam; Ebadat, Saeedeh; Azadmanesh, Kayhan; Barkhordari, Farzaneh

2017-01-01

Establishing stable Chinese Hamster Ovary (CHO) cells producing monoclonal antibodies (mAbs) usually pass through the random integration of vectors to the cell genome, which is sensitive to gene silencing. One approach to overcome this issue is to target a highly transcribed region in the genome. Transposons are useful devices to target active parts of genomes, and PiggyBac (PB) transposon can be considered as a good option. In the present study, three PB transposon donor vectors containing both heavy and light chains were constructed, one contained independent expression cassettes while the others utilized either an Internal Ribosome Entry Site (IRES) or 2A element to express mAb. Conventional cell pools were created by transferring donor vectors into the CHO cells, whereas transposon-based cells were generated by transfecting the cells with donor vectors with a companion of a transposase-encoding helper vector, with 1:2.5 helper/donor vectors ratio. To evaluate the influence of helper/donor vectors ratio on expression, the second transposon-based cell pools were generated with 1:5 helper/donor ratio. Expression levels in the transposon-based cells were two to five -folds more than those created by conventional method except for the IRES-mediated ones, in which the observed difference increased more than 100-fold. The results were dependent on both donor vector design and vectors ratios. PMID:28662065

Effect of lipoxygenase metabolites of arachidonic acid on proliferation of human T cells and T cell subsets.

PubMed

Gualde, N; Atluru, D; Goodwin, J S

1985-02-01

The lipoxygenase products LTB4 and 15 HPETE have been reported to stimulate T suppressor cell function and also to inhibit [3H]thymidine incorporation into mitogen-stimulated T cells. This present report documents that although these compounds do indeed inhibit [3H]thymidine incorporation into unfractionated T cells, they significantly enhance [3H]thymidine incorporation into T cell preparation enriched for cells bearing the cytotoxic suppressor cell phenotype identified by the OKT8 monoclonal antibody. The mitogen response of T cells enriched for OKT4+ helper-inducer cells is inhibited in manner similar to the response of unfractionated T cells. Thus, LTB4 and 15 HPETE stimulate both the function and the proliferation of the cytotoxic-suppressor T cell subset.

Multivalent Presentation of MPL by Porous Silicon Microparticles Favors T Helper 1 Polarization Enhancing the Anti-Tumor Efficacy of Doxorubicin Nanoliposomes

PubMed Central

Liu, Xuewu; Yang, Marie; Williams, Laura; Savage, David J.; Gu, Jianhua; Rhudy, Jessica R.; Yokoi, Kenji; Lavelle, Ed C.; Serda, Rita E.

2014-01-01

Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1β levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80+ macrophages, however, a specific reduction was observed in CD204+ macrophages. PMID:24736547

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

Multivalent presentation of MPL by porous silicon microparticles favors T helper 1 polarization enhancing the anti-tumor efficacy of doxorubicin nanoliposomes.

PubMed

Meraz, Ismail M; Hearnden, Claire H; Liu, Xuewu; Yang, Marie; Williams, Laura; Savage, David J; Gu, Jianhua; Rhudy, Jessica R; Yokoi, Kenji; Lavelle, Ed C; Serda, Rita E

2014-01-01

Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1β levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80+ macrophages, however, a specific reduction was observed in CD204+ macrophages.

FOXP3 and GARP (LRRC32): the master and its minion.

PubMed

Probst-Kepper, Michael; Buer, Jan

2010-02-05

The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (T(reg)) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human T(reg) cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype.

T cell-B cell interactions in primary immunodeficiencies.

PubMed

Tangye, Stuart G; Deenick, Elissa K; Palendira, Umaimainthan; Ma, Cindy S

2012-02-01

Regulated interactions between cells of the immune system facilitate the generation of successful immune responses, thereby enabling efficient neutralization and clearance of pathogens and the establishment of both cell- and humoral-mediated immunological memory. The corollary of this is that impediments to efficient cell-cell interactions, normally necessary for differentiation and effector functions of immune cells, underly the clinical features and disease pathogenesis of primary immunodeficiencies. In affected individuals, these defects manifest as impaired long-term humoral immunity and susceptibility to infection by specific pathogens. In this review, we discuss the importance of, and requirements for, effective interactions between B cells and T cells during the formation of CD4(+) T follicular helper cells and the elicitation of cytotoxic function of virus-specific CD8(+) T cells, as well as how these processes are abrogated in primary immunodeficiencies due to loss-of-function mutations in defined genes. © 2012 New York Academy of Sciences.

The Role of Th17 in Neuroimmune Disorders: Target for CAM Therapy. Part I.

PubMed

Vojdani, Aristo; Lambert, Jama

2011-01-01

CD4(+) effector cells, based on cytokine production, nuclear receptors and signaling pathways, have been categorized into four subsets. T-helper-1 cells produce IFN-γ, TNF-β, lymphotoxin and IL-10; T-helper-2 cells produce IL-4, IL-5, IL-10, IL-13, IL-21 and IL-31; T-helper-3, or regulatory T-cells, produce IL-10, TGF-β and IL-35; and the recently discovered T-helper-17 cell produces IL-17, IL-17A, IL-17F, IL-21, IL-26 and CCL20. By producing IL-17 and other signaling molecules, Th17 contributes to the pathogenesis of multiple autoimmune diseases including allergic inflammation, rheumatoid arthritis, autoimmune gastritis, inflammatory bowel disease, psoriasis and multiple sclerosis. In this article, we review the differential regulation of inflammation in different tissues with a major emphasis on enhancement of neuroinflammation by local production of IL-17 in the brain. By understanding the role of pathogenic factors in the induction of autoimmune diseases by Th17 cells, CAM practitioners will be able to design CAM therapies targeting Th17 and associated cytokine activities and signaling pathways to repair the intestinal and blood-brain barriers for their patients with autoimmunities, in particular, those with neuroinflammation and neurodegeneration.

Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice

PubMed Central

Mundt, Sarah; Basler, Michael; Buerger, Stefanie; Engler, Harald; Groettrup, Marcus

2016-01-01

Apart from its role in MHC class I antigen processing, the immunoproteasome has recently been implicated in the modulation of T helper cell differentiation under polarizing conditions in vitro and in the pathogenesis of autoimmune diseases in vivo. In this study, we investigated the influence of LMP7 on T helper cell differentiation in response to the fungus Candida albicans. We observed a strong effect of ONX 0914, an LMP7-selective inhibitor of the immunoproteasome, on IFN-γ and IL-17A production by murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans in vitro. Using a murine model of systemic candidiasis, we could confirm reduced generation of IFN-γ- and IL-17A-producing cells in ONX 0914 treated mice in vivo. Interestingly, ONX 0914 treatment resulted in increased susceptibility to systemic candidiasis, which manifested at very early stages of infection. Mice treated with ONX 0914 showed markedly increased kidney and brain fungal burden which resulted in enhanced neutrophil recruitment and immunopathology. Together, these results strongly suggest a role of the immunoproteasome in promoting proinflammatory T helper cells in response to C. albicans but also in affecting the innate antifungal immunity in a T helper cell-independent manner. PMID:26776888

GATA-3 function in innate and adaptive immunity.

PubMed

Tindemans, Irma; Serafini, Nicolas; Di Santo, James P; Hendriks, Rudi W

2014-08-21

The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor. Copyright © 2014 Elsevier Inc. All rights reserved.

Randomized Multicenter Trial of the Effects of Melanoma-Associated Helper Peptides and Cyclophosphamide on the Immunogenicity of a Multipeptide Melanoma Vaccine

PubMed Central

Slingluff, Craig L.; Petroni, Gina R.; Chianese-Bullock, Kimberly A.; Smolkin, Mark E.; Ross, Merrick I.; Haas, Naomi B.; von Mehren, Margaret; Grosh, William W.

2011-01-01

Purpose This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8+ T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4+ or CD8+ T-cell responses to that vaccine. Patients and Methods In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex–restricted melanoma peptides (12MP) to stimulate CD8+ T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4+ T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded. Results Vaccination with 12MP plus tetanus induced CD8+ T-cell responses in 78% of patients and CD4+ T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8+ responses in 19% of patients and CD4+ responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm. Conclusion Melanoma-associated helper peptides paradoxically decreased CD8+ T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells. PMID:21690475

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

Overexpression of GATA-3 in T cells accelerates dextran sulfate sodium-induced colitis.

PubMed

Okamura, Midori; Yoh, Keigyou; Ojima, Masami; Morito, Naoki; Takahashi, Satoru

2014-01-01

Ulcerative colitis (UC) is an inflammatory bowel disease, and its pathogenesis includes genetic, environmental, and immunological factors, such as T helper cells and their secreted cytokines. T helper cells are classified as Th1, Th2, and Th17 cells. However, it is unclear which T helper cells are important in UC. Dextran sulfate sodium (DSS)-induced colitis is a commonly used model of UC. In this study, we induced DSS colitis in Th1 dominant (T-bet transgenic (Tg)) mice, Th2 dominant (GATA-3 Tg) mice, and Th17 dominant (RORγt Tg) mice to elucidate the roles of T helper cell in DSS colitis. The results showed that GATA-3 Tg mice developed the most severe DSS colitis compared with the other groups. GATA-3 Tg mice showed a significant decreased in weight from day 1 to day 7, and an increased high score for the disease activity index compared with the other groups. Furthermore, GATA-3 Tg mice developed many ulcers in the colon, and many neutrophils and macrophages were detected on day 4 after DSS treatment. Measurement of GATA-3-induced cytokines demonstrated that IL-13 was highly expressed in the colon from DSS-induced GATA-3 Tg mice. In conclusion, GATA-3 overexpression in T-cells and IL-13 might play important roles in the development of DSS colitis.

Human immunodeficiency virus infection of helper T cell clones. Early proliferative defects despite intact antigen-specific recognition and interleukin 4 secretion.

PubMed Central

Laurence, J; Friedman, S M; Chartash, E K; Crow, M K; Posnett, D N

1989-01-01

HIV selectively inhibited the proliferative response of clonal CD4+ T lymphocytes to alloantigen while other alloantigen-dependent responses were unperturbed. Specifically, impaired blastogenesis could be dissociated from alloantigen-specific induction of the B cell activation molecule CD23, IL-4 release, and inositol lipid hydrolysis. In addition, membrane expression of pertinent T cell receptor molecules, including CD2, CD3, and T cell antigen receptor (Ti), remained intact. Using two MHC class II-specific human CD4+ helper T cell clones, the proliferative defect was shown to be an early consequence of HIV infection, occurring within 4 d of viral inoculation and preceding increases in mature virion production. It was generalizable to three distinct methods of T cell activation, all independent of antigen-presenting cells: anti-CD3 mediated cross-linking of the CD3/Ti complex; anti-CD2 and phorbol 12-myristic 13-acetate (PMA); and anti-CD28 plus PMA. These abnormalities were not mitigated by addition of exogenous IL-2, even though expression of the IL-2 receptor (CD25) was unaltered. These studies define a selective blockade in T cell function early after HIV exposure that could serve as a model for certain in vivo manifestations of AIDS. PMID:2470786

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

PubMed Central

Sojka, Dorothy K.; Fowell, Deborah J.

2011-01-01

CD4+CD25+Forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) control immune responses to self and foreign antigens in secondary lymphoid organs and at tissue sites of inflammation. Tregs can modify the function of many immune cells and have been proposed to block early proliferation, differentiation, and effector function. Acute ablation of Tregs has revealed rapid cytokine production immediately after Treg removal, suggesting that Tregs may regulate effector function acutely rather than regulating the programming for immune function. We developed in vitro and in vivo models that enabled the direct test of Treg regulation of T-helper cell type 1 (Th1) differentiation. CD28 signaling is known to abrogate Treg suppression of IL-2 secretion and proliferation, but our studies show that Treg suppression of IFN-γ during Th1 priming proceeds despite enhanced CD28 signaling. Importantly, during Th1 differentiation, Tregs inhibited early IFN-γ transcription without disrupting expression of Th1-specific T-box transcription factor (Tbet) and Th1 programming. Acute shutoff of effector cytokine production by Tregs was selective for IFN-γ but not TNF-α and was independent of TGF-β and Epstein-Barr virus-induced gene 3. In vivo, Tregs potently controlled CD4 IFN-γ and CD4 effector cell expansion in the lymph node (four- to fivefold reduction) but not Th1 programming, independent of IL-10. Tregs additionally reduced CD4 IFN-γ in the inflamed dermis (twofold reduction) dependent on their production of IL-10. We propose a model for Treg inhibition of effector function based on acute cytokine regulation. Interestingly, Tregs used different regulatory mechanisms to regulate IFN-γ (IL-10–dependent or –independent) subject to the target T-cell stage of activation and its tissue location. PMID:22025707

Human Immunodeficiency Virus-1 (HIV-1)

DTIC Science & Technology

1991-03-19

shall be staged according to the following scheme: Stage HIV-I Chronic T-Helper Delayed Thrush Oppor- Antibody Lymph - Cells per Hyper- tunistic and/or...isolation also fulfills criteria to document infection. 12. Chronic lymphadenopathy is defined as two or more extrainguinal sites 2-3 with lymph ... nodes greater than, or equal to, 1 centimeter in diameter that persist for more than 3 months. 13. T-helper cells a.. expressed as cells per mm 3

Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4+ Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

PubMed Central

Li, Tingfeng; Steede, N. Kalaya; Nguyen, Hong-Nam P.; Freytag, Lucy C.; McLachlan, James B.; Mettu, Ramgopal R.; Robinson, James E.

2014-01-01

ABSTRACT Helper T-cell epitope dominance in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is not adequately explained by peptide binding to major histocompatibility complex (MHC) proteins. Antigen processing potentially influences epitope dominance, but few, if any, studies have attempted to reconcile the influences of antigen processing and MHC protein binding for all helper T-cell epitopes of an antigen. Epitopes of gp120 identified in both humans and mice occur on the C-terminal flanks of flexible segments that are likely to be proteolytic cleavage sites. In this study, the influence of gp120 conformation on the dominance pattern in gp120 from HIV strain 89.6 was examined in CBA mice, whose MHC class II protein has one of the most well defined peptide-binding preferences. Only one of six dominant epitopes contained the most conserved element of the I-Ak binding motif, an aspartic acid. Destabilization of the gp120 conformation by deletion of single disulfide bonds preferentially enhanced responses to the cryptic I-Ak motif-containing sequences, as reported by T-cell proliferation or cytokine secretion. Conversely, inclusion of CpG in the adjuvant with gp120 enhanced responses to the dominant CD4+ T-cell epitopes. The gp120 destabilization affected secretion of some cytokines more than others, suggesting that antigen conformation could modulate T-cell functions through mechanisms of antigen processing. IMPORTANCE CD4+ helper T cells play an essential role in protection against HIV and other pathogens. Thus, the sites of helper T-cell recognition, the dominant epitopes, are targets for vaccine design; and the corresponding T cells may provide markers for monitoring infection and immunity. However, T-cell epitopes are difficult to identify and predict. It is also unclear whether CD4+ T cells specific for one epitope are more protective than T cells specific for other epitopes. This work shows that the three-dimensional (3D) structure of an HIV protein partially determines which epitopes are dominant, most likely by controlling the breakdown of HIV into peptides. Moreover, some types of signals from CD4+ T cells are affected by the HIV protein 3D structure; and thus the protectiveness of a particular peptide vaccine could be related to its location in the 3D structure. PMID:24920818

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.

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.

Analysis of intracellular cytokines using flowcytometry.

PubMed

Arora, Sunil K

2002-01-01

Characterization of T-cell clones and identification of functional subsets of the helper T-cells with polarized cytokine production is based on testing of cytokine expression. Several methods have been developed that allow cytokine expression to be measured like ELISA, RT-PCR, ELISPOT, ISH and flowcytometry. Among all these methods, monitoring of cytokine production using flowcytometric analysis has its own advantages and disadvantages. Multi-parametric characterization of cytokine production on single cell basis, without long-term culture and cloning along with high throughput of samples is main feature attached to flowcytometric analysis. The interpretation may be difficult at times due to change in the phenotype of the cells. Cells with similar surface phenotype but synthesizing different cytokines and having different functional characteristics can be analyzed with this technique.

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

Congenitally athymic nude (nu/nu) mice have Thy-1-bearing immunocompetent helper T cells in their peritoneal cavity

PubMed Central

1980-01-01

Heavily irradiated peritoneal cells (PC) from congenitally athymic nude (nu/nu) mice markedly restored the impaired in vitro antibody response of nu/nu spleen cells to sheep erythrocyte antigens (T-dependent antigen), whereas irradiated spleen or lymph node cells from nu/nu mice had no effect on the response. This activity of the irradiated PC of nu/nu mice was completely abolished by treatment with anti-Thy-1.2 antiserum plus normal guinea pig serum (C') and is, therefore, attributable to a function of matured T cells. PMID:6966314

Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen.

PubMed

Plantinga, Maud; Guilliams, Martin; Vanheerswynghels, Manon; Deswarte, Kim; Branco-Madeira, Filipe; Toussaint, Wendy; Vanhoutte, Leen; Neyt, Katrijn; Killeen, Nigel; Malissen, Bernard; Hammad, Hamida; Lambrecht, Bart N

2013-02-21

Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung. Copyright © 2013 Elsevier Inc. All rights reserved.

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

PubMed Central

de Beaucoudrey, Ludovic; Puel, Anne; Filipe-Santos, Orchidée; Cobat, Aurélie; Ghandil, Pegah; Chrabieh, Maya; Feinberg, Jacqueline; von Bernuth, Horst; Samarina, Arina; Jannière, Lucile; Fieschi, Claire; Stéphan, Jean-Louis; Boileau, Catherine; Lyonnet, Stanislas; Jondeau, Guillaume; Cormier-Daire, Valérie; Le Merrer, Martine; Hoarau, Cyrille; Lebranchu, Yvon; Lortholary, Olivier; Chandesris, Marie-Olivia; Tron, François; Gambineri, Eleonora; Bianchi, Lucia; Rodriguez-Gallego, Carlos; Zitnik, Simona E.; Vasconcelos, Julia; Guedes, Margarida; Vitor, Artur Bonito; Marodi, Laszlo; Chapel, Helen; Reid, Brenda; Roifman, Chaim; Nadal, David; Reichenbach, Janine; Caragol, Isabel; Garty, Ben-Zion; Dogu, Figen; Camcioglu, Yildiz; Gülle, Sanyie; Sanal, Ozden; Fischer, Alain; Abel, Laurent; Stockinger, Birgitta; Picard, Capucine; Casanova, Jean-Laurent

2008-01-01

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo. PMID:18591412

Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma.

PubMed

Matsumoto, Yosuke; Nagoshi, Hisao; Yoshida, Mihoko; Kato, Seiichi; Kuroda, Junya; Shimura, Kazuho; Kaneko, Hiroto; Horiike, Shigeo; Nakamura, Shigeo; Taniwaki, Masafumi

2017-11-01

Objective It has been postulated that the normal counterpart of angioimmunoblastic T-cell lymphoma (AITL) is the follicular helper T-cell (TFH). Recent immunological studies have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with T-cell, helper T-cell (Th), and TFH differentiation are reportedly BCL11B, Th-POK, and BCL6, respectively. We explored the postulated normal counterpart of AITL with respect to the expression of the master regulators of T-cell differentiation. Methods We performed an immunohistochemical analysis in 15 AITL patients to determine the expression of the master regulators and several surface markers associated with T-cell differentiation. Results BCL11B was detected in 10 patients (67%), and the surface marker of T-cells (CD3) was detected in all patients. Only 2 patients (13%) expressed the marker of naïve T-cells (CD45RA), but all patients expressed the marker of effector T-cells (CD45RO). Nine patients expressed Th-POK (60%), and 7 (47%) expressed a set of surface antigens of Th (CD4-positive and CD8-negative). In addition, BCL6 and the surface markers of TFH (CXCL13, PD-1, and SAP) were detected in 11 (73%), 8 (53%), 14 (93%), and all patients, respectively. Th-POK-positive/BCL6-negative patients showed a significantly shorter overall survival (OS) than the other patients (median OS: 33.0 months vs. 74.0 months, p=0.020; log-rank test). Conclusion Many of the AITL patients analyzed in this study expressed the master regulators of T-cell differentiation. The clarification of the diagnostic significance and pathophysiology based on the expression of these master regulators in AITL is expected in the future.

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.

Peripheral T cell lymphomas: an immunological study of seven unusual cases.

PubMed

Raziuddin, S; Latif, A B; Arif, S; Ahad, A; Zaidi, A Z

1988-05-01

A multiparameter study of malignant lymph node cells and peripheral blood lymphocytes of seven patients with peripheral T cell lymphoma is presented. The results of monoclonal marker studies showed three cases of helper-suppressor T cell lymphoma (OKT4+, OKT8+), one case of suppressor T cell lymphoma (OKT8+), and three cases of helper T cell lymphoma (OKT4+). Immunophenotypic heterogeneity of neoplastic T cells with expression of pan-T antigens, OKT3+, and OKT11+ (erythrocyte rosetting+) was observed in most patients. Six of the seven cases tested showed Ia and DR antigens. No relationship was detected between patterns of reactivity with T cell reagents and histological types. When tested, the in-vitro malignant T cells of five patients proliferated in response to concanavalin A (Con A), but had poor response to phytohaemagglutinin. The interleukin 2 receptors showed maximum expression on Con A-activated T cells of five patients, and phytohaemagglutinin-activated T cells of one patient. The neoplastic T cells (OKT4+, OKT8+) of one patient studied had suppressor activity for IgG and IgA, and helper activity for IgM synthesis on pokeweed mitogen-induced normal B cell differentiations.

Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia.

PubMed Central

Waldmann, T A; Broder, S; Goldman, C K; Frost, K; Korsmeyer, S J; Medici, M A

1983-01-01

The pathogenesis of the immunoglobulin deficiency of 20 patients with ataxia telangiectasia was studied using an in vitro immunoglobulin biosynthesis system. 10 patients had no detectable IgA in their serum as assessed by radial diffusion in agar and 3 had a reduced serum IgA concentration. The peripheral blood mononuclear cells of 17 of the patients and 17 normal controls were cultured with pokeweed mitogen for 12 d and the immunoglobulin in the supernatants measured. The immunoglobulin synthesis was below the lower limit of the normal 95% confidence interval for IgM in 5 patients, for IgG in 8, and for IgA in 14. The mononuclear cells from 9 of the 10 patients with a serum IgA concentration less than 0.1 mg/ml failed to synthesize IgA in vitro. None of the patients manifested excessive suppressor cell activity. All patients had reduced but measurable helper T cell activity for immunoglobulin synthesis by co-cultured normal pokeweed mitogen-stimulated B cells (geometric mean 22% of normal). Furthermore, the addition of normal irradiated T cells to patient peripheral blood mononuclear cells led to an augmentation of IgM synthesis in 15 of 17 and to increased IgG synthesis in 9 of the 17 patients studied, including 9 of the 12 patients who had synthesized IgG before the addition of the irradiated T cells. In addition, IgA synthesis was increased in all eight patients examined that had serum IgA concentrations greater than 0.1 mg/ml. These studies suggest that a helper T cell defect contributes to the diminished immunoglobulin synthesis. However, a helper T cell defect does not appear to be the sole cause since there was no IgA synthesis by the peripheral blood mononuclear cells of 9 of the 10 patients with a profoundly reduced serum IgA even when co-cultured with normal T cells. Furthermore, the cells of the nine patients with profoundly reduced IgA levels examined also failed to produce IgA when stimulated with the relatively helper T cell-independent polyclonal activators, Nocardia water soluble mitogen or Epstein-Barr virus. Taken together these data support the view that the reduced immunoglobulin synthesis of these patients is due to defects of both B cells and helper T cells. Such a broad defect in lymphocyte maturation taken in conjunction with our demonstration of persistent alpha fetoprotein production by ataxia telangiectasia patients provides support for the proposal that these patients exhibit a generalized defect in tissue differentiation. PMID:6822665

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.

CD21+ (B2 antigen+) cell decrement and CD4+CD29+ (helper-inducer) cell increment suggest an activation of cell immune reactivity in multiple sclerosis.

PubMed

Gambi, D; Porrini, A M; Giampietro, A; Macor, S

1991-08-01

Two-color flow cytometric analysis on peripheral blood lymphocytes of 35 untreated multiple sclerosis (MS) patients, 17 other medical disease (OMD) patients and 14 healthy control (HC) subjects was performed to evaluate the levels of different T and B cell subpopulations. In MS patients we observed an increase in CD4+CD29+ helper-inducer cells but this increase was not related to the different phases of the disease. We hypothesize that this change is related to the reduction of CD21+ cells expressing B2 antigen, a 140 kDa molecule disappearing after B cell activation. An increased level of CD4+CD45RA- (helper-inducer-like cells) and a reduction of CD4+CD29- (suppressor-inducer-like cells) were also present in our patients. These findings demonstrate an immune 'disequilibrium' in MS, which is linked with an increased level of CD25+ cells expressing the interleukin-2 (IL-2) receptor. IL-2, besides being a T cell growth factor, is also a B cell growth factor. These data let us hypothesize that an activation of the immune response is present in MS.

Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging.

PubMed

Sage, Peter T; Tan, Catherine L; Freeman, Gordon J; Haigis, Marcia; Sharpe, Arlene H

2015-07-14

Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

FOXP3 and GARP (LRRC32): the master and its minion

PubMed Central

2010-01-01

The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (Treg) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human Treg cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype. Reviewers: Dr Jim Di Danto, Dr Benedita Rocha and Dr Werner Solbach. PMID:20137067

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

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

PubMed Central

Watanabe, Yukiko; Onodera, Atsushi; Kanai, Urara; Ichikawa, Tomomi; Obata-Ninomiya, Kazushige; Wada, Tomoko; Kiuchi, Masahiro; Iwamura, Chiaki; Tumes, Damon J.; Shinoda, Kenta; Yagi, Ryoji; Motohashi, Shinichiro; Hirahara, Kiyoshi; Nakayama, Toshinori

2014-01-01

Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin−/− T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression. PMID:25136117

STAT4 and T-bet control follicular helper T cell development in viral infections.

PubMed

Weinstein, Jason S; Laidlaw, Brian J; Lu, Yisi; Wang, Jessica K; Schulz, Vincent P; Li, Ningcheng; Herman, Edward I; Kaech, Susan M; Gallagher, Patrick G; Craft, Joe

2018-01-02

Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response. T-bet is important for Tfh cell production of IFN-γ, but not IL-21, and for a robust GC reaction. STAT4, phosphorylated in Tfh cells upon infection, is required for expression of T-bet and Bcl6 and for IFN-γ and IL-21. These data indicate that T-bet is expressed with Bcl6 in Tfh cells and is required alongside STAT4 to coordinate Tfh cell IL-21 and IFN-γ production and for promotion of the GC response after acute viral challenge. © 2018 Weinstein et al.

Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1.

PubMed

Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A; Wang, Chao; Schnell, Alexandra; Lee, Youjin; Sobel, Raymond; Regev, Aviv; Kuchroo, Vijay K

2018-03-20

The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin-17 (IL-17)-producing T helper 17 (Th17) cells. Here, we demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T-cell- and Th17-cell-specific deletion of Fas were protected from induced autoimmunity, and Th17 cell differentiation and stability were impaired. Fas-deficient Th17 cells instead developed a Th1-cell-like transcriptional profile, which a new algorithm predicted to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1, and Fas deficiency enhanced IL-6-induced STAT1 activation and nuclear translocation, whereas deficiency of STAT1 reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of opposing STAT1 and STAT3 to have a direct impact on autoimmunity. Copyright © 2018. Published by Elsevier Inc.

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.

Two roles for CD4 cells in the control of the generation of cytotoxic T lymphocytes.

PubMed

Cassell, D; Forman, J

1991-01-01

The generation of CTL against Qa-1 Ag in C57BL/6 (B6) (Qa-1b) and B6.Tlaa (Qa-1a) congenic strains requires in vivo priming with the Qa-1 alloantigen together with a helper Ag, such as H-Y. The primed precursors obtained from these female mice generate Qa-1-specific CTL activity upon culture in vitro. Although the presence of the H-Y helper Ag is not required for the in vitro sensitization, no response occurs in the absence of CD4 cells. Addition of unprimed B6.Tlaa CD4 cells from Qa-1 incompatible radiation bone marrow chimeras (B6.Tlaa----B6), that are presumably tolerant to Qa-1b, provide helper activity for Qa-1b-specific CTL. This indicates that although CD4 cells are obligatory for the Qa-1 response, they need not be specific for alloantigens on the APC to generate helper activity in in vitro cultures. Addition of unirradiated B6 CD8-depleted spleen cells to CD4-depleted B6.Tlaa anti-B6 cultures in the presence of either B6.Tlaa CD4 cells or rIL-2 prevents the generation of Qa-1 specific CTL. This inhibition is not due to an anti-idiotypic Ts cell since B6.Tlaa----B6 chimeric cells do not suppress an anti-Qa-1b response. Rather, this finding is consistent with that of a veto cell mechanism. To determine whether CD4 cells themselves exhibit veto activity, highly purified CD4 populations were tested for their ability to inhibit the generation of Qa-1-specific CTL. CD4 cells precultured for 2 to 3 days with Con A and rIL-2 specifically inhibit CTL activity whereas resting cells do not, similar to that noted for CD8 veto cells. The relative efficiency of activated CD4 cells is greater than that of resting NK cells but is less than that of activated CD8 or NK cells. Thus, CD4 cells not only provide helper activity for CTL precursors, but also act as veto cells to prevent the generation of CTL activity.

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

PubMed

Livingston, Kimberly A; Jiang, Xiaowen; Stephensen, Charles B

2013-04-30

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 vaccination. Blood was drawn before, 3, 7, 14, and 28days after vaccination and peripheral blood mononuclear cells (PBMC) were cultured for 7days with TT, negative control (diluent), and a positive control (Staphylococcus enterotoxin B [SEB]). Activation markers (CD25 and CD69) were measured after 44h (n=8), cytokines in supernatant after 3 and 7days, and intracellular cytokine staining (ICS) of proliferated cells (identified by dye dilution) after 7days (n=6). Vaccination increased TT-specific expression of CD25 and CD69 on CD3(+)CD4(+) lymphocytes, and TT-specific proliferation at 7, 14 and 28days post vaccination. Vaccination induced TT-specific Th1 (IFN-γ, TNF-α, and IL-2) Th2 (IL-13, IL-5, and IL-4), Th17 (IL-17A) and IL-10(+) cells as measured by ICS. TT-specific Th1 cells were the most abundant (12-15% of all TT-specific CD4(+) T-cells) while IL10(+) (1.8%) Th17 (1.1%) and Th2 cells (0.2-0.6%) were less abundant. TT-specific cytokine concentrations in PBMC supernatants followed the same pattern where a TT-specific IL-9 response was also seen. In conclusion, TT booster vaccination induced a broad T-helper cell response. This method of evaluating cytokine phenotypes may be useful in examining the impact of nutrition and environmental conditions on the plasticity of T-helper cell memory responses. Published by Elsevier B.V.

The Roles of T Helper 1, T Helper 17 and Regulatory T Cells in the Pathogenesis of Sarcoidosis.

PubMed

Mortaz, Esmaeil; Rezayat, Fatemeh; Amani, Davar; Kiani, Arda; Garssen, Johan; Adcock, Ian M; Velayati, Aliakbar

2016-08-01

Sarcoidosis is a systemic granulomatous disorder of unidentified etiology, with a heterogeneous clinical presentation. It is characterized by a reduced delayed-type hypersensitivity to tuberculin and common antigens. The balance between Th1, Th17 and Regulatory T(Treg) cells controls T-cell proliferation and activation.The Th17/Treg ratio in the peripheral blood and bronchoalveolar lavage fluidis increased in patients with active sarcoidosis. Amplified IL-17A expression in granulomas and the presence of IL-17A+, IL-17A+IL-4+ and IL-17A+IFN-γ+ memory T helper cells in the circulation and BAL indicate Th17 cell involvement in granuloma induction and/or maintenance in sarcoidosis. Sarcoidosis should therefore be considered as a Th1/Th17 multisystem disorder and anti-IL-17/Th17 approaches that control and reduce IL-17Amay be an option, therefore, for the treatment of sarcoidosis.Here we provide a short overview as to the role of Th17 cells as critical cells in the pathogenesis of sarcoidosis.

Antigen-specific helper factors present in the supernatant of concanavalin A-induced spleen cell cultures.

PubMed

Kilburn, D G; Anaka, R

1981-08-01

The supernatants from cultures of concanavalin A-induced spleen cells contained both antigen-specific and nonspecific (Interleukin 2) helper factors (Hf). The antigen-specific factor could be isolated from the supernatant by adsorption onto and elution from antigen-Sepharose immunoadsorbents. Specific Hf was produced in cultures of either immune or nonimmune spleen cells although in the latter case the quantity of Hf was significantly less. The specific Hf did not manifest the thymocyte stimulatory property of 112.

Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions.

PubMed

Bauché, David; Marie, Julien C

2017-04-01

The relationship between host organisms and their microbiota has co-evolved towards an inter-dependent network of mutualistic interactions. This interplay is particularly well studied in the gastrointestinal tract, where microbiota and host immune cells can modulate each other directly, as well as indirectly, through the production and release of chemical molecules and signals. In this review, we define the functional impact of transforming growth factor-beta (TGF-β) on this complex interplay, especially through its modulation of the activity of local regulatory T cells (Tregs), type 17 helper (Th17) cells, innate lymphoid cells (ILCs) and B cells.

Noncoding RNAs: New Players in Pulmonary Medicine and Sarcoidosis.

PubMed

Salamo, Oriana; Mortaz, Esmaeil; Mirsaeidi, Mehdi

2018-02-01

Noncoding RNAs (ncRNAs) are coded by 98% of human genomic DNA. They are grouped into two major classes according to length: small ncRNAs and long ncRNAs. They regulate genome organization, stability, and physiological processes that maintain cellular homeostasis. Recently, great interest has emerged in ncRNAs because of their significant roles in the development of inflammatory diseases, including sarcoidosis. Some have been introduced as novel markers for disease activity, such as increased levels of microRNA-34a in peripheral blood mononuclear cells of patients with sarcoidosis, re-emphasizing the inflammatory component in sarcoidosis. They are also important factors in the outcome of sarcoidosis. Dysregulation of microRNA-let7f leads to overexpression of profibrotic factors and could be related to the pathogenesis of pulmonary fibrosis in patients with sarcoidosis, owing to their stimulatory effect on collagen expression and deposition. However, many unanswered questions remain about the association of ncRNAs and sarcoidosis. By understanding the functions of ncRNAs in T-helper cell type 1 and T-helper cell type 17, we may uncover the mechanism of action of those cells in sarcoidosis. Further translational research is needed to define the RNA gene fingerprint of different sarcoidosis stages.

A conversation across generations: soma-germ cell crosstalk in plants.

PubMed

Feng, Xiaoqi; Zilberman, Daniel; Dickinson, Hugh

2013-02-11

Plants undergo alternation of generation in which reproductive cells develop in the plant body ("sporophytic generation") and then differentiate into a multicellular gamete-forming "gametophytic generation." Different populations of helper cells assist in this transgenerational journey, with somatic tissues supporting early development and single nurse cells supporting gametogenesis. New data reveal a two-way relationship between early reproductive cells and their helpers involving complex epigenetic and signaling networks determining cell number and fate. Later, the egg cell plays a central role in specifying accessory cells, whereas in both gametophytes, companion cells contribute non-cell-autonomously to the epigenetic landscape of the gamete genomes. Copyright © 2013 Elsevier Inc. All rights reserved.

Transcriptional Regulation of Th17 Cell Differentiation

PubMed Central

Ivanov, Ivaylo I.; Zhou, Liang; Littman, Dan R.

2009-01-01

The paradigm of effector T helper cell differentiation into either Th1 or Th2 lineages has been profoundly shaken by the discovery of T cells that secrete IL-17 and other inflammatory cytokines. This subset, referred to as Th17, is centrally involved in autoimmune disease and is important in host defense at mucosal surfaces. In mouse, a series of cytokines, including IL-6, IL-21, IL-23, and TGF-β, function sequentially or synergistically to induce the Th17 lineage. Other cytokines, including IL-2, IL-4, IFNγ, and IL-27, inhibit differentiation of this lineage. Here we review how the nuclear orphan receptor RORγt functions to coordinate the diverse cytokine-induced signals and thus control Th17 cell differentiation. PMID:18053739

Innate scavenger receptor-A regulates adaptive T helper cell responses to pathogen infection

PubMed Central

Xu, Zhipeng; Xu, Lei; Li, Wei; Jin, Xin; Song, Xian; Chen, Xiaojun; Zhu, Jifeng; Zhou, Sha; Li, Yong; Zhang, Weiwei; Dong, Xiaoxiao; Yang, Xiaowei; Liu, Feng; Bai, Hui; Chen, Qi; Su, Chuan

2017-01-01

The pattern recognition receptor (PRR) scavenger receptor class A (SR-A) has an important function in the pathogenesis of non-infectious diseases and in innate immune responses to pathogen infections. However, little is known about the role of SR-A in the host adaptive immune responses to pathogen infection. Here we show with mouse models of helminth Schistosoma japonicum infection and heat-inactivated Mycobacterium tuberculosis stimulation that SR-A is regulated by pathogens and suppresses IRF5 nuclear translocation by direct interaction. Reduced abundance of nuclear IRF5 shifts macrophage polarization from M1 towards M2, which subsequently switches T-helper responses from type 1 to type 2. Our study identifies a role for SR-A as an innate PRR in regulating adaptive immune responses. PMID:28695899

Higher Frequency of CD4+CXCR5+ICOS+PD1+ T Follicular Helper Cells in Patients With Infectious Mononucleosis.

PubMed

Liu, Jinlin; Zhou, Yonglie; Yu, Qinghua; Zhao, Zhao; Wang, Huan; Luo, Xiaoming; Chen, Yanxia; Zhu, Zhongliang; Chen, Guoqing; Wu, Mao; Qiu, Liannv

2015-11-01

Follicular helper T (Tfh) cells are recognized as a distinct CD4helper T cell subset, and mainly dysregulated in the autoimmune disease, whether it plays a role in the infectious mononucleosis (IM) diseases is unknown. In this study, we found that the CD4CXCR5 Tfh cells were not significantly changed, but the CD4CXCR5ICOS and CD4CXCR5ICOSPD1 Tfh subsets were significantly increased in the IM patients, and all these cells were significantly changed after antiviral therapy. Second, only the numbers of CD4CXCR5ICOSPD1 Tfh cells correlated with the Epstein-Barr virus (EBV) DNA load, negatively correlated with the numbers of naive B cells and amount of IL-21, and positively correlated with the numbers of plasma cells, memory B cells, and atypical lymphocytes. Third, the frequency of CD4CXCR5ICOSPD1 Tfh subset was significantly higher in lymphadenectasis or hepatosplenomegaly patients, and associated with the level of alanine aminotransferase (ALT). All together, our findings discovered this CD4CXCR5ICOSPD1 Tfh cell subset might play an important role in the pathogenesis of IM.

Determination of P-glycoprotein surface expression and functional ability after in vitro treatment with darunavir or raltegravir in lymphocytes of healthy donors.

PubMed

Tempestilli, Massimo; Gentilotti, Elisa; Tommasi, Chiara; Nicastri, Emanuele; Martini, Federico; De Nardo, Pasquale; Narciso, Pasquale; Pucillo, Leopoldo P

2013-08-01

It has been shown that P-glycoprotein (P-gp) can greatly affect the cell uptake of antiretroviral drugs, thus hampering their access to HIV-1 replication sites. Lymphocytes are important sites of replication of HIV and target of other drugs, modification on these cells of P-gp could have an effect on pharmacokinetic of antiretrovirals and drug substrates. Blood samples from 16 healthy volunteers were used to determine the expression of P-gp on total, T and T helper lymphocytes after exposure to darunavir, a second generation protease inhibitor, and raltegravir, the first approved integrase inhibitor. Moreover, the effect of the drugs on P-gp functional activity was also studied by the rhodamine-123 efflux test. Darunavir, but not raltegravir, exposure caused a moderate, dose-dependent increment in P-gp expression in total, T and T helper lymphocytes, as demonstrated by the relative frequency of P-gp+ cells and by the amount of P-gp molecules present on cell surface. Functionally, incubation with darunavir led to a marked inhibition of P-gp activity measured by the efflux of rhodamine-123 similar to that observed by verapamil, a specific P-gp inhibitor. Raltegravir was not able to modify the efflux of rhodamine-123 level. Data show that darunavir, unlike raltegravir, may modify the expression and functionality of P-gp on human lymphocytes, thus leading to potential changes in intracellular concentrations of darunavir in patients treated with other drugs substrate of P-gp and vice versa. Our study highlights the need for studies on drug interactions via the P-gp modulation mechanism, especially with the current multi-drug regimens. Copyright © 2013 Elsevier B.V. All rights reserved.

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

The Multifaceted Role of T-Helper Responses in Host Defense against Aspergillus fumigatus.

PubMed

Dewi, Intan M W; van de Veerdonk, Frank L; Gresnigt, Mark S

2017-10-04

The ubiquitous opportunistic fungal pathogen Aspergillus fumigatus rarely causes infections in immunocompetent individuals. A healthy functional innate immune system plays a crucial role in preventing Aspergillus -infection. This pivotal role for the innate immune system makes it a main research focus in studying the pathogenesis of aspergillosis. Although sometimes overshadowed by the innate immune response, the adaptive immune response, and in particular T-helper responses, also represents a key player in host defense against Aspergillus . Virtually all T-helper subsets have been described to play a role during aspergillosis, with the Th1 response being crucial for fungal clearance. However; morbidity and mortality of aspergillosis can also be partly attributed to detrimental immune responses resulting from adaptive immune activation. Th2 responses benefit fungal persistence; and are the foundation of allergic forms of aspergillosis. The Th17 response has two sides; although crucial for granulocyte recruitment, it can be involved in detrimental immunopathology. Regulatory T-cells, the endogenous regulators of inflammatory responses, play a key role in controlling detrimental inflammatory responses during aspergillosis. The current knowledge of the adaptive immune response against A. fumigatus is summarized in this review. A better understanding on how T-helper responses facilitate clearance of Aspergillus -infection and control inflammation can be the fundamental basis for understanding the pathogenesis of aspergillosis and for the development of novel host-directed therapies.

Pathological and therapeutic roles of innate lymphoid cells in diverse diseases.

PubMed

Kim, Jisu; Kim, Geon; Min, Hyeyoung

2017-11-01

Innate lymphoid cells (ILCs) are a recently defined type of innate-immunity cells that belong to the lymphoid lineage and have lymphoid morphology but do not express an antigen-specific B cell or T-cell receptor. ILCs regulate immune functions prior to the formation of adaptive immunity and exert effector functions through a cytokine release. ILCs have been classified into three groups according to the transcription factors that regulate their development and function and the effector cytokines they produce. Of note, ILCs resemble T helper (Th) cells, such as Th1, Th2, and Th17 cells, and show a similar dependence on transcription factors and distinct cytokine production. Despite their short history in immunology, ILCs have received much attention, and numerous studies have revealed biological functions of ILCs including host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. Here, we describe recent findings about the roles of ILCs in the pathogenesis of various diseases and potential therapeutic targets.

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.

miR-155 deficiency protects mice from experimental colitis by reducing T helper type 1/type 17 responses

PubMed Central

Singh, Udai P; Murphy, Angela E; Enos, Reilly T; Shamran, Haidar A; Singh, Narendra P; Guan, Honbing; Hegde, Venkatesh L; Fan, Daping; Price, Robert L; Taub, Dennis D; Mishra, Manoj K; Nagarkatti, Mitzi; Nagarkatti, Prakash S

2014-01-01

Inflammatory bowel disease (IBD), a chronic intestinal inflammatory condition that affects millions of people worldwide, results in high morbidity and exorbitant health-care costs. The critical features of both innate and adaptive immunity are to control inflammation and dysfunction in this equilibrium is believed to be the reason for the development of IBD. miR-155, a microRNA, is up-regulated in various inflammatory disease states, including IBD, and is a positive regulator of T-cell responses. To date, no reports have defined a function for miR-155 with regard to cellular responses in IBD. Using an acute experimental colitis model, we found that miR-155−/− mice, as compared to wild-type control mice, have decreased clinical scores, a reversal of colitis-associated pathogenesis, and reduced systemic and mucosal inflammatory cytokines. The increased frequency of CD4+ lymphocytes in the spleen and lamina propria with dextran sodium sulphate induction was decreased in miR-155−/− mice. Similarly, miR-155 deficiency abrogated the increased numbers of interferon-γ expressing CD4+ T cells typically observed in wild-type mice in this model. The frequency of systemic and mucosal T helper type 17-, CCR9-expressing CD4+ T cells was also reduced in miR-155−/− mice compared with control mice. These findings strongly support a role for miR-155 in facilitating pro-inflammatory cellular responses in this model of IBD. Loss of miR-155 also results in decreases in T helper type 1/type 17, CD11b+, and CD11c+ cells, which correlated with reduced clinical scores and severity of disease. miR-155 may serve as a potential therapeutic target for the treatment of IBD. PMID:24891206

Developmental origins of inflammatory and immune diseases

PubMed Central

Chen, Ting; Liu, Han-xiao; Yan, Hui-yi; Wu, Dong-mei; Ping, Jie

2016-01-01

Epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exert a profound influence on physiological function and risk of diseases in adult life. The concepts of the ‘developmental programming’ and Developmental Origins of Health and Diseases (DOHaD) have become well accepted and have been applied across almost all fields of medicine. Adverse intrauterine environments may have programming effects on the crucial functions of the immune system during critical periods of fetal development, which can permanently alter the immune function of offspring. Immune dysfunction may in turn lead offspring to be susceptible to inflammatory and immune diseases in adulthood. These facts suggest that inflammatory and immune disorders might have developmental origins. In recent years, inflammatory and immune disorders have become a growing health problem worldwide. However, there is no systematic report in the literature on the developmental origins of inflammatory and immune diseases and the potential mechanisms involved. Here, we review the impacts of adverse intrauterine environments on the immune function in offspring. This review shows the results from human and different animal species and highlights the underlying mechanisms, including damaged development of cells in the thymus, helper T cell 1/helper T cell 2 balance disturbance, abnormal epigenetic modification, effects of maternal glucocorticoid overexposure on fetal lymphocytes and effects of the fetal hypothalamic–pituitary–adrenal axis on the immune system. Although the phenomena have already been clearly implicated in epidemiologic and experimental studies, new studies investigating the mechanisms of these effects may provide new avenues for exploiting these pathways for disease prevention. PMID:27226490

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.

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.

Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis.

PubMed

Singh, Brijendra; Kasam, Rajesh K; Sontake, Vishwaraj; Wynn, Thomas A; Madala, Satish K

2017-11-01

IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.

Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems.

PubMed

Okamoto, Kazuo; Nakashima, Tomoki; Shinohara, Masahiro; Negishi-Koga, Takako; Komatsu, Noriko; Terashima, Asuka; Sawa, Shinichiro; Nitta, Takeshi; Takayanagi, Hiroshi

2017-10-01

The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system. Copyright © 2017 the American Physiological Society.

Characterization of the gag/fusion protein encoded by the defective Duplan retrovirus inducing murine acquired immunodeficiency syndrome.

PubMed Central

Huang, M; Jolicoeur, P

1990-01-01

Murine acquired immunodeficiency syndrome is induced by a defective retrovirus. Sequencing of this defective viral genome revealed a long open reading frame which encodes a putative gag/fusion protein, N-MA-p12-CA-NC-COOH, (D. C. Aziz, Z. Hanna, and P. Jolicoeur, Nature (London) 338:505-508, 1989). We raised a specific antibody to the unique p12 domain of this gag fusion precursor, Pr60gag. We found that Pr60gag was indeed encoded by the defective viral genome both in cell-free translation reticulocyte extracts and in infected mouse fibroblasts. Pr60gag was found to be myristylated, phosphorylated, and attached to the cell membrane, like other helper murine leukemia virus (MuLV) gag precursors. Pr60gag was not substantially cleaved within the nonproducer cells and was not released from these cells. However, in the presence of helper MuLV proteins, it formed phenotypically mixed particles. In these particles, Pr60gag was only partially cleaved. In helper MuLV-producing cells harboring the defective virus, a gag-related p40 intermediate was generated both intracellularly and extracellularly. In these cells, Pr60gag appeared to behave as a dominant negative mutant, interfering with proper cleavage of helper Pr65gag. Our data indicate that Pr60gag is a major (and possibly the only) gene product of the defective murine acquired immunodeficiency syndrome virus and is likely to harbor some determinants of pathogenicity of this virus. Images PMID:2243376

Multipronged CD4 T cell effector and memory responses cooperate to provide potent immunity against respiratory virus

PubMed Central

Strutt, Tara M.; McKinstry, K. Kai; Marshall, Nikki B.; Vong, Allen M.; Dutton, Richard W.; Swain, Susan L.

2014-01-01

Summary Over the last decade, the known spectrum of CD4 T cell effect or subsets has become much broader and it has become clear that there are multiple dimensions by which subsets with a particular cytokine commitment can be further defined, including their stage of differentiation, their location and most importantly, their ability to carryout discrete functions. Here we focus on our studies that highlight the synergy among discrete subsets, especially those defined by helper and cytotoxic function, in mediating viral protection and on distinctions between CD4 T cell effectors located in spleen, draining lymph node, and in tissue sites of infection. What emerges is a surprising multiplicity of CD4 T cell functions that indicate a large arsenal of mechanisms by which CD4 T cells act to combat viruses. PMID:23947353

Interleukin-18 and CD30 serum levels in patients with moderate-severe depression.

PubMed Central

Merendino, Rosaria Alba; Di Rosa, Antonio Enrico; Di Pasquale, Giuseppe; Minciullo, Paola Lucia; Mangraviti, Carmela; Costantino, Antonella; Ruello, Antonella; Gangemi, Sebastiano

2002-01-01

Interleukin-18 (IL-18), a pro-inflammatory cytokine that plays an important role in the T-cell-helper type 1 response, is a new member of the family of cytokines produced in the brain. CD30 is a marker of T-cell-helper type 2 lymphocytes. We evaluated IL-18 and CD30 serum levels in 10 patients affected by moderate-severe depression (MSD). We demonstrated for the first time that serum IL-18 levels of MSD patients were significantly higher than those of healthy donors. On the contrary, no significant difference was found between serum CD30 levels of MSD patients compared with those of healthy donors. These data strengthen the hypothesis that MSD disease is associated with an inflammatory response, mainly T-cell-helper type 1, and suggest an important role for IL-18 in the pathophysiology of MSD. PMID:12396479

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation

PubMed Central

Chen, Chen; Zhou, Yifan; Wang, Jingqi; Yan, Yaping; Peng, Lisheng; Qiu, Wei

2018-01-01

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Growing evidence has proven that T helper 17 (Th17) cells are one of the regulators of neuroinflammation mechanisms in MS disease. Researchers have demonstrated that some microRNAs (miRNAs) are associated with disease activity and duration, even with different MS patterns. miRNAs regulate CD4+ T cells to differentiate toward various T cell subtypes including Th17 cells. In this review, we discuss the possible mechanisms of miRNAs in MS pathophysiology by regulating CD4+ T cell differentiation into Th17 cells, and potential miRNA targets for current disease-modifying treatments.

Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells

PubMed Central

Muraro, Elena; Merlo, Anna; Martorelli, Debora; Cangemi, Michela; Dalla Santa, Silvia; Dolcetti, Riccardo; Rosato, Antonio

2017-01-01

CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors. PMID:28289418

Innate Functions of Immunoglobulin M Lessen Liver Gene Transfer with Helper-Dependent Adenovirus

PubMed Central

Unzu, Carmen; Morales-Kastresana, Aizea; Sampedro, Ana; Serrano-Mendioroz, Irantzu; Azpilikueta, Arantza; Ochoa, María Carmen; Dubrot, Juan; Martínez-Ansó, Eduardo

2014-01-01

The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell-deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-naïve WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-naïve mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors. PMID:24465560

Use of total lymphoid irradiation (TLI) in studies of the T cell dependence of autoantibody production in rheumatoid arthritis

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

Tanay, A.; Strober, S.; Logue, G.L.

1984-02-01

The effect of total lymphoid irradiation (TLI) on T cell-dependent and -independent humoral immune responses was studied in patients with intractable rheumatoid arthritis (RA). The serum levels of several autoantibodies and of antibodies to diphtheria (DT) and tetanus (TT) toxoids and to pneumococcal polysaccharide (PPS; 12 antigenic types) were studied before and after TLI. In addition, the patients were given a booster injection of DT and TT and a single injection of pneumococcal vaccine after radiotherapy. Antibody levels to DT and TT decreased about twofold after TLI and did not rise significantly after a booster injection. However, there was nomore » reduction in antibody levels to PPS after TLI, and a significant rise in titers was observed after a single vaccination. The serum levels of rheumatoid factor (RF), anti-nuclear antibody (ANA), and granulocyte associated IgG rose slightly after TLI. Thus, the autoantibodies and antibodies to polysaccharides appear to be relatively independent of helper T cell function, which is markedly reduced after TLI. On the other hand, antibodies to protein antigens such as DT and TT appear to be more closely dependent upon T helper function in man, as has been reported in rodents. The findings suggest that T cell-independent autoantibody responses alone do not maintain the joint disease activity in RA, because improvement in joint disease after TLI has been reported.« less

CD1d-restricted immunoglobulin G formation to GPI-anchored antigens mediated by NKT cells.

PubMed

Schofield, L; McConville, M J; Hansen, D; Campbell, A S; Fraser-Reid, B; Grusby, M J; Tachado, S D

1999-01-08

Immunoglobulin G (IgG) responses require major histocompatibility complex (MHC)-restricted recognition of peptide fragments by conventional CD4(+) helper T cells. Immunoglobulin G responses to glycosylphosphatidylinositol (GPI)- anchored protein antigens, however, were found to be regulated in part through CD1d-restricted recognition of the GPI moiety by thymus-dependent, interleukin-4-producing CD4(+), natural killer cell antigen 1.1 [(NK1.1)+] helper T cells. The CD1-NKT cell pathway regulated immunogobulin G responses to the GPI-anchored surface antigens of Plasmodium and Trypanosoma and may be a general mechanism for rapid, MHC-unrestricted antibody responses to diverse pathogens.

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

Saponins from soy bean and mung bean inhibit the antigen specific activation of helper T cells by blocking cell cycle progression.

PubMed

Lee, Suk Jun; Bae, Joonbeom; Kim, Sunhee; Jeong, Seonah; Choi, Chang-Yong; Choi, Sang-Pil; Kim, Hyun-Sook; Jung, Woon-Won; Imm, Jee-Young; Kim, Sae Hun; Chun, Taehoon

2013-02-01

Treatment of helper T (Th) cells with saponins from soy bean and mung bean prevented their activation by inhibiting cell proliferation and cytokine secretion. However, the saponins did not affect the expression of major histocompatibility complex class II (A(b)) and co-stimulatory molecule (CD86) on professional antigen-presenting cells. Instead, the saponins directly inhibited Th cell proliferation by blocking the G(1) to S phase cell cycle transition. Moreover, blocking of the cell cycle by the saponins was achieved by decreased expression of cyclin D1 and cyclin E, and constitutive expression of p27(KIP1). Saponins also increased stability of p27(KIP1) in Th cells after antigenic stimulation.

Isolation of Human Innate Lymphoid Cells.

PubMed

Krabbendam, Lisette; Nagasawa, Maho; Spits, Hergen; Bal, Suzanne M

2018-06-29

Innate lymphoid cells (ILCs) are innate immune cells of lymphoid origin that have important effector and regulatory functions in the first line of defense against pathogens, but also regulate tissue homeostasis, remodeling, and repair. Their function mirrors T helper cells and cytotoxic CD8 + T lymphocytes, but they lack expression of rearranged antigen-specific receptors. Distinct ILC subsets are classified in group 1 ILCs (ILC1s), group 2 ILCs (ILC2s), and group 3 ILCs (ILC3s and lymphoid tissue-inducer cells), based on the expression of transcription factors and the cytokines they produce. As the frequency of ILCs is low, their isolation requires extensive depletion of other cell types. The lack of unique cell surface antigens further complicates the identification of these cells. Here, methods for ILC isolation and characterization from human peripheral blood and different tissues are described. © 2018 by John Wiley & Sons, Inc. © 2018 John Wiley & Sons, Inc.

Lymphocyte Subsets and Interleukin-2 Receptors in Autistic Children.

ERIC Educational Resources Information Center

Denney, Douglas R.; And Others

1996-01-01

Blood samples were obtained from 10 male autistic children, ages 7-15 years, and 10 controls. The children with autism had a lower percentage of helper-inducer cells and a lower helper:suppressor ratio, with both measures inversely related to the severity of autistic symptoms. (Author/DB)

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.

Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies.

PubMed

Viisanen, Tyyne; Ihantola, Emmi-Leena; Näntö-Salonen, Kirsti; Hyöty, Heikki; Nurminen, Noora; Selvenius, Jenni; Juutilainen, Auni; Moilanen, Leena; Pihlajamäki, Jussi; Veijola, Riitta; Toppari, Jorma; Knip, Mikael; Ilonen, Jorma; Kinnunen, Tuure

2017-02-01

Although type 1 diabetes (T1D) is primarily perceived as a T cell-driven autoimmune disease, islet autoantibodies are the best currently available biomarker for autoimmunity and disease risk. These antibodies are produced by autoreactive B cells, the activation of which is largely dependent on the function of CD4 + CXCR5 + follicular T helper cells (Tfh). In this study, we have comprehensively characterized the Tfh- as well as B-cell compartments in a large cohort of children with newly diagnosed T1D or at different stages of preclinical T1D. We demonstrate that the frequency of CXCR5 + PD-1 + ICOS + -activated circulating Tfh cells is increased both in children with newly diagnosed T1D and in autoantibody-positive at-risk children with impaired glucose tolerance. Interestingly, this increase was only evident in children positive for two or more biochemical autoantibodies. No alterations in the circulating B-cell compartment were observed in children with either prediabetes or diabetes. Our results demonstrate that Tfh activation is detectable in the peripheral blood close to the presentation of clinical T1D but only in a subgroup of children identifiable by positivity for multiple autoantibodies. These findings suggest a role for Tfh cells in the pathogenesis of human T1D and carry important implications for targeting Tfh cells and/or B cells therapeutically. © 2017 by the American Diabetes Association.

Higher Frequency of CD4+CXCR5+ICOS+PD1+ T Follicular Helper Cells in Patients With Infectious Mononucleosis

PubMed Central

Liu, Jinlin; Zhou, Yonglie; Yu, Qinghua; Zhao, Zhao; Wang, Huan; Luo, Xiaoming; Chen, Yanxia; Zhu, Zhongliang; Chen, Guoqing; Wu, Mao; Qiu, Liannv

2015-01-01

Abstract Follicular helper T (Tfh) cells are recognized as a distinct CD4+helper T cell subset, and mainly dysregulated in the autoimmune disease, whether it plays a role in the infectious mononucleosis (IM) diseases is unknown. In this study, we found that the CD4+CXCR5+ Tfh cells were not significantly changed, but the CD4+CXCR5+ICOS+ and CD4+CXCR5+ICOS+PD1+ Tfh subsets were significantly increased in the IM patients, and all these cells were significantly changed after antiviral therapy. Second, only the numbers of CD4+CXCR5+ICOS+PD1+ Tfh cells correlated with the Epstein-Barr virus (EBV) DNA load, negatively correlated with the numbers of naive B cells and amount of IL-21, and positively correlated with the numbers of plasma cells, memory B cells, and atypical lymphocytes. Third, the frequency of CD4+CXCR5+ICOS+PD1+ Tfh subset was significantly higher in lymphadenectasis or hepatosplenomegaly patients, and associated with the level of alanine aminotransferase (ALT). All together, our findings discovered this CD4+CXCR5+ICOS+PD1+ Tfh cell subset might play an important role in the pathogenesis of IM. PMID:26559315

An in vitro study of functional maturation of murine thymus cells.

PubMed

Chakravarty, A K

1977-05-26

Critical time of onset of thymus cell functions in ontogeny was studied in vitro. Collaborative function in an antibody response and ability to induce a graft-versus-host (GvH) response by murine thymocytes from different stages of ontogeny were investigated. Thymocytes from as early as 16-day mouse embryos were capable of collaborating in the antibody response to sheep-erythrocyte-antigen in vitro following 24 h of pretreatment with concanavalin A (con A). By contrast, maturation of thymus cell function as measured by competence to induce a graft-versus-host reaction, was first manifested by newborn thymus cells, and pretreatment with con A did not facilitate the maturation of this thymus cell function. Experiments to understand the effect of con A on the expression of cell surface antigens have also been reported. Con A-treated thymus cells of different ontogenic stages tested were less susceptible to killing by anti-theta serum than nontreated thymus cells; reverse was true with anti-H-2 serum. The significance of the differential susceptibility of con A-treated thymus cells to anti-sera treatment and the finding that mouse thymocytes can provide helper function as early as the 16th day of gestation have been discussed.

Enteric pathogens and gut function: Role of cytokines and STATs.

PubMed

Shea-Donohue, Terez; Fasano, Alessio; Smith, Allen; Zhao, Aiping

2010-09-01

The gut harbors the largest immune system in the body. The mucosa is considered to be the initial site of interaction with commensal and pathogenic organisms; therefore, it is the first line of defense against the pathogens. In response to the invasion of various pathogens, naïve CD4(+) cells differentiate into subsets of T helper (Th) cells that are characterized by different cytokine profiles. Cytokines bind to cell surface receptors on both immune and non-immune cells leading to activation of JAK-STAT signaling pathway and influence gut function by upregulating the expression of specific target genes. This review considers the roles of cytokines and receptor-mediated activation of STATs on pathogen-induced changes in gut function. The focus on STAT4 and STAT6 is because of their requirement for the full development of Th1 and Th2 cytokine profiles.

Enteric pathogens and gut function: Role of cytokines and STATs

PubMed Central

Fasano, Alessio; Smith, Allen; Zhao, Aiping

2010-01-01

The gut harbors the largest immune system in the body. The mucosa is considered to be the initial site of interaction with commensal and pathogenic organisms; therefore, it is the first line of defense against the pathogens. In response to the invasion of various pathogens, naïve CD4+ cells differentiate into subsets of T helper (Th) cells that are characterized by different cytokine profiles. Cytokines bind to cell surface receptors on both immune and non-immune cells leading to activation of JAK-STAT signaling pathway and influence gut function by upregulating the expression of specific target genes. This review considers the roles of cytokines and receptor-mediated activation of STATs on pathogen-induced changes in gut function. The focus on STAT4 and STAT6 is because of their requirement for the full development of Th1 and Th2 cytokine profiles. PMID:21327040

NBR1 is a new PB1 signalling adapter in Th2 differentiation and allergic airway inflammation in vivo

PubMed Central

Yang, Jun-Qi; Liu, Hongzhu; Diaz-Meco, Maria T; Moscat, Jorge

2010-01-01

Allergic airway inflammation is a disease in which T helper 2 (Th2) cells have a critical function. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. Recently, a network of PB1-containing adapters and kinases has been shown to be essential in this process owing to its function in regulating cell polarity and the activation of critical transcription factors. Here, we show in vivo data showing that T-cell-specific NBR1-deficient mice show impaired lung inflammation and have defective Th2 differentiation ex vivo with alterations in T-cell polarity and the selective inhibition of Gata3 and nuclear factor of activated T c1 activation. These results establish NBR1 as a novel PB1 adapter in Th2 differentiation and asthma. PMID:20808283

Humanized mouse model for assessing the human immune response to xenogeneic and allogeneic decellularized biomaterials.

PubMed

Wang, Raymond M; Johnson, Todd D; He, Jingjin; Rong, Zhili; Wong, Michelle; Nigam, Vishal; Behfar, Atta; Xu, Yang; Christman, Karen L

2017-06-01

Current assessment of biomaterial biocompatibility is typically implemented in wild type rodent models. Unfortunately, different characteristics of the immune systems in rodents versus humans limit the capability of these models to mimic the human immune response to naturally derived biomaterials. Here we investigated the utility of humanized mice as an improved model for testing naturally derived biomaterials. Two injectable hydrogels derived from decellularized porcine or human cadaveric myocardium were compared. Three days and one week after subcutaneous injection, the hydrogels were analyzed for early and mid-phase immune responses, respectively. Immune cells in the humanized mouse model, particularly T-helper cells, responded distinctly between the xenogeneic and allogeneic biomaterials. The allogeneic extracellular matrix derived hydrogels elicited significantly reduced total, human specific, and CD4 + T-helper cell infiltration in humanized mice compared to xenogeneic extracellular matrix hydrogels, which was not recapitulated in wild type mice. T-helper cells, in response to the allogeneic hydrogel material, were also less polarized towards a pro-remodeling Th2 phenotype compared to xenogeneic extracellular matrix hydrogels in humanized mice. In both models, both biomaterials induced the infiltration of macrophages polarized towards a M2 phenotype and T-helper cells polarized towards a Th2 phenotype. In conclusion, these studies showed the importance of testing naturally derived biomaterials in immune competent animals and the potential of utilizing this humanized mouse model for further studying human immune cell responses to biomaterials in an in vivo environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers

PubMed Central

Tsytsykova, Alla V.; Rajsbaum, Ricardo; Falvo, James V.; Ligeiro, Filipa; Neely, Simon R.; Goldfeld, Anne E.

2007-01-01

Here we provide a mechanism for specific, efficient transcription of the TNF gene and, potentially, other genes residing within multigene loci. We identify and characterize highly conserved noncoding elements flanking the TNF gene, which undergo activation-dependent intrachromosomal interactions. These elements, hypersensitive site (HSS)−9 and HSS+3 (9 kb upstream and 3 kb downstream of the TNF gene, respectively), contain DNase I hypersensitive sites in naive, T helper 1, and T helper 2 primary T cells. Both HSS-9 and HSS+3 inducibly associate with acetylated histones, indicative of chromatin remodeling, bind the transcription factor nuclear factor of activated T cells (NFAT)p in vitro and in vivo, and function as enhancers of NFAT-dependent transactivation mediated by the TNF promoter. Using the chromosome conformation capture assay, we demonstrate that upon T cell activation intrachromosomal looping occurs in the TNF locus. HSS-9 and HSS+3 each associate with the TNF promoter and with each other, circularizing the TNF gene and bringing NFAT-containing nucleoprotein complexes into close proximity. TNF gene regulation thus reveals a mode of intrachromosomal interaction that combines a looped gene topology with interactions between enhancers and a gene promoter. PMID:17940009

Cyclic AMP-induced Chromatin Changes Support the NFATc-mediated Recruitment of GATA-3 to the Interleukin 5 Promoter*

PubMed Central

Klein-Hessling, Stefan; Bopp, Tobias; Jha, Mithilesh K.; Schmidt, Arthur; Miyatake, Shoichiro; Schmitt, Edgar; Serfling, Edgar

2008-01-01

Elevated intracellular cyclic AMP levels, which suppress the proliferation of naive T cells and type 1 T helper (Th1) cells are a property of T helper 2 (Th2) cells and regulatory T cells. While cyclic AMP signals interfere with the IL-2 promoter induction, they support the induction of Th2-type genes, in particular of il-5 gene. We show here that cyclic AMP signals support the generation of three inducible DNase I hypersensitive chromatin sites over the il-5 locus, including its promoter region. In addition, cyclic AMP signals enhance histone H3 acetylation at the IL-5 promoter and the concerted binding of GATA-3 and NFATc to the promoter. This is facilitated by direct protein-protein interactions involving the C-terminal Zn2+-finger of GATA-3 and the C-terminal region of the NFATc1 DNA binding domain. Because inhibition of NFATc binding to the IL-5 promoter in vivo also affects the binding of GATA-3, one may conclude that upon induction of Th2 effector cells NFATc recruits GATA-3 to Th2-type genes. These data demonstrate the functional importance of cyclic AMP signals for the interplay between GATA-3 and NFATc factors in the transcriptional control of lymphokine expression in Th2 effector cells. PMID:18772129

Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3.

PubMed

Lee, Seon-Yeong; Moon, Su-Jin; Kim, Eun-Kyung; Seo, Hyeon-Beom; Yang, Eun-Ji; Son, Hye-Jin; Kim, Jae-Kyung; Min, Jun-Ki; Park, Sung-Hwan; Cho, Mi-La

2017-04-01

Circulating autoantibodies and immune complex deposition are pathological hallmarks of systemic lupus erythematosus (SLE). B cell differentiation into plasma cells (PCs) and some T cell subsets that function as B cell helpers can be therapeutic targets of SLE. Mechanistic target of rapamycin (mTOR) signaling is implicated in the formation of B cells and germinal centers (GCs). We assessed the effect of metformin, which inhibits mTOR, on the development of autoimmunity using Roquin san/san mice. Oral administration of metformin inhibited the formation of splenic follicles and inflammation in kidney and liver tissues. It also decreased serum levels of anti-dsDNA Abs without affecting serum glucose levels. Moreover, metformin inhibited CD21 high CD23 low marginal zone B cells, B220 + GL7 + GC B cells, B220 - CD138 + PCs, and GC formation. A significant reduction in ICOS + follicular helper T cells was found in the spleens of the metformin-treated group compared with the vehicle-treated group. In addition, metformin inhibited Th17 cells and induced regulatory T cells. These alterations in B and T cell subsets by metformin were associated with enhanced AMPK expression and inhibition of mTOR-STAT3 signaling. Furthermore, metformin induced p53 and NF erythroid-2-related factor-2 activity in splenic CD4 + T cells. Taken together, metformin-induced alterations in AMPK-mTOR-STAT3 signaling may have therapeutic value in SLE by inhibiting B cell differentiation into PCs and GCs. Copyright © 2017 by The American Association of Immunologists, Inc.

Peripheral leukocyte subpopulations and catecholamine levels in astronauts as a function of mission duration

NASA Technical Reports Server (NTRS)

Mills, P. J.; Meck, J. V.; Waters, W. W.; D'Aunno, D.; Ziegler, M. G.

2001-01-01

OBJECTIVE: The objective of this study was to determine the effects of spaceflight duration on immune cells and their relationship to catecholamine levels. METHODS: Eleven astronauts who flew aboard five different US Space Shuttle flights ranging in duration from 4 to 16 days were studied before launch and after landing. RESULTS: Consistent with prior studies, spaceflight was associated with a significant increase in the number of circulating white blood cells (p <.01), including neutrophils (p <.01), monocytes (p <.05), CD3+CD4+ T-helper cells (p <.05), and CD19+ B cells (p <.01). In contrast, the number of CD3-CD16+56+ natural killer cells was decreased (p <.01). Plasma norepinephrine levels were increased at landing (p <.01) and were significantly correlated with the number of white blood cells (p <.01), neutrophils (p <.01), monocytes (p <.01), and B cells (p <.01). Astronauts who were in space for approximately 1 week showed a significantly larger increase on landing in plasma norepinephrine (p =.02) and epinephrine (p =.03) levels, as well as number of circulating CD3+CD4+ T-helper cells (p <.05) and CD3+CD8+ T-cytotoxic cells (p <.05) as compared with astronauts in space for approximately 2 weeks. CONCLUSIONS: The data suggest that the stress of spaceflight and landing may lead to a sympathetic nervous system-mediated redistribution of circulating leukocytes, an effect potentially attenuated after longer missions.

Depressed primary in vitro antibody response in untreated systemic lupus erythematosus. T helper cell defect and lack of defective suppressor cell function.

PubMed Central

Delfraissy, J F; Segond, P; Galanaud, P; Wallon, C; Massias, P; Dormont, J

1980-01-01

The in vitro antibody response of peripheral blood lymphocytes (PBL) from 19 patients with untreated systemic lupus erythematosus (SLE) was compared with that of 20 control patients and 44 normal subjects. Trinitrophenyl polyacrylamide beads (TNP-PAA) were used to induce IgM anti-TNP plaque-forming cells. SLE patients displayed a markedly depressed, and in most instances virtually absent, response. This was not due to an unusual kinetics of the response; nor could it be induced by preincubation of SLE patients' PBL. In co-cultures of SLE patients and normal PBL, the former, with few exceptions, did not exert a suppressive effect. In four patients the anti-TNP response of either unfractionated or T-depleted SLE PBL could be restored by T cells from a normal individual. Conversely in three of these patients, SLE T cells could not support the response of normal B cells, suggesting a T helper cell defect in SLE PBL. Concanavalin A (Con A)-induced suppressor cells of the antibody response could be assayed by two approaches: (a) in responder SLE patients, by the direct addition of Con A to TNP-PAA-stimulated cultures; (b) in seven patients by transfer of Con A-activated cells to the responding culture of a normal allogeneic donor. In both cases SLE PBL were able to exert a suppressive effect to the same extent as normal PBL. PMID:6447163

The Role of B Cells for in Vivo T Cell Responses to a Friend Virus-Induced Leukemia

NASA Astrophysics Data System (ADS)

Schultz, Kirk R.; Klarnet, Jay P.; Gieni, Randall S.; Hayglass, Kent T.; Greenberg, Philip D.

1990-08-01

B cells can function as antigen-presenting cells and accessory cells for T cell responses. This study evaluated the role of B cells in the induction of protective T cell immunity to a Friend murine leukemia virus (F-MuLV)-induced leukemia (FBL). B cell-deficient mice exhibited significantly reduced tumor-specific CD4^+ helper and CD8^+ cytotoxic T cell responses after priming with FBL or a recombinant vaccinia virus containing F-MuLV antigens. Moreover, these mice had diminished T cell responses to the vaccinia viral antigens. Tumor-primed T cells transferred into B cell-deficient mice effectively eradicated disseminated FBL. Thus, B cells appear necessary for efficient priming but not expression of tumor and viral T cell immunity.

PubstractHelper: A Web-based Text-Mining Tool for Marking Sentences in Abstracts from PubMed Using Multiple User-Defined Keywords.

PubMed

Chen, Chou-Cheng; Ho, Chung-Liang

2014-01-01

While a huge amount of information about biological literature can be obtained by searching the PubMed database, reading through all the titles and abstracts resulting from such a search for useful information is inefficient. Text mining makes it possible to increase this efficiency. Some websites use text mining to gather information from the PubMed database; however, they are database-oriented, using pre-defined search keywords while lacking a query interface for user-defined search inputs. We present the PubMed Abstract Reading Helper (PubstractHelper) website which combines text mining and reading assistance for an efficient PubMed search. PubstractHelper can accept a maximum of ten groups of keywords, within each group containing up to ten keywords. The principle behind the text-mining function of PubstractHelper is that keywords contained in the same sentence are likely to be related. PubstractHelper highlights sentences with co-occurring keywords in different colors. The user can download the PMID and the abstracts with color markings to be reviewed later. The PubstractHelper website can help users to identify relevant publications based on the presence of related keywords, which should be a handy tool for their research. http://bio.yungyun.com.tw/ATM/PubstractHelper.aspx and http://holab.med.ncku.edu.tw/ATM/PubstractHelper.aspx.

Induction of IL21 in Peripheral T Follicular Helper Cells Is an Indicator of Influenza Vaccine Response in a Previously Vaccinated HIV-Infected Pediatric Cohort.

PubMed

de Armas, Lesley R; Cotugno, Nicola; Pallikkuth, Suresh; Pan, Li; Rinaldi, Stefano; Sanchez, M Celeste; Gonzalez, Louis; Cagigi, Alberto; Rossi, Paolo; Palma, Paolo; Pahwa, Savita

2017-03-01

HIV-infected patients of all ages frequently underperform in response to seasonal influenza vaccination, despite virologic control of HIV. The molecular mechanisms governing this impairment, as well as predictive biomarkers for responsiveness, remain unknown. This study was performed in samples obtained prevaccination (T0) from HIV-infected children who received the 2012-2013 seasonal influenza vaccine. Response status was determined based on established criterion for hemagglutination inhibition titer; participants with a hemagglutination titer ≥1:40 plus a ≥4-fold increase over T0 at 3 wk postvaccination were designated as responders. All children had a history of prior influenza vaccinations. At T0, the frequencies of CD4 T cell subsets, including peripheral T follicular helper (pTfh) cells, which provide help to B cells for developing into Ab-secreting cells, were similar between responders and nonresponders. However, in response to in vitro stimulation with influenza A/California/7/2009 (H1N1) Ag, differential gene expression related to pTfh cell function was observed by Fluidigm high-density RT-PCR between responders and nonresponders. In responders, H1N1 stimulation at T0 also resulted in CXCR5 induction (mRNA and protein) in CD4 T cells and IL21 gene induction in pTfh cells that were strongly associated with H1N1-specific B cell responses postvaccination. In contrast, CD4 T cells of nonresponders exhibited increased expression of IL2 and STAT5 genes, which are known to antagonize peripheral Tfh cell function. These results suggest that the quality of pTfh cells at the time of immunization is important for influenza vaccine responses and provide a rationale for targeted, ex vivo Ag-driven molecular profiling of purified immune cells to detect predictive biomarkers of the vaccine response. Copyright © 2017 by The American Association of Immunologists, Inc.

CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation.

PubMed

Rampuria, Pragya; Lang, Mark L

2015-05-01

NKT follicular helper cells (NKTfh cells) are a recently discovered functional subset of CD1d-restricted NKT cells. Given the potential for NKTfh cells to promote specific antibody responses and germinal center reactions, there is much interest in determining the conditions under which NKTfh cells proliferate and/or differentiate in vivo and in vitro. We confirm that NKTfh cells expressing the canonical semi-invariant Vα14 TCR were CXCR5(+)/ICOS(+)/PD-1(+)/Bcl6(+) and increased in number following administration of the CD1d-binding glycolipid α-galactosylceramide (α-GC) to C57Bl/6 mice. We show that the α-GC-stimulated increase in NKTfh cells was CD1d-dependent since the effect was diminished by reduced CD1d expression. In vivo and in vitro treatment with α-GC, singly or in combination with IL-2, showed that NKTfh cells increased in number to a greater extent than total NKT cells, but proliferation was near-identical in both populations. Acquisition of the NKTfh phenotype from an adoptively transferred PD-1-depleted cell population was also evident, showing that peripheral NKT cells differentiated into NKTfh cells. Therefore, the α-GC-stimulated, CD1d-dependent increase in peripheral NKTfh cells is a result of cellular proliferation and differentiation. These findings advance our understanding of the immune response following immunization with CD1d-binding glycolipids. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets

PubMed Central

2017-01-01

CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors. However, recent studies indicate that the master regulators are often coexpressed. Furthermore, the expression of master regulators can be dynamic and quantitative. In this review, we will first discuss similarities and differences between the development and functions of CD4 T cell and ILC subsets and then summarize recent literature on quantitative, dynamic, and cell type–specific balance between the master transcription factors in determining heterogeneity and plasticity of these subsets. PMID:28630089

Immunoregulation.

DTIC Science & Technology

1981-05-01

variety of antigens, KLH, GAT, TGAL and antigens from pathogenic bacteria such as Streptococcus mutans . Furthermore, we now have these systems...histocompatibility complex; PBL, peripheral blood lymphocytes; SAI/II, Streptococcus mutans antigen I/II complex; MHFSAI/II, monkey helper factor specific...from Streptococcus mutans . Helper activity was removed from supernatants of monkey cells by affinity chromatography on Sepharose 4B insolubilized

Developmental origins of inflammatory and immune diseases.

PubMed

Chen, Ting; Liu, Han-Xiao; Yan, Hui-Yi; Wu, Dong-Mei; Ping, Jie

2016-08-01

Epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exert a profound influence on physiological function and risk of diseases in adult life. The concepts of the 'developmental programming' and Developmental Origins of Health and Diseases (DOHaD) have become well accepted and have been applied across almost all fields of medicine. Adverse intrauterine environments may have programming effects on the crucial functions of the immune system during critical periods of fetal development, which can permanently alter the immune function of offspring. Immune dysfunction may in turn lead offspring to be susceptible to inflammatory and immune diseases in adulthood. These facts suggest that inflammatory and immune disorders might have developmental origins. In recent years, inflammatory and immune disorders have become a growing health problem worldwide. However, there is no systematic report in the literature on the developmental origins of inflammatory and immune diseases and the potential mechanisms involved. Here, we review the impacts of adverse intrauterine environments on the immune function in offspring. This review shows the results from human and different animal species and highlights the underlying mechanisms, including damaged development of cells in the thymus, helper T cell 1/helper T cell 2 balance disturbance, abnormal epigenetic modification, effects of maternal glucocorticoid overexposure on fetal lymphocytes and effects of the fetal hypothalamic-pituitary-adrenal axis on the immune system. Although the phenomena have already been clearly implicated in epidemiologic and experimental studies, new studies investigating the mechanisms of these effects may provide new avenues for exploiting these pathways for disease prevention. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Induction of polyclonal antibody synthesis by human allogeneic and autologous helper factors

PubMed Central

1979-01-01

Human helper factors were obtained from supernates of 48 h unidirectional allogeneic and autologous mixed lymphocyte reactions. These supernates were shown to induce the production of large amounts of immunoglobulin by tonsillar and peripheral blood mononuclear cells. Abundant polyclonal activation to antibody production occurred in these cultures in the absence of antigenic challenge which was similar in degree to that produced by pokeweed mitogen. This was documented by quantitating plasma cells, specific plaque-forming cells, and secreted immunoglobulin. In addition, the supplementation of companion cultures with sheep erythrocytes resulted in a significant enhancement of the specific plaque-forming cell response without an appreciable change in plasma cell number of secreted Ig. PMID:156242

Helper-Dependent Adenoviral Vectors.

PubMed

Rosewell, Amanda; Vetrini, Francesco; Ng, Philip

2011-10-29

Helper-dependent adenoviral vectors are devoid of all viral coding sequences, possess a large cloning capacity, and can efficiently transduce a wide variety of cell types from various species independent of the cell cycle to mediate long-term transgene expression without chronic toxicity. These non-integrating vectors hold tremendous potential for a variety of gene transfer and gene therapy applications. Here, we review the production technologies, applications, obstacles to clinical translation and their potential resolutions, and the future challenges and unanswered questions regarding this promising gene transfer technology.

Helper-Dependent Adenoviral Vectors

PubMed Central

Rosewell, Amanda; Vetrini, Francesco; Ng, Philip

2012-01-01

Helper-dependent adenoviral vectors are devoid of all viral coding sequences, possess a large cloning capacity, and can efficiently transduce a wide variety of cell types from various species independent of the cell cycle to mediate long-term transgene expression without chronic toxicity. These non-integrating vectors hold tremendous potential for a variety of gene transfer and gene therapy applications. Here, we review the production technologies, applications, obstacles to clinical translation and their potential resolutions, and the future challenges and unanswered questions regarding this promising gene transfer technology. PMID:24533227

Functional and quantitative alterations in T lymphocyte subpopulations in acute toxoplasmosis.

PubMed

Luft, B J; Kansas, G; Engleman, E G; Remington, J S

1984-11-01

The cellular immune response to Toxoplasma gondii has been studied in 23 patients with acute toxoplasma infection. Abnormalities of T cell subpopulations included a marked and significant elevation in suppressor (Leu 2) T cells in patients with prolonged symptoms due to acute infection and either a decrease in the number of T helper cells or an increase in the number of suppressor cells--or both--in patients with asymptomatic lymphadenopathy. There was no significant difference in lymphocyte proliferation to phytohemagglutinin or pokeweed mitogen among the various groups tested. The peak lymphocyte response to toxoplasma antigen, however, was significantly depressed in patients with acute infection compared with that in chronically infected control patients. The kinetics of the depression were consistent with the induction of a non-Leu 2 suppressor cell. These results demonstrate marked quantitative alterations in T lymphocyte subpopulations and functional alterations of T cells to toxoplasma antigen during infection with T. gondii.

[Exosomes and Immune Cells].

PubMed

Seo, Naohiro

2017-05-01

In addition to the cytokines and cytotoxic granules, exosomes have been known as the intercellular communicator and cytotoxic missile of immune cells for the past decade. It has been well known that mature dendritic cell(DC)-derived exosomes participate in the T cell and natural killer(NK)cell activation, while immature DCs secrete tolerogenic exosomes for regulatory T(Treg)cell generation. Treg cell-derived EVs act as a suppressor against pathogenic type-1 T helper(Th1)cell responses. CD8+ T cells produce tumoricidal exosomes for preventing tumor invasion and metastasis transiently after T cell receptor(TCR)-mediated stimulation. Thus, immune cells produce functional exosomes in the activation state- and/or differentiation stage-dependent manner. In this review, the role of immune cell-derived exosomes will be introduced, focusing mainly on immune reaction against tumor.

Development of T follicular helper cells and their role in disease and immune system.

PubMed

Eivazi, Sadegh; Bagheri, Salman; Hashemzadeh, Mohammad Sadegh; Ghalavand, Majdedin; Qamsari, Elmira Safaie; Dorostkar, Ruhollah; Yasemi, Maryam

2016-12-01

The T follicular helper cells (TFH) are a subset of CD4+ T cells specialized to regulate antibody responses. The production of these cells is associated with the dendritic cells (DCs) and B cells. TFH cells help B cells form germinal centers (GC) differentiate into memory and plasma cells (antibody-secreting cells) as humoral responses. In addition, there is strong evidence that TFH cells play a pivotal role in the development of long-lived humoral immunity. Molecular factors such as transcription factors, surface receptors, cytokine and micro RNAs are involved in the formation of TFH cells. Such TFH cells are diagnosed by transcription factor (BCL-6), surface marker expression (including CXCR5, PD-1, ICOS and CD40L) and a unique cytokine production pattern (such as IL-21 and IL-6). Memory TFH cells, accompanied by memory B cells, are known to be formed during antibody responses. It is now clear that the precise control of TFH cells is critically important for both inducing the optimal affinity maturation of antibody responses and preventing self-reactivity. Exclusive controls of TFH cell function and production are essential for human health. However, it is important to note that excessive activities may lead to autoimmune diseases, while reduced activity often results in immunodeficiency. It has also been shown that TFH cells are associated with cancers such as angioimmunoblastic T-cell lymphoma (AITL), follicular T-cell lymphoma (FTCL) and nonspecific Peripheral T-cell lymphomas (PTCLs). The biology of TFH cells, including their differentiation and transcriptional regulation will be described in the present review. Some of The developments of these cells in immunodeficiency diseases, autoimmunity and cancer will also be taken into account. Copyright © 2016. Published by Elsevier Masson SAS.

Biological behavior of tumors and associated retroviremia in cats inoculated with Snyder-Theilen fibrosarcoma virus and the phenomenon of tumor recurrence after primary regression.

PubMed Central

Pedersen, N C; Johnson, L; Theilen, G H

1984-01-01

The fate of tumors and associated retroviremia was studied in 111 cats infected with the Snyder-Theilen strain of feline sarcoma virus (FeSV). Tumors appeared at the site of inoculation within 7 to 10 days. A retroviremia, due mainly to the associated feline leukemia virus helper virus (FeLV-helper), developed at the same time as tumors. Of the cats, 44 developed progressively growing tumors and therefore had to be killed, and 67 developed tumors that regressed. There was a strong correlation between the persistence of the accompanying retroviremia and the growth of the tumors. The 44 cats with progressively growing fibrosarcomas remained retroviremic until death. Conversely, 53 of the 67 cats with solitary, regressing tumors were only transiently retroviremic. Tumor regression in these cats paralleled the disappearance of retrovirus from the blood. The fate of tumors and retroviremia was not always the same, however. Twelve cats remained persistently retroviremic after all signs of gross tumors disappeared. Two other kittens became nonviremic within 20 days after inoculation, yet tumors continued to grow and even metastasize for another 3 to 5 weeks before regressing. Fibrosarcomas recurred 3 weeks to 8 months later in 8 of 12 persistently retroviremic cats with regressed tumors. Although the blood and bone marrow from these cats contained predominantly FeLV-helper, tumor cells yielded both FeSV and FeLV-helper. Of 53 animals, 3 developed recurrent fibrosarcomas 5 weeks to 8 months after all signs of tumors and retroviremia had disappeared. Cells cultured from these tumors appeared initially like normal fibroblasts and were virus nonproducers. After one to three passages in culture, however, cells became malignantly transformed and replicated both FeSV and FeLV-helper. Cultures of the bone marrow from these and other nonviremic cats with regressed tumors yielded only FeLV-helper. PMID:6319286

Control of epithelial cell function by interleukin-22-producing RORγt+ innate lymphoid cells

PubMed Central

Sanos, Stephanie L; Vonarbourg, Cedric; Mortha, Arthur; Diefenbach, Andreas

2011-01-01

It is rapidly emerging that the defence system of innate lymphocytes is more diverse than previously recognized. In addition to natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, and natural helper cells have now been identified. LTi cells are developmentally dependent on the orphan transcription factor RORγt and instruct lymph node development during embryogenesis. More recently, it has become evident, that in addition to their role for lymph organ development, LTi cells are also potent producers of cytokines such as interleukin-22 (IL-22) and IL-17 in adult mice. In addition to LTi cells, another RORγt-dependent innate lymphocyte subset co-expressing RORγt and NK cell receptors (NKRs) has been identified. These NKR+ RORγt+ cells are also potent producers of IL-22 but it is unclear whether they are part of the NK cell or LTi cell lineage. This review will highlight recent progress in understanding development and function of innate IL-22-producing lymphocyte subsets. PMID:21391996

Artemisinin analogue SM934 attenuate collagen-induced arthritis by suppressing T follicular helper cells and T helper 17 cells

PubMed Central

Lin, Ze-Min; Yang, Xiao-Qian; Zhu, Feng-Hua; He, Shi-Jun; Tang, Wei; Zuo, Jian-Ping

2016-01-01

SM934 is an artemisinin analogue with immunosuppressive properties and potent therapeutic activity against lupus-like diseases in autoimmune mice. In this report, the therapeutic efficacy and underlying mechanisms of SM934 on rheumatoid arthritis (RA) was investigated using collagen-induced arthritis (CIA) in DBA/1J mice. We demonstrated that SM934 treatment alleviate the severity of arthritis in CIA mice with established manifestations. The therapeutic benefits were associated with ameliorated joint swelling and reduced extent of bone erosion and destruction. Further, administration of SM934 diminished the development of T follicular helper (Tfh) cells and Th17 cells and suppressed the production of pathogenic antibodies, without altering the proportion of germinal center B cells. Ex vivo, SM934 treatment inhibited the bovine type II collagen (CII) induced proliferation and inflammatory cytokines secretion of CII -reactive T cells. In vitro, SM934 impeded the polarization of naïve CD4+ T cells into Tfh cells and the expression of its transcript factor Bcl-6. Moreover, SM934 decreased the IL-21-producing CD4+ T cells and dampened the IL-21 downstream signaling through STAT3. These finding offered the convincing evidence that artemisinin derivative might attenuate RA by simultaneously interfering with the generation of Tfh cells and Th17 cells as well as the subsequent antibody-mediated immune responses. PMID:27897259

Increasing JAK/STAT Signaling Function of Infant CD4+ T Cells during the First Year of Life

PubMed Central

dela Peña-Ponce, Myra Grace; Rodriguez-Nieves, Jennifer; Bernhardt, Janice; Tuck, Ryan; Choudhary, Neelima; Mengual, Michael; Mollan, Katie R.; Hudgens, Michael G.; Peter-Wohl, Sigal; De Paris, Kristina

2017-01-01

Most infant deaths occur in the first year of life. Yet, our knowledge of immune development during this period is scarce and derived from cord blood (CB) only. To more effectively combat pediatric diseases, a deeper understanding of the kinetics and the factors that regulate the maturation of immune functions in early life is needed. Increased disease susceptibility of infants is generally attributed to T helper 2-biased immune responses. The differentiation of CD4+ T cells along a specific T helper cell lineage is dependent on the pathogen type, and on costimulatory and cytokine signals provided by antigen-presenting cells. Cytokines also regulate many other aspects of the host immune response. Therefore, toward the goal of increasing our knowledge of early immune development, we defined the temporal development of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling function of CD4+ T cells using cross-sectional blood samples from healthy infants ages 0 (birth) to 14 months. We specifically focused on cytokines important in T cell differentiation (IFN-γ, IL-12, and IL-4) or in T cell survival and expansion (IL-2 and IL-7) in infant CD4+ T cells. Independent of the cytokine tested, JAK/STAT signaling in infant compared to adult CD4+ T cells was impaired at birth, but increased during the first year, with the most pronounced changes occurring in the first 6 months. The relative change in JAK/STAT signaling of infant CD4+ T cells with age was distinct for each cytokine tested. Thus, while about 60% of CB CD4+ T cells could efficiently activate STAT6 in response to IL-4, less than 5% of CB CD4+ T cells were able to activate the JAK/STAT pathway in response to IFN-γ, IL-12 or IL-2. By 4–6 months of age, the activation of the cytokine-specific STAT molecules was comparable to adults in response to IL-4 and IFN-γ, while IL-2- and IL-12-induced STAT activation remained below adult levels even at 1 year. These results suggest that common developmental and cytokine-specific factors regulate the maturation of the JAK/STAT signaling function in CD4+ T cells during the first year of life. PMID:28271056

Requirements of transcription factor Smad-dependent and -independent TGF-β signaling to control discrete T-cell functions.

PubMed

Gu, Ai-Di; Wang, Yunqi; Lin, Lin; Zhang, Song S; Wan, Yisong Y

2012-01-17

TGF-β modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-β achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad-dependent and -independent TGF-β signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activated and produced effector cytokines in vivo on deletion of both Smad2 and Smad3. In addition, TGF-β failed to suppress T helper differentiation efficiently and to promote induced Treg generation of non-Treg cells lacking both Smad2 and Smad3, suggesting that Smad-dependent signaling is obligatory to mediate TGF-β function in non-Treg cells. Unexpectedly, however, the development, homeostasis, and function of Treg cells remained intact in the absence of Smad2 and Smad3, suggesting that the Smad-independent pathway is important for Treg function. Indeed, Treg-specific deletion of TGF-β-activated kinase 1 led to failed Treg homeostasis and lethal immune disorder in mice. Therefore, Smad-dependent and -independent TGF-β signaling discretely controls non-Treg and Treg function to modulate immune tolerance and immune homeostasis.

Multiple layers of transcriptional regulation by PLZF in NKT-cell development.

PubMed

Mao, Ai-Ping; Constantinides, Michael G; Mathew, Rebecca; Zuo, Zhixiang; Chen, Xiaoting; Weirauch, Matthew T; Bendelac, Albert

2016-07-05

The transcription factor PLZF [promyelocytic leukemia zinc finger, encoded by zinc finger BTB domain containing 16 (Zbtb16)] is induced during the development of innate and innate-like lymphocytes to direct their acquisition of a T-helper effector program, but the molecular mechanisms involved are poorly understood. Using biotinylation-based ChIP-seq and microarray analysis of both natural killer T (NKT) cells and PLZF-transgenic thymocytes, we identified several layers of regulation of the innate-like NKT effector program. First, PLZF bound and regulated genes encoding cytokine receptors as well as homing and adhesion receptors; second, PLZF bound and activated T-helper-specific transcription factor genes that in turn control T-helper-specific programs; finally, PLZF bound and suppressed the transcription of Bach2, a potent general repressor of effector differentiation in naive T cells. These findings reveal the multilayered architecture of the transcriptional program recruited by PLZF and elucidate how a single transcription factor can drive the developmental acquisition of a broad effector program.

Construction and production of oncotropic vectors, derived from MVM(p), that share reduced sequence homology with helper plasmids.

PubMed

Clément, Nathalie; Velu, Thierry; Brandenburger, Annick

2002-09-01

The production of currently available vectors derived from autonomous parvoviruses requires the expression of capsid proteins in trans, from helper sequences. Cotransfection of a helper plasmid always generates significant amounts of replication-competent virus (RCV) that can be reduced by the integration of helper sequences into a packaging cell line. Although stocks of minute virus of mice (MVM)-based vectors with no detectable RCV could be produced by transfection into packaging cells; the latter appear after one or two rounds of replication, precluding further amplification of the vector stock. Indeed, once RCVs become detectable, they are efficiently amplified and rapidly take over the culture. Theoretically RCV-free vector stocks could be produced if all homology between vector and helper DNA is eliminated, thus preventing homologous recombination. We constructed new vectors based on the structure of spontaneously occurring defective particles of MVM. Based on published observations related to the size of vectors and the sequence of the viral origin of replication, these vectors were modified by the insertion of foreign DNA sequences downstream of the transgene and by the introduction of a consensus NS-1 nick site near the origin of replication to optimize their production. In one of the vectors the inserted fragment of mouse genomic DNA had a synergistic effect with the modified origin of replication in increasing vector production.

Innate lymphoid cells and the MHC.

PubMed

Robinette, M L; Colonna, M

2016-01-01

Innate lymphoid cells (ILCs) are a new class of immune cells that include natural killer (NK) cells and appear to be the innate counterparts to CD4(+) helper T cells and CD8(+) cytotoxic T cells based on developmental and functional similarities. Like T cells, both NK cells and other ILCs also show connections to the major histocompatibility complex (MHC). In human and mouse, NK cells recognize and respond to classical and nonclassical MHC I molecules as well as structural homologues, whereas mouse ILCs have recently been shown to express MHC II. We describe the history of MHC I recognition by NK cells and discuss emerging roles for MHC II expression by ILC subsets, making comparisons between both mouse and human when possible. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Simultaneous detection of circulating immunological parameters and tumor biomarkers in early stage breast cancer patients during adjuvant chemotherapy.

PubMed

Rovati, B; Mariucci, S; Delfanti, S; Grasso, D; Tinelli, C; Torre, C; De Amici, M; Pedrazzoli, P

2016-06-01

Chemotherapy-induced immune suppression has mainly been studied in patients with advanced cancer, but the influence of chemotherapy on the immune system in early stage cancer patients has so far not been studied systematically. The aim of the present study was to monitor the immune system during anthracycline- and taxane-based adjuvant chemotherapy in early stage breast cancer patients, to assess the impact of circulating tumor cells on selected immune parameters and to reveal putative angiogenic effects of circulating endothelial cells. Peripheral blood samples from 20 early stage breast cancer patients were analyzed using a flow cytometric multi-color of antibodies to enumerate lymphocyte and dendritic cell subsets, as well as endothelial and tumor cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of various serological factors. During chemotherapy, all immunological parameters and angiogenesis surrogate biomarkers showed significant decreases. The numbers of circulating tumor cells showed significant inverse correlations with the numbers of T helper cells, a lymphocyte subset directly related to effective anti-tumor responses. Reduced T helper cell numbers may contribute to systemic immunosuppression and, as such, the activation of dormant tumor cells. From our results we conclude that adjuvant chemotherapy suppresses immune function in early stage breast cancer patients. In addition, we conclude that the presence of circulating tumor cells, defined as pan-cytokeratin(+), CD326(+), CD45(-) cells, may serve as an important indicator of a patient's immune status. Further investigations are needed to firmly define circulating tumor cells as a predictor for the success of breast cancer adjuvant chemotherapy.

Natural killer T cells are required for the development of a superantigen-driven T helper type 2 immune response in mice

PubMed Central

Nomizo, Auro; Postol, Edilberto; de Alencar, Raquel; Cardillo, Fabíola; Mengel, José

2005-01-01

We show, here, that one single injection or weekly injections of staphylococcal enterotoxin B (SEB), starting in 1-day-old newborn mice, induced a powerful immune response with a T helper type 2 (Th2) pattern, as judged by the isotype and cytokine profile, with the production of large amounts of SEB-specific immunoglobulin G1 (IgG1), detectable levels of SEB-specific IgE and increased production of interleukin-4 by spleen cells. These protocols also induced an increase in the levels of total IgE in the serum. Memory of SEB was transferred to secondary recipients by using total spleen cells from primed animals. The secondary humoral response in transferred mice was diminished if spleen cells from SEB-treated mice were previously depleted of CD3+ or Vβ8+ T cells or NK1.1+ cells. In vivo depletion of NK1.1+ cells in adult mice resulted in a marked reduction in the SEB-specific antibody response in both the primary and secondary immune responses. Additionally, purified NK1.1+ T cells were able to perform SEB-specific helper B-cell actions in vitro and in vivo. These results suggest that NK1.1+ T cells are required for the full development of humoral immunological memory, whilst making neonatal tolerance to SEB unachievable. PMID:16162272

Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells[S

PubMed Central

Jaudszus, Anke; Gruen, Michael; Watzl, Bernhard; Ness, Christina; Roth, Alexander; Lochner, Alfred; Barz, Dagmar; Gabriel, Holger; Rothe, Michael; Jahreis, Gerhard

2013-01-01

Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. PMID:23349208

What happens in the thymus does not stay in the thymus: how T cells recycle the CD4+-CD8+ lineage commitment transcriptional circuitry to control their function

PubMed Central

Vacchio, Melanie S.; Bosselut, Rémy

2016-01-01

MHC-restricted CD4+ and CD8+ T cell are at the core of most adaptive immune responses. Although these cells carry distinct functions, they arise from a common precursor during thymic differentiation, in a developmental sequence that matches CD4 and CD8 expression and functional potential with MHC restriction. While the transcriptional control of CD4+-CD8+ lineage choice in the thymus is now better understood, less was known about what maintains the CD4+- and CD8+-lineage integrity of mature T cells. In this review, we discuss the mechanisms that establish in the thymus, and maintain in post-thymic cells, the separation of these lineages. We focus on recent studies that address the mechanisms of epigenetic control of Cd4 expression and emphasize how maintaining a transcriptional circuitry nucleated around Thpok and Runx proteins, the key architects of CD4+-CD8+ lineage commitment in the thymus, is critical for CD4+ T cell helper functions. PMID:27260768

Induction of IL-21 in Peripheral T Follicular Helper cells is Indicator of Influenza Vaccine Response in Previously Vaccinated HIV-Infected Pediatric Cohort

PubMed Central

de Armas, Lesley R.; Cotugno, Nicola; Pallikkuth, Suresh; Pan, Li; Rinaldi, Stefano; Sanchez, M. Celeste; Gonzalez, Louis; Cagigi, Alberto; Rossi, Paolo; Palma, Paolo; Pahwa, Savita

2016-01-01

HIV-infected patients of all ages frequently underperform in responsiveness to seasonal influenza vaccination despite virologic control of HIV. Molecular mechanisms governing this impairment as well as predictive biomarkers for responsiveness remain unknown. This study was performed in pre-vaccination samples (T0) of HIV-infected children who received the 2012–2013 seasonal influenza vaccine. Response status was determined based on established criteria of hemagglutination inhibition (HAI) titer; participants with HAI ≥ 1:40 plus ≥ 4-fold increase over T0 at three weeks post-vaccination (T1) were designated as responders. All children had a history of prior influenza vaccinations. At T0, frequencies of CD4 T cell subsets, including peripheral T follicular helper (pTfh) cells which provide help to B cells for developing into Ab secreting cells were similar between responders and non-responders. However, in response to in vitro stimulation with H1N1 antigen, differential gene expression related to pTfh function was observed by Fluidigm high density RT-PCR between responders and non-responders. In responders, H1N1 stimulation at pre-vaccination also resulted in CXCR5 induction (mRNA and protein) in CD4 T cells and IL21 gene induction in pTfh cells that strongly associated with H1N1-specific B cell responses post-vaccination. In contrast, CD4 T cells of non-responders exhibited increased expression of IL2 and STAT5 genes which are known to antagonize pTfh function. These results suggest that the quality of pTfh at the time of immunization are important for influenza vaccine responses and provide a rationale for targeted, ex vivo antigen-driven molecular profiling of purified immune cells to detect predictive biomarkers of vaccine response. PMID:28130496

Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells

PubMed Central

Ogasawara, Takashi; Hatano, Masahiko; Satake, Hisae; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hirata, Hirokuni; Sugiyama, Kumiya; Fukushima, Yasutsugu; Nakae, Susumu; Matsumoto, Kenji; Saito, Hirohisa; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi

2017-01-01

Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6’s association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation. PMID:28096407

PPAR-γ in innate and adaptive lung immunity.

PubMed

Nobs, Samuel Philip; Kopf, Manfred

2018-05-16

The transcription factor PPAR-γ (peroxisome proliferator-activated receptor-γ) is a key regulator of lung immunity exhibiting multiple cell type specific roles in controlling development and function of the lung immune system. It is strictly required for the generation of alveolar macrophages by controlling differentiation of fetal lung monocyte precursors. Furthermore, it plays an important role in lung allergic inflammation by licensing lung dendritic cell t helper 2 (Th2) priming capacity as well as acting as a master transcription factor for pathogenic Th2 cells. Due to this plethora of functions and its involvement in multiple pulmonary diseases including asthma and pulmonary alveolar proteinosis, understanding the role of PPAR-γ in lung immunity is an important subject of ongoing research. ©2018 Society for Leukocyte Biology.

Review series on helminths, immune modulation and the hygiene hypothesis: Immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies?

PubMed Central

Jackson, Joseph A; Friberg, Ida M; Little, Susan; Bradley, Janette E

2009-01-01

Although the molecules and cells involved in triggering immune responses against parasitic worms (helminths) remain enigmatic, research has continued to implicate expansions of T-helper type 2 (Th2) cells and regulatory T-helper (Treg) cells as a characteristic response to these organisms. An intimate association has also emerged between Th2 responses and wound-healing functions. As helminth infections in humans are associated with a strong Th2/Treg immunoregulatory footprint (often termed a ‘modified Th2’ response), plausible links have been made to increased susceptibility to microbial pathogens in helminth-infected populations in the tropics and to the breakdowns in immunological control (allergy and autoimmunity) that are increasing in frequency in helminth-free developed countries. Removal of helminths and their anti-inflammatory influence may also have hazards for populations exposed to infectious agents, such as malaria and influenza, whose worst effects are mediated by excessive inflammatory reactions. The patterns seen in the control of helminth immunity are discussed from an evolutionary perspective. Whilst an inability to correctly regulate the immune system in the absence of helminth infection might seem highly counter-adaptive, the very ancient and pervasive relationship between vertebrates and helminths supports a view that immunological control networks have been selected to function within the context of a modified Th2 environment. The absence of immunoregulatory stimuli from helminths may therefore uncover maladaptations that were not previously exposed to selection. PMID:19120495

Divergent response profile in activated cord blood T cells from first-born child implies birth-order-associated in utero immune programming.

PubMed

Kragh, M; Larsen, J M; Thysen, A H; Rasmussen, M A; Wolsk, H M; Bisgaard, H; Brix, S

2016-03-01

First-born children are at higher risk of developing a range of immune-mediated diseases. The underlying mechanism of 'birth-order effects' on disease risk is largely unknown, but in utero programming of the child's immune system may play a role. We studied the association between birth order and the functional response of stimulated cord blood T cells. Purified cord blood T cells were polyclonally activated with anti-CD3-/anti-CD28-coated beads in a subgroup of 28 children enrolled in the COPSAC2010 birth cohort. Expression levels of seven activation markers on helper and cytotoxic T cells as well as the percentage of CD4(+) CD25(+) T cells were assessed by flow cytometry. Production of IFN-γ, TNF-α, IL-17, IL-4, IL-5, IL-13, and IL-10 was measured in the supernatants. IL-10 secretion (P = 0.007) and CD25 expression on CD4(+) helper T cells (P = 0.0003) in the activated cord blood T cells were selectively reduced in first-born children, while the percentage of circulating CD4(+) CD25(+) cord blood T cells was independent of birth order. First-born infants display a reduced anti-inflammatory profile in T cells at birth. This possible in utero 'birth-order' T-cell programming may contribute to later development of immune-mediated diseases by increasing overall immune reactivity in first-born children as compared to younger siblings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Th9 Cells: Probable players in ulcerative colitis pathogenesis.

PubMed

Shohan, Mojtaba; Elahi, Shokrollah; Shirzad, Hedayatollah; Rafieian-Kopaei, Mahmoud; Bagheri, Nader; Soltani, Emad

2018-04-19

T lymphocytes represent an important part of adaptive immune system undertaking different functions to regulate immune responses. CD4+ T cells are the most important activator cells in inflammatory conditions. Depending on the type of induced cells and inflamed sites, expression and activity of different subtypes of helper T cells are changed. Recent studies have confirmed the existence of a new subset of helper T lymphocytes called Th9. Naive T cells can differentiate into Th9 subtypes if they are exposed simultaneously by interleukin (IL) 4 and transforming growth factor β and also secondary activation of a complicated network of transcription factors such as interferon regulatory factor 4 (IRF4) and Smads which are essential for adequate induction of this phenotype. Th9 cells specifically produce interleukin 9 and their probable roles in promoting intestinal inflammation are being investigated in human subjects and experimental models of ulcerative colitis (UC). Recently, infiltration of Th9 cells, overexpression of IL-9, and certain genes associated with Th9 differentiation have been demonstrated in inflammatory microenvironment of UC. Intestinal oversecretion of IL-9 protein is likely to break down epithelial barriers and compromise tolerance to certain commensal microorganisms which leads to inflammation. Th9 pathogenicity has not yet been adequately explored in UC and they are far from being considered as inflammatory cells in this milieu, therefore precise understanding the role of these newly identified cells in particular their potential role in gut pathogenesis may enable us to develop novel therapeutic approaches for inflammatory bowel disease. So, this article tries to discuss the latest knowledge on the above-mentioned field.

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease.

PubMed

Takeuchi, Mai; Sato, Yasuharu; Ohno, Kyotaro; Tanaka, Satoshi; Takata, Katsuyoshi; Gion, Yuka; Orita, Yorihisa; Ito, Toshihiro; Tachibana, Tomoyasu; Yoshino, Tadashi

2014-08-01

IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFβ1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection.

PubMed

Chiodi, Francesca; Bekele, Yonas; Lantto Graham, Rebecka; Nasi, Aikaterini

2017-01-01

IL-7 was previously shown to upregulate the expression of molecules important for interaction of CD4+ T cells with B cells. It is poorly studied whether IL-7 has a role in the biology of T follicular helper (Tfh) cells and whether IL-7 dysregulates the expression of B-cell costimulatory molecules on Tfh cells. We review the literature and provide arguments in favor of IL-7 being involved in the biology of human Tfh cells. The CD127 IL-7 receptor is expressed on circulating Tfh and non-Tfh cells, and we show that IL-7, but not IL-6 or IL-21, upregulates the expression of CD70 and PD-1 on these cells. We conclude that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on Tfh cells and lead to abnormal B cell differentiation.

Failure of itraconazole to prevent T-helper type 2 cell immune deviation: Implications for chronic rhinosinusitis.

PubMed

Kennedy, Joshua L; Steinke, John W; Liu, Lixia; Negri, Julie; Borish, Larry; Payne, Spencer C

2016-11-01

T-helper (Th) type 2 cell inflammation is the hallmark of several disease processes, including asthma, atopic dermatitis, and some forms of chronic rhinosinusitis. Itraconazole has been used as both an antifungal and an anti-inflammatory agent, with some success in many of these diseases, in part, by altering Th2 cytokine expression by T cells. It is not known whether this merely reflects inhibition of established Th2-like cells or the inhibition of differentiation of naive T cells into Th2-like cells. To evaluate the role of itraconazole in the differentiation of naive T cells during activation. Naive CD45RA+ T cells were isolated from peripheral blood mononuclear cells from healthy volunteers. Th1 and Th2 type cells were differentiated in the presence of varying concentrations of itraconazole. After stimulation with anti-CD3 and anti-CD28 beads, carboxyfluorescein succinimidyl ester dilution was performed to evaluate proliferation and intracellular cytokine staining for interleukin (IL) 4 and interferon (IFN) gamma within proliferating T cells was measured along with enzyme-linked immunosorbent assay for secreted IL-5, IL-13, and IFN gamma. Itraconazole had no effect on proliferation of unbiased, Th1, or Th2 cells. Similarly, there was no effect of itraconazole on either intracellular cytokine staining of IL-4 and IFN gamma or secreted cytokine expression of IFN gamma, IL-5, and IL-13 in any of the cell populations. Itraconazole did not alter the ability of naive T cells to proliferate or secrete cytokines under Th1 or Th2 deviating conditions in vitro. As such, reported inhibition of Th2-like lymphocyte function by itraconazole reflected action on mature effector cells and may have underscored why antifungal treatment failed in many clinical trials of eosinophilic chronic rhinosinusitis.

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.

CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease.

PubMed

Valentine, Kristen M; Davini, Dan; Lawrence, Travis J; Mullins, Genevieve N; Manansala, Miguel; Al-Kuhlani, Mufadhal; Pinney, James M; Davis, Jason K; Beaudin, Anna E; Sindi, Suzanne S; Gravano, David M; Hoyer, Katrina K

2018-05-09

CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2-deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2-deficient mice. CD8 T cells express the B cell follicle-localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality. Copyright © 2018 by The American Association of Immunologists, Inc.

Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells

PubMed Central

Clear, Andrew; Owen, Andrew; Iqbal, Sameena; Lee, Abigail; Matthews, Janet; Wilson, Andrew; Calaminici, Maria; Gribben, John G.

2013-01-01

CD4+ T-helper cells (THs) dominate the classical Hodgkin lymphoma (CHL) microenvironment, but their role is poorly understood. Advances in flow cytometry and immunohistochemistry permit more detailed investigation of this aspect of CHL pathophysiology. To address the hypothesis that the TH-infiltrate, rather than being TH2-enriched, senescent and hypofunctional, is TH1 and activation marker-rich, cytokine-secretory and proliferative, we applied comprehensive flow cytometric immunophenotyping and functional assays of cytokine secretion/proliferation to TH cells from 18 CHL-derived single-cell suspensions (SCSs) compared to reactive lymph nodes (RLNs). CHL-derived TH cells express TH1-associated CXCR3/CCR5 and TNFα/IFNγ/interleukin-2 (IL-2) and less TH2-associated CCR3/CCR4, with no IL-4/IL-13. They lack exhaustion-/suppression-associated PD1, CD57 and terminally differentiated effector memory cells, with more central memory cells, activation-associated partners of Hodgkin Reed Sternberg (HRS) cell-expressed CD30/OX40-L/ICOS-L, and other activation markers. TH cell lines established from CHL and RLN-derived SCSs remain cytokine-secretory. We confirmed and extended these studies using tissue microarray immunohistochemistry (TMA-IHC) from a large CHL tissue bank (n = 122) and demonstrate TH1-associated TBET is abundant in CHL, and TH2-associated CMAF/GATA3 and exhaustion-associated PD1 expressed at significantly lower levels. These molecular insights into the CHL-associated TH offer potential diagnostic, prognostic and pharmacologically modifiable therapeutic targets and do not support the established view of a TH2-enriched, senescent/exhausted, hypofunctional, hypoproliferative infiltrate. PMID:24004665

Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells.

PubMed

Greaves, Paul; Clear, Andrew; Owen, Andrew; Iqbal, Sameena; Lee, Abigail; Matthews, Janet; Wilson, Andrew; Calaminici, Maria; Gribben, John G

2013-10-17

CD4(+) T-helper cells (THs) dominate the classical Hodgkin lymphoma (CHL) microenvironment, but their role is poorly understood. Advances in flow cytometry and immunohistochemistry permit more detailed investigation of this aspect of CHL pathophysiology. To address the hypothesis that the TH-infiltrate, rather than being TH2-enriched, senescent and hypofunctional, is TH1 and activation marker-rich, cytokine-secretory and proliferative, we applied comprehensive flow cytometric immunophenotyping and functional assays of cytokine secretion/proliferation to TH cells from 18 CHL-derived single-cell suspensions (SCSs) compared to reactive lymph nodes (RLNs). CHL-derived TH cells express TH1-associated CXCR3/CCR5 and TNFα/IFNγ/interleukin-2 (IL-2) and less TH2-associated CCR3/CCR4, with no IL-4/IL-13. They lack exhaustion-/suppression-associated PD1, CD57 and terminally differentiated effector memory cells, with more central memory cells, activation-associated partners of Hodgkin Reed Sternberg (HRS) cell-expressed CD30/OX40-L/ICOS-L, and other activation markers. TH cell lines established from CHL and RLN-derived SCSs remain cytokine-secretory. We confirmed and extended these studies using tissue microarray immunohistochemistry (TMA-IHC) from a large CHL tissue bank (n = 122) and demonstrate TH1-associated TBET is abundant in CHL, and TH2-associated CMAF/GATA3 and exhaustion-associated PD1 expressed at significantly lower levels. These molecular insights into the CHL-associated TH offer potential diagnostic, prognostic and pharmacologically modifiable therapeutic targets and do not support the established view of a TH2-enriched, senescent/exhausted, hypofunctional, hypoproliferative infiltrate.

Ghrelin Inhibits the Differentiation of T Helper 17 Cells through mTOR/STAT3 Signaling Pathway

PubMed Central

Xu, Yanhui; Li, Ziru; Yin, Yue; Lan, He; Wang, Jun; Zhao, Jing; Feng, Juan; Li, Yin; Zhang, Weizhen

2015-01-01

Enhanced activity of interleukin 17 (IL-17) producing T helper 17 (Th17) cells plays an important role in autoimmune and inflammatory diseases. Significant loss of body weight and appetite is associated with chronic inflammation and immune activation, suggesting the cross talk between immune and neuroendocrine systems. Ghrelin has been shown to regulate the organism immune function. However, the effects of ghrelin on the differentiation of Th17 cells remain elusive. In the present study, we observed the enhanced differentiation of Th17 cells in spleens of growth hormone secretagogue receptor 1a (GHSR1a)-/- mice. Treatment of ghrelin repressed Th17 cell differentiation in a time- and concentration-dependent manner. Phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) was increased in the spleens of GHSR1a-/- mice. Activation of mTOR signaling by injection of Cre-expressiong adenovirus into tuberous sclerosis complex 1 (TSC1) loxp/loxp mice increased the differentiation of Th17 cells in spleen, which was associated with an increment in the phosphorylation of STAT3. Activation of mTOR signaling by leucine or overexpression of p70 ribosome protein subunit 6 kinase 1 (S6K1) activated mTOR signaling in isolated T cells, while reversed the ghrelin-induced inhibition of iTh17 cell differentiation. In conclusion, mTOR mediates the inhibitory effect of ghrelin on the differentiation of Th17 cells by interacting with STAT3. PMID:25658305

Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation

PubMed Central

Ke, Fang; Zhang, Lingyun; Liu, Zhaoyuan; Yan, Sha; Xu, Zhenyao; Bai, Jing; Zhu, Huiyuan; Lou, Fangzhou; Cai, Wei; Sun, Yang; Gao, Yuanyuan; Wang, Hong

2016-01-01

T helper 17 (Th17) cells play an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Th17 cell differentiation from naïve T cells can be induced in vitro by the cytokines transforming growth factor β1 and interleukin-6. However, it remains unclear whether other regulatory factors control the differentiation of Th17 cells. Mesenchymal stem cells (MSCs) have emerged as a promising candidate for inhibiting Th17 cell differentiation and autoimmune diseases. Despite the fact that several molecules have been linked to the immunomodulatory function of MSCs, many other key MSC-secreted regulators that are involved in inhibiting Th17 cell polarization are ill-defined. In this study, we demonstrated that the intraperitoneal administration of skin-derived MSCs (S-MSCs) substantially ameliorated the development of EAE in mice. We found that the proinflammatory cytokine tumor necrosis factor (TNF)-α, a key mediator in the pathophysiology of MS and EAE, was capable of promoting Th17 cell differentiation. Moreover, under inflammatory conditions, we demonstrated that S-MSCs produced high amounts of soluble TNF receptor 1 (sTNFR1), which binds TNF-α and antagonizes its function. Knockdown of sTNFR1 in S-MSCs decreased their inhibitory effect on Th17 cell differentiation ex vivo and in vivo. Thus, our data identified sTNFR1 and its target TNF-α as critical regulators for Th17 cell differentiation, suggesting a previously unrecognized mechanism for MSC therapy in Th17-mediated autoimmune diseases. Significance This study showed that administration of skin-derived mesenchymal stem cells (S-MSCs) was able to alleviate the clinical score of experimental autoimmune encephalomyelitis by inhibiting the differentiation of T helper 17 (Th17) cells. Tumor necrosis factor (TNF)-α is a critical cytokine for promoting Th17 cell differentiation. It was discovered that activated S-MSCs produced high amount of soluble TNF receptor 1 (sTNFR1), which neutralized TNF-α and inhibited Th17 cell polarization. The data identified S-MSC-secreted sTNFR1 and its target TNF-α as essential regulators for Th17 cell differentiation and revealed a novel mechanism underlying MSC-mediated immunomodulatory function in autoimmunity. PMID:26819253

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.

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

Influenza virus site recognized by a murine helper T cell specific for H1 strains. Localization to a nine amino acid sequence in the hemagglutinin molecule.

PubMed

Hackett, C J; Dietzschold, B; Gerhard, W; Ghrist, B; Knorr, R; Gillessen, D; Melchers, F

1983-08-01

The functional helper T cell line Vir-2, derived from a PR8 (H1N1) influenza virus-immunized BALB/c mouse, proliferates in response to syngeneic antigen-presenting cells and naturally occurring strains of subtype H1 human influenza virus from 1934-1957 and 1977-1980 isolates. A conserved region of the hemagglutinin molecule around amino acid position 115 in the heavy chain (HA1) was implicated as being important in this recognition by the lack of stimulatory activity associated with a glutamic acid to lysine substitution at position 115 in the laboratory mutant RV6, derived from wild-type PR8. Characterization of the stimulatory determinant on the wild-type hemagglutinin molecule was then undertaken using cleavage products and synthetic peptides. Vir-2 cells recognized the reduced and alkylated purified HA1 of PR8 virus, and this reactivity was retained after cleavage at methionine and tryptophan residues. High-pressure liquid chromatography separation of cleavage fragments indicated that a short sequence of the HA1 containing residue 115 was being recognized. This recognition was localized to a nine amino acid segment (positions 111-119) by assaying stimulation with synthetic peptide homologues of different lengths from that region. As with native hemagglutinin, Vir-2 cells responded to active peptides when presented by H-2d but not H-2k antigen-presenting cells.

Atypical angioimmunoblastic T-cell lymphomas masquerading as systemic polyclonal B-immunoblastic proliferation.

PubMed

Papadi, Bhavesh; Polski, Jacek M; Clarkson, David R; Liu-Dumlao, Theresa O

2012-09-01

Angioimmunoblastic T cell lymphoma (AITL) is a relatively rare peripheral T cell lymphoma derived from follicular T helper cells. AITL has a varied presentation, both clinically and morphologically. AITL can pose a diagnostic challenge as it may be difficult to identify and characterize the neoplastic cells among the polymorphous infiltrates composed of polyclonal B immunoblasts and plasma cells. In AITL, the reactive B cell and plasma cell proliferation is secondary to dysregulated secretion of cytokines such as interleukin-6 by the neoplastic follicular T helper cells. SPBIP is a condition of unknown etiopathogenesis characterized by systemic involvement by polyclonal B immunoblasts and plasma cells. We report two cases of AITL, which are presented with atypical findings making it difficult to diagnose. The cases had features similar to SPBIP. Our cases highlight the importance of screening cases of polyclonal plasmacytosis and SPBIP like cases for underlying AITL.

Two separable functional domains of simian virus 40 large T antigen: carboxyl-terminal region of simian virus 40 large T antigen is required for efficient capsid protein synthesis.

PubMed Central

Tornow, J; Polvino-Bodnar, M; Santangelo, G; Cole, C N

1985-01-01

The carboxyl-terminal portion of simian virus 40 large T antigen is essential for productive infection of CV-1 and CV-1p green monkey kidney cells. Mutant dlA2459, lacking 14 base pairs at 0.193 map units, was positive for viral DNA replication, but unable to form plaques in CV-1p cells (J. Tornow and C.N. Cole, J. Virol. 47:487-494, 1983). In this report, the defect of dlA2459 is further defined. Simian virus 40 late mRNAs were transcribed, polyadenylated, spliced, and transported in dlA2459-infected cells, but the level of capsid proteins produced in infected CV-1 green monkey kidney cells was extremely low. dlA2459 large T antigen lacks those residues known to be required for adenovirus helper function, and the block to productive infection by dlA2459 occurs at the same stage of infection as the block to productive adenovirus infection of CV-1 cells. These results suggest that the adenovirus helper function is required for productive infection by simian virus 40. Mutant dlA2459 was able to grow on the Vero and BSC-1 lines of African green monkey kidney cells. Additional mutants affecting the carboxyl-terminal portion of large T were prepared. Mutant inv2408 contains an inversion of the DNA between the BamHI and BclI sites (0.144 to 0.189 map units). This inversion causes transposition of the carboxyl-terminal 26 amino acids of large T antigen and the carboxyl-terminal 18 amino acids of VP1. This mutant was viable, even though the essential information absent from dlA2459 large T antigen has been transferred to the carboxyl terminus of VP1 of inv2408. The VP1 polypeptide carrying this carboxyl-terminal portion of large T could overcome the defect of dlA2459. This indicates that the carboxyl terminus of large T antigen is a separate and separable functional domain. Images PMID:2982029

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo.

PubMed

Brahmakshatriya, Vinayak; Kuang, Yi; Devarajan, Priyadharshini; Xia, Jingya; Zhang, Wenliang; Vong, Allen Minh; Swain, Susan L

2017-04-01

Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6-independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses. Copyright © 2017 by The American Association of Immunologists, Inc.

Nanoparticle-based B-cell targeting vaccines: Tailoring of humoral immune responses by functionalization with different TLR-ligands.

PubMed

Zilker, Claudia; Kozlova, Diana; Sokolova, Viktoriya; Yan, Huimin; Epple, Matthias; Überla, Klaus; Temchura, Vladimir

2017-01-01

Induction of an appropriate type of humoral immune response during vaccination is essential for protection against viral and bacterial infections. We recently observed that biodegradable calcium phosphate (CaP) nanoparticles coated with proteins efficiently targeted and activated naïve antigen-specific B-cells in vitro. We now compared different administration routes for CaP-nanoparticles and demonstrated that intramuscular immunization with such CaP-nanoparticles induced stronger immune responses than immunization with monovalent antigen. Additional functionalization of the CaP-nanoparticles with TRL-ligands allowed modulating the IgG subtype response and the level of mucosal IgA antibodies. CpG-containing CaP-nanoparticles were as immunogenic as a virus-like particle vaccine. Functionalization of CaP-nanoparticles with T-helper cell epitopes or CpG also allowed overcoming lack of T-cell help. Thus, our results indicate that CaP-nanoparticle-based B-cell targeting vaccines functionalized with TLR-ligands can serve as a versatile platform for efficient induction and modulation of humoral immune responses in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

In Vitro Generation of IL-35-expressing Human Wharton's Jelly-derived Mesenchymal Stem Cells Using Lentiviral Vector.

PubMed

Amari, Afshin; Ebtekar, Massoumeh; Moazzeni, Seyed Mohammad; Soleimani, Masoud; Mohammadi Amirabad, Leila; Tahoori, Mohammad Taher; Massumi, Mohammad

2015-08-01

Human Wharton's Jelly-derived Mesenchymal Stem Cells (hWJ-MSCs) are easily available cells without transplant rejection problems or ethical concerns compared to bone-marrow-derived MSCs for prospective clinical applications. These cells display immunosuppressive properties and may be able to play an important role in autoimmune disorders. Regulatory T-cells (Treg) are important to prevent autoimmune disease development. Interleukin 35 (IL-35) induces the proliferation of Treg cell populations and reduces the activity of T helper 17 (Th17) and T helper 1 (Th1) cells, which play a central role in initiation of inflammation and autoimmune disease. Recent studies identified IL-35 as a new inhibitory cytokine required for the suppressive function of Treg cells. We created IL-35-producing hWJ-MSCs as a good vehicle for reduction of inflammation and autoimmune diseases. We isolated hWJ-MSCs based on explant culture. HWJ-MSCs were transduced at MOI=50 (Multiplicity of Infection) with lentiviral particles harboring murine Interleukin 35 (mIL-35). Expression of IL-35 in hWJ-MSCs was quantified by an IL-35 ELISA kit. IL-35 bioactivity was analyzed by inhibiting the proliferation of mouse splenocytes using CFSE cell proliferation kit. Frequency of CD4+CD25+CD127 low/neg Foxp3+ Treg cells was measured by flow cytometry. There was an up to 85% GFP positive transduction rate, and the cells successfully released a high level of mIL-35 protein (750 ng/ml). IL-35 managed to inhibit CD4+ T cell proliferation with PHA, and improved the frequency of Treg cells. Our data suggest that transduced hWJ-MSCs overexpressing IL-35 may provide a useful approach for basic research on gene therapy for autoimmune disorders.

Apigenin Attenuates Experimental Autoimmune Myocarditis by Modulating Th1/Th2 Cytokine Balance in Mice.

PubMed

Zhang, Shouxin; Liu, Xiaoyan; Sun, Chengming; Yang, Jun; Wang, Lihong; Liu, Jie; Gong, Lei; Jing, Yanyan

2016-04-01

This study aims to investigate the protective effect of apigenin on the development of experimental autoimmune myocarditis (EAM) and the underlying mechanisms. An EAM model was induced in BALB/c mice by the injection of porcine cardiac myosin. Apigenin was orally administered from day 1 to 21. The severity of myocarditis was assessed by determination of heart weight/body weight ratio (HW/BW) and histopathological evaluation. Echocardiography was conducted to evaluate the cardiac function and heart structure. Antigen-specific T cell proliferation responses to cardiac myosin were evaluated by the lymphocyte proliferation assay. ELISA was used to determine serum levels of type 1 helper (Th1) and Th2 cytokines. Apigenin treatment significantly decreased HW/BW. Histopathologic analysis showed that the infiltration of inflammatory cells was reduced significantly by apigenin treatment. Meanwhile, apigenin administration effectively ameliorated autoimmune myocarditis-induced cardiac hypertrophy and cardiac dysfunction as well as inhibited lymphocyte proliferation in mice immunized with myosin. Furthermore, Th1 cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) were significantly downregulated, while Th2 cytokines IL-4 and IL-10 were markedly upregulated. The results indicated that apigenin can alleviate EAM due to its immunomodulatory reactions in modification of helper T cell balance.

Increased Frequency of T Follicular Helper Cells and Elevated Interleukin-27 Plasma Levels in Patients with Pemphigus

PubMed Central

Schmidt, Thomas; Seipelt, Maria; Tackenberg, Björn; Möbs, Christian; Ghoreschi, Kamran; Hertl, Michael; Eming, Rüdiger

2016-01-01

Pemphigus is an autoimmune disease in which IgG auto-antibodies (auto-ab) against the desmosomal cadherins desmoglein (Dsg) 3 and Dsg1 cause loss of epidermal keratinocyte adhesion. Aim of this study was to investigate cytokines derived from antigen-presenting cells (APC) and their relation to CD4+ T cell subpopulations and to the auto-ab response in pemphigus. In this regard, patients with pemphigus were compared to patients with myasthenia gravis (MG), an unrelated auto-ab–mediated autoimmune disease, and healthy controls. In pemphigus and MG, the plasma concentrations of the APC-derived immunomodulatory cytokine IL-27 were highly increased. Strikingly, IL-27 strongly correlated with Dsg-specific IgG auto-ab titers. T helper (Th) 17 cells were augmented in both pemphigus and MG patients while T follicular helper (Tfh) cells, which are essential in providing B cell help, were increased only in pemphigus along with increasing plasma concentrations of IL-21, a cytokine produced by Th17 and Tfh cells. Moreover, we could detect Dsg3-specific autoreactive T cells producing IL-21 upon ex vivo stimulation with Dsg3. These findings suggest that IL-27 and IL-21-producing T cells, are involved in the pathogenesis of pemphigus. The further characterization of IL-21-producing T cells and of the role of IL-27 will lead to a more defined understanding of the auto-ab response in pemphigus. PMID:26872212

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.

Gastrointestinal immune system and its disorders.

PubMed

Keren, D F

1990-01-01

Over the past 15 years the basic details of the mucosal immune response have been described. The challenge of the next decade is to expand these details and to relate this basic information to pathologic processes in the gastrointestinal tract. It is now clear that secretory IgA is the main immunoglobulin produced by the mucosa. Further, we know that oral rather than parenteral priming preferentially stimulates a secretory IgA response. IgA protects mainly by binding to an intraluminal microorganism or toxin and thereby interfering with its absorption across the gut epithelium. The cellular basis for the IgA response has also been elucidated to some degree. It is clear that the response is highly T cell dependent and requires both helper T cells and switch T cells. With the use of monoclonal antibodies, we have begun to learn about cell-mediated functions in the gut. Suppressor/cytotoxic lymphocytes are largely sequestered in the epithelium whereas helper/inducer lymphocytes mainly reside in the lamina propria. In diseases such as celiac disease and inflammatory bowel disease, several alterations in the gastrointestinal immune system have been described. Some, such as the finding of antibody to gliaden, may be causally related to the disease. Others, such as antibodies to luminal bacteria, likely are secondary events. The challenge of the next decade is to expand these details and to relate this basic information to pathologic processes along the gastrointestinal tract.

Ontogeny of surface markers on functionally distinct T cell subsets in the chicken.

PubMed

Traill, K N; Böck, G; Boyd, R L; Ratheiser, K; Wick, G

1984-01-01

Three subsets of chicken peripheral T cells (T1, T2 and T3) have been identified in peripheral blood of adult chickens on the basis of fluorescence intensity after staining with certain xenogeneic anti-thymus cell sera (from turkeys and rabbits). They differentiate between 3-10 weeks of age in parallel with development of responsiveness to the mitogens concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM). Functional tests on the T subsets, sorted with a fluorescence-activated cell sorter, have shown that T2, 3 cells respond to Con A, PHA and PWM and are capable of eliciting a graft-vs.-host reaction (GvHR). In contrast, although T1 cells respond to Con A, they respond poorly to PHA and not at all to PWM or in GvHR. There was some indication of cooperation between T1 and T2,3 cells for the PHA response. Parallels between these chicken subsets and helper and suppressor/cytotoxic subsets in mammalian systems are discussed.

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.

Neisseria meningitidis expressing lgtB lipopolysaccharide targets DC-SIGN and modulates dendritic cell function.

PubMed

Steeghs, Liana; van Vliet, Sandra J; Uronen-Hansson, Heli; van Mourik, Andries; Engering, Anneke; Sanchez-Hernandez, Martha; Klein, Nigel; Callard, Robin; van Putten, Jos P M; van der Ley, Peter; van Kooyk, Yvette; van de Winkel, Jan G J

2006-02-01

Neisseria meningitidis lipopolysaccharide (LPS) has been identified as a major determinant of dendritic cell (DC) function. Here we report that one of a series of meningococcal mutants with defined truncations in the lacto-N-neotetraose outer core of the LPS exhibited unique strong adhesion and internalization properties towards DC. These properties were mediated by interaction of the GlcNAc(beta1-3)-Gal(beta1-4)-Glc-R oligosaccharide outer core of lgtB LPS with the dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) lectin receptor. Activation of DC-SIGN with this novel oligosaccharide ligand skewed T-cell responses driven by DC towards T helper type 1 activity. Thus, the use of lgtB LPS may provide a powerful instrument to selectively induce the desired arm of the immune response and potentially increase vaccine efficacy.

An efficient deletion mutant packaging system for defective herpes simplex virus vectors: Potential applications to human gene therapy and neuronal physiology

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

Geller, A.I.; Keyomarsi, K.; Bryan, J.

1990-11-01

The authors have previously described a defective herpes simplex virus (HSV-1) vector system that permits that introduction of virtually any gene into nonmitotic cells. pHSVlac, the prototype vector, stably expresses Escherichia coli {beta}-galactosidase from a constitutive promoter in many human cell lines, in cultured rat neurons from throughout the nervous system, and in cells in the adult rat brain. HSV-1 vectors expressing other genes may prove useful for studying neuronal physiology or performing human gene therapy for neurological diseases, such as Parkinson disease or brain tumors. A HSV-1 temperature-sensitive (ts) mutant, ts K, has been used as helper virus; tsmore » mutants revert to wild type. In contrast, HSV-1 deletion mutants essentially cannot revert to wild type; therefore, use of a deletion mutant as helper virus might permit human gene therapy with HSV-1 vectors. They now report an efficient packaging system for HSV-1 VECTORS USING A DELETION MUTANT, d30EBA, as helper virus; virus is grown on the complementing cell line M64A. pHSVlac virus prepared using the deletion mutant packaging system stably expresses {beta}-galactosidase in cultured rat sympathetic neurons and glia. Both D30EBA and ts K contain a mutation in the IE3 gene of HSV-1 strain 17 and have the same phenotype; therefore, changing the helper virus from ts K to D30EBA does not alter the host range or other properties of the HSV-1 vector system.« less

The analysis of some indices of immune response, DNA repair, and micronuclei content in cells from tick-borne encephalitis patients.

PubMed

Ilyinskikh, N N; Zagromov, E J; Lepekhin, A V

1990-12-01

Patients with tick-borne encephalitis (TBE) had higher counts of red blood cells (RBC) with micronuclei. The majority of patients revealed decreased capacity of blood lymphoid cells for DNA repair except those with a 2-wave pattern of the course of disease; in the latter, the DNA repair was significantly higher than in healthy donors. Patients with TBE revealed lower T-lymphocyte counts due to a decrease in the amount of T-helper cells (the level of T-suppressors was elevated). The intensity of antibody production against TBE virus was significantly enhanced by termination of disease in the majority of patients. The count of natural killer cells was decreased, particularly at the initial stage of disease. At the time of admission to hospital the counts of RBC with micronuclei and of T-helper cells were in reverse proportion. At the terminal stage of disease the same correlation was noted between RBC counts with micronuclei and the antibody level. At the onset of disease a direct correlation was noted between DNA repair and B-lymphocyte and T-helper counts. At the final stage of disease the reverse correlation between the activity of DNA-repair systems and T-suppressor counts was registered. Three months after discharge from hospital, the indices of micronuclear test, natural killer cell activity, and DNA repair returned to normal.

Differential TCR signals for T helper cell programming.

PubMed

Morel, Penelope A

2018-05-02

Upon encounter with their cognate antigen naïve CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen presenting cells, cytokines and costimulatory molecules. The strength of the T cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength. This review examines the recent literature in this area and highlights important new developments in our understanding of Th cell differentiation and TCR signal strength. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Human Effector Memory T Helper Cells Engage with Mouse Macrophages and Cause Graft-versus-Host-Like Pathology in Skin of Humanized Mice Used in a Nonclinical Immunization Study.

PubMed

Sundarasetty, Balasai; Volk, Valery; Theobald, Sebastian J; Rittinghausen, Susanne; Schaudien, Dirk; Neuhaus, Vanessa; Figueiredo, Constanca; Schneider, Andreas; Gerasch, Laura; Mucci, Adele; Moritz, Thomas; von Kaisenberg, Constantin; Spineli, Loukia M; Sewald, Katherina; Braun, Armin; Weigt, Henning; Ganser, Arnold; Stripecke, Renata

2017-06-01

Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4 + T cells in peripheral blood and lymph nodes. No weight loss, human malignancies, or systemic graft-versus-host (GVH) disease were observed. However, for one reconstitution cohort, some mice immunized with iDCpp65 showed GVH-like signs on the skin. Histopathology analyses of the inflamed skin revealed intrafollicular and perifollicular human CD4 + cells near F4/80 + mouse macrophages around hair follicles. In spleen, CD4 + cells formed large clusters surrounded by mouse macrophages. In plasma, high levels of human T helper 2-type inflammatory cytokines were detectable, which activated in vitro the STAT5 pathway of murine macrophages. Despite this inflammatory pattern, human CD8 + T cells from mice with GVH reacted against the pp65 antigen in vitro. These results uncover a dynamic cross-species interaction between human memory T cells and mouse macrophages in the skin and lymphatic tissues of humanized mice. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity

PubMed Central

Hemmers, Saskia; Schizas, Michail; Faire, Mehlika B.; Konopacki, Catherine; Schmidt-Supprian, Marc; Germain, Ronald N.

2017-01-01

The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR-mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity. An induced switch of the T reg cell TCR repertoire to a random repertoire also preserved, albeit to a limited degree, the ability to suppress lymphadenopathy and T helper cell type 2 activation. At the same time, these perturbations of the T reg cell TCR repertoire led to marked immune cell activation, tissue inflammation, and an ultimately severe autoimmunity, indicating the importance of diversity and specificity for optimal T reg cell function. PMID:28130403

Measles virus-induced suppression of immune responses.

PubMed

Griffin, Diane E

2010-07-01

Measles is an important cause of child mortality that has a seemingly paradoxical interaction with the immune system. In most individuals, the immune response is successful in eventually clearing measles virus (MV) infection and in establishing life-long immunity. However, infection is also associated with persistence of viral RNA and several weeks of immune suppression, including loss of delayed type hypersensitivity responses and increased susceptibility to secondary infections. The initial T-cell response includes CD8+ and T-helper 1 CD4+ T cells important for control of infectious virus. As viral RNA persists, there is a shift to a T-helper 2 CD4+ T-cell response that likely promotes B-cell maturation and durable antibody responses but may suppress macrophage activation and T-helper 1 responses to new infections. Suppression of mitogen-induced lymphocyte proliferation can be induced by lymphocyte infection with MV or by lymphocyte exposure to a complex of the hemagglutinin and fusion surface glycoproteins without infection. Dendritic cells (DCs) are susceptible to infection and can transmit infection to lymphocytes. MV-infected DCs are unable to stimulate a mixed lymphocyte reaction and can induce lymphocyte unresponsiveness through expression of MV glycoproteins. Thus, multiple factors may contribute both to measles-induced immune suppression and to the establishment of durable protective immunity.

Cellular basis for neonatally induced T-suppressor activity. Primary B cell maturation is blocked by suppressor-helper interactions restricted by loci on chromosome 12

PubMed Central

1985-01-01

The cellular mechanism and genetic restriction of neonatally induced HA- specific suppressor T (Ts) cells have been examined. The in vivo effect of these Ts cells on antibody production, primary B cell proliferation, B cell surface marker changes, and helper T (Th) cell priming during primary responses to HA have been determined. The results indicate that, although antigen-induced B cell proliferative responses and surface marker changes occur in the presence of Ts cells, differentiation to Ig secretion, and long-lived memory B cell production are prevented. Further, antigen-specific Th cell priming is completely ablated by Ts cells, suggesting that Ts act by preventing the delivery of Th signals required for both the later stages of primary B cell maturation, and the formation of memory B cell populations. Finally, in vivo cell mixing experiments using congenic mice indicate that this Ts-Th interaction is restricted by loci on mouse chromosome 12. PMID:2580040

The role of transforming growth factor β in T helper 17 differentiation.

PubMed

Zhang, Song

2018-04-23

T helper 17 (Th17) cells play critical roles in inflammatory and autoimmune diseases. The lineage-specific transcription factor RORγt is the key regulator for Th17 cell fate commitment. A substantial number of studies have established the importance of transforming growth factor β (TGF-β) -dependent pathways in inducing RORγt expression and Th17 differentiation. TGF-β superfamily members TGF-β 1 , TGF-β 3 or activin A, in concert with interleukin-6 or interleukin-21, differentiate naive T cells into Th17 cells. Alternatively, Th17 differentiation can occur through TGF-β-independent pathways. However, the mechanism of how TGF-β-dependent and TGF-β-independent pathways control Th17 differentiation remains controversial. This review focuses on the perplexing role of TGF-β in Th17 differentiation, depicts the requirement of TGF-β for Th17 development, and underscores the multiple mechanisms underlying TGF-β-promoted Th17 generation, pathogenicity and plasticity. With new insights and comprehension from recent findings, this review specifically tackles the involvement of the canonical TGF-β signalling components, SMAD2, SMAD3 and SMAD4, summarizes diverse SMAD-independent mechanisms, and highlights the importance of TGF-β signalling in balancing the reciprocal conversion of Th17 and regulatory T cells. Finally, this review includes discussions and perspectives and raises important mechanistic questions about the role of TGF-β in Th17 generation and function. © 2018 John Wiley & Sons Ltd.

Immunologic analyses of peripheral leukocytes from workers at an ethical narcotics manufacturing facility.

PubMed

Biagini, R E; Henningsen, G M; Klincewicz, S L

1995-01-01

Little information exists about possible adverse health effects associated with workplace exposure to opiate compounds. We have previously reported opiate-specific IgG antibodies, positive epicutaneous tests, and pulmonary function decrements in workers exposed occupationally to opiates. In the present work, we extended these findings to investigate the effect of occupational opiate exposure on lymphocyte subpopulations and mitogen-induced lymphoblastogenesis. Thirty-three opiate-exposed workers and 8 nonexposed control workers were evaluated for lymphocyte subpopulation absolute numbers and percentages, by evaluating cell surface antigen expression with flow cytometry. A complete blood count with differential, common clinical chemistry parameters, and serum immunoglobulin levels were also evaluated. Opiate-exposed workers showed significantly (p < .05) increased absolute numbers and percentages of HLA-DR+ cells (MHC class II histocompatibility antigen), significantly (p < .01) decreased percentages of T helper-inducer (CD4+) cells, and significantly (p < .05) decreased numbers of basophils, compared with nonexposed opiate workers from the same factory. A trend toward reduction in the T helper-inducer (CD4+)/T cytotoxic-suppressor (CD8+) lymphocyte ratio was also evident. There was also a significant decrease in lymphocyte activity stimulated by pokeweed mitogen (p < .05) in opiate-exposed workers. These data indicate that occupational opiate exposure may change the number and types of circulating peripheral blood leukocytes, or alternatively, alter the expression of receptors on the surface of these cells. In addition, occupational opiate exposure appears to decrease the sensitivity of B-cells to pokeweed mitogen stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Opinion: Interactions of innate and adaptive lymphocytes

PubMed Central

Gasteiger, Georg; Rudensky, Alexander Y.

2015-01-01

Innate lymphocytes, including natural killer (NK) cells and the recently discovered innate lymphoid cells (ILCs) have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. Less well understood is the contribution of the adaptive immune system to the orchestration of innate lymphocyte responses. We review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which adaptive T cells function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential role of regulatory and helper T cells in these processes and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes. PMID:25132095

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke.

PubMed

Shichita, Takashi; Ago, Tetsuro; Kamouchi, Masahiro; Kitazono, Takanari; Yoshimura, Akihiko; Ooboshi, Hiroaki

2012-11-01

Post-ischemic inflammation is an essential step in the progression of ischemic stroke. This review focuses on the function of infiltrating immune cells, macrophages, and T cells, in ischemic brain injury. The brain is a sterile organ; however, the activation of Toll-like receptor (TLR) 2 and TLR4 is pivotal in the beginning of post-ischemic inflammation. Some endogenous TLR ligands are released from injured brain cells, including high mobility group box 1 and peroxiredoxin family proteins, and activate the infiltrating macrophages and induce the expression of inflammatory cytokines. Following this step, T cells also infiltrate into the ischemic brain and mediate post-ischemic inflammation in the delayed phase. Various cytokines from helper T cells and γδT cells function as neurotoxic (IL-23/IL-17, IFN-γ) or neuroprotective (IL-10, IL-4) mediators. Novel neuroprotective strategies should therefore be developed through more detailed understanding of this process and the regulation of post-ischemic inflammation. © 2012 The Authors Journal of Neurochemistry © International Society for Neurochemistry.

A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin

PubMed Central

Ernst, Katharina; Liebscher, Markus; Mathea, Sebastian; Granzhan, Anton; Schmid, Johannes; Popoff, Michel R.; Ihmels, Heiko; Barth, Holger; Schiene-Fischer, Cordelia

2016-01-01

Hsp70 family proteins are folding helper proteins involved in a wide variety of cellular pathways. Members of this family interact with key factors in signal transduction, transcription, cell-cycle control, and stress response. Here, we developed the first Hsp70 low molecular weight inhibitor specifically targeting the peptide binding site of human Hsp70. After demonstrating that the inhibitor modulates the Hsp70 function in the cell, we used the inhibitor to show for the first time that the stress-inducible chaperone Hsp70 functions as molecular component for entry of a bacterial protein toxin into mammalian cells. Pharmacological inhibition of Hsp70 protected cells from intoxication with the binary actin ADP-ribosylating iota toxin from Clostridium perfringens, the prototype of a family of enterotoxins from pathogenic Clostridia and inhibited translocation of its enzyme component across cell membranes into the cytosol. This finding offers a starting point for novel therapeutic strategies against certain bacterial toxins. PMID:26839186

Circulating Th1 cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children

PubMed Central

Obeng-Adjei, Nyamekye; Portugal, Silvia; Tran, Tuan M.; Yazew, Takele B.; Skinner, Jeff; Li, Shanping; Jain, Aarti; Felgner, Philip L.; Doumbo, Ogobara K.; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter D.

2015-01-01

SUMMARY Malaria-specific antibody responses are short-lived in children, leaving them susceptible to repeated bouts of febrile malaria. The cellular and molecular mechanisms underlying this apparent immune deficiency are poorly understood. Recently, T follicular helper (Tfh) cells have been shown to play a critical role in generating long-lived antibody responses. We show that Malian children have resting PD-1+CXCR5+CD4+ Tfh cells in circulation that resemble germinal center Tfh cells phenotypically and functionally. Within this population PD-1+CXCR5+CXCR3− Tfh cells are superior to Th1-polarized PD-1+CXCR5+CXCR3+ Tfh cells in helping B cells. Longitudinally, we observed that malaria drives Th1 cytokine responses, and accordingly, the less functional Th1-polarized Tfh subset was preferentially activated and its activation did not correlate with antibody responses. These data provide insights into the Tfh cell biology underlying suboptimal antibody responses to malaria in children, and suggest that vaccine strategies that promote CXCR3− Tfh cell responses may improve malaria vaccine efficacy. PMID:26440897

The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity.

PubMed

Yi, Woelsung; Gupta, Sanjay; Ricker, Edd; Manni, Michela; Jessberger, Rolf; Chinenov, Yurii; Molina, Henrik; Pernis, Alessandra B

2017-08-15

Post-transcriptional modifications can control protein abundance, but the extent to which these alterations contribute to the expression of T helper (T H ) lineage-defining factors is unknown. Tight regulation of Bcl6 expression, an essential transcription factor for T follicular helper (T FH ) cells, is critical as aberrant T FH cell expansion is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we show that lack of the SLE risk variant Def6 results in deregulation of Bcl6 protein synthesis in T cells as a result of enhanced activation of the mTORC1-4E-BP-eIF4E axis, secondary to aberrant assembly of a raptor-p62-TRAF6 complex. Proteomic analysis reveals that this pathway selectively controls the abundance of a subset of proteins. Rapamycin or raptor deletion ameliorates the aberrant T FH cell expansion in mice lacking Def6. Thus deregulation of mTORC1-dependent pathways controlling protein synthesis can result in T-cell dysfunction, indicating a mechanism by which mTORC1 can promote autoimmunity.Excessive expansion of the T follicular helper (T FH ) cell pool is associated with autoimmune disease and Def6 has been identified as an SLE risk variant. Here the authors show that Def6 limits proliferation of T FH cells in mice via alteration of mTORC1 signaling and inhibition of Bcl6 expression.

Treatment of Guillain-Barré syndrome with Bifidobacterium infantis through regulation of T helper cells subsets.

PubMed

Shi, Peng; Qu, Hongdang; Nian, Di; Chen, Yuhua; Liu, Xiaolin; Li, Qiang; Li, Qianqian; Wang, Chun; Ye, Ming; Ma, Bo

2018-06-13

Guillain-Barré syndrome (GBS) is a rare, autoimmune-mediated disease. The use of Bifidobacterium is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells. In this study, we explored the differentiation of T helper cell subsets in patients with GBS. We also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model. We used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS. The expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells. We concluded from this study that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies might be required to fully understand the mechanism of action. Copyright © 2018. Published by Elsevier B.V.

IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection

PubMed Central

Chiodi, Francesca; Bekele, Yonas; Lantto Graham, Rebecka; Nasi, Aikaterini

2017-01-01

IL-7 was previously shown to upregulate the expression of molecules important for interaction of CD4+ T cells with B cells. It is poorly studied whether IL-7 has a role in the biology of T follicular helper (Tfh) cells and whether IL-7 dysregulates the expression of B-cell costimulatory molecules on Tfh cells. We review the literature and provide arguments in favor of IL-7 being involved in the biology of human Tfh cells. The CD127 IL-7 receptor is expressed on circulating Tfh and non-Tfh cells, and we show that IL-7, but not IL-6 or IL-21, upregulates the expression of CD70 and PD-1 on these cells. We conclude that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on Tfh cells and lead to abnormal B cell differentiation. PMID:28473831

The nuclear orphan receptors COUP-TF and ARP-1 positively regulate the trout estrogen receptor gene through enhancing autoregulation.

PubMed Central

Lazennec, G; Kern, L; Valotaire, Y; Salbert, G

1997-01-01

The rainbow trout estrogen receptor (rtER) is a positively autoregulated gene in liver cells. In a previous report, we showed that upregulation is mediated by an estrogen response element (ERE) located in the proximal promoter of the gene and that a half binding site for nuclear receptors (5'-TGACCT-3') located 15 bp upstream of the ERE is involved in the magnitude of the estrogen response. We now report that the human orphan receptor COUP-TF and a COUP-TF-like protein from trout liver are able to bind to the consensus half-site. When cotransfected with the rtER gene proximal promoter, COUP-TF had no regulatory functions on its own. Interestingly, COUP-TF enhanced rtER transactivation properties in the presence of estradiol in a dose-dependent manner when cotransfected with the rtER gene promoter. Unliganded retinoid receptor heterodimers had the same helper function as COUP-TF in the presence of estradiol but were switched to repressors when the ligand all-trans-retinoic acid was added. Mutation of the consensus half-site only slightly reduced COUP-TF helper function, suggesting that it actually results from a complex mechanism that probably involves both DNA binding of COUP-TF to the promoter and protein-protein interaction with another transcription factor bound to the promoter. Nevertheless, a DNA-binding-defective mutant of COUP-TF was also defective in ER helper function. Competition footprinting analysis suggested that COUP-TF actually establishes contacts with the consensus upstream half-site and the downstream ERE half-site that would form a DR-24-like response element. Interaction of COUP-TF with the DR-24 element was confirmed in footprinting assays by using nuclear extracts from Saccharomyces cerevisiae expressing COUP-TF. Finally, interaction of COUP-TF with mutants of the rtER gene promoter showed that COUP-TF recognizes the ERE when the upstream half-site is mutated. These data show that COUP-TF may activate transcription through interaction with other nuclear receptors. This cross-talk between liganded nuclear receptors and orphan receptors is likely to modulate the spectrum of action of a particular ligand-receptor complex and may participate in the cell-type specificity of the ligand effect. PMID:9271383

A Molecular Analysis of the Induction of Class II Major Histocompatibility Antigen Expression on Murine Macrophages by Interferon-Gamma and Its Down-Regulation by Interferon-Alpha/Beta and Dexamethasone

DTIC Science & Technology

1989-11-09

Approved for public release , distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17...kilobasepairs KCl, potassium chloride LFA, lymphocyte function associated LPS, lipopolysaccharide LT, lymphotoxin LV, lentivirus J.LCi, microcurie ...process has also been studied extensively. IL 1 is released from macrophages following contact with helper T cells and one of its targets is the

Highlights of the advances in basic immunology in 2011.

PubMed

Liu, Juan; Liu, Shuxun; Cao, Xuetao

2012-05-01

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells.

Highlights of the advances in basic immunology in 2011

PubMed Central

Liu, Juan; Liu, Shuxun; Cao, Xuetao

2012-01-01

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells. PMID:22522654

The spectrum of STAT functions in mammary gland development

PubMed Central

Hughes, Katherine; Watson, Christine J.

2012-01-01

The signal transducer and activator of transcription (STAT) family of transcription factors have a spectrum of functions in mammary gland development. In some cases these roles parallel those of STATs in other organ systems, while in other instances the function of individual STATs in the mammary gland is specific to this tissue. In the immune system, STAT6 is associated with differentiation of T helper cells, while in the mammary gland, it has a fundamental role in the commitment of luminal epithelial cells to the alveolar lineage. STAT5A is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. By contrast, the initiation of regression following weaning heralds a dramatic and specific activation of STAT3, reflecting its pivotal role in the regulation of cell death and tissue remodeling during mammary involution. Although it has been demonstrated that STAT1 is regulated during a mammary developmental cycle, it is not yet determined whether it has a specific, non-redundant function. Thus, the mammary gland constitutes an unusual example of an adult organ in which different STATs are sequentially activated to orchestrate the processes of functional differentiation, cell death and tissue remodeling. PMID:24058764

Modulation of surgical fibrosis by microbial zwitterionic polysaccharides

NASA Astrophysics Data System (ADS)

Ruiz-Perez, Begonia; Chung, Doo R.; Sharpe, Arlene H.; Yagita, Hideo; Kalka-Moll, Wiltrud M.; Sayegh, Mohamed H.; Kasper, Dennis L.; Tzianabos, Arthur O.

2005-11-01

Bacterial carbohydrates have long been considered T cell-independent antigens that primarily induce humoral immune responses. Recently, it has been demonstrated that bacterial capsules that possess a zwitterionic charge motif can activate CD4+ T cells after processing and presentation by antigen-presenting cells. Here we show that these zwitterionic polysaccharides can prevent T helper 1-mediated fibrosis by signaling for the release of IL-10 from CD4+ T cells in vivo. IL-10 production by these T cells and their ability to prevent fibrosis is controlled by the inducible costimulator (ICOS)-ICOS ligand pathway. These data demonstrate that the interaction of the zwitterionic polysaccharides with T cells results in modulation of surgical fibrosis in vivo and suggest a previously undescribed approach to "harnessing" T cell function to prevent inflammatory tissue disorders in humans. IL-10 | microbial polysaccharides | inducible costimulator

Therapeutic PD-L1 and LAG-3 blockade rapidly clears established blood-stage Plasmodium infection

PubMed Central

Butler, Noah S.; Moebius, Jacqueline; Pewe, Lecia L.; Traore, Boubacar; Doumbo, Ogobara K.; Tygrett, Lorraine T.; Waldschmidt, Thomas J.; Crompton, Peter D.; Harty, John T.

2011-01-01

Plasmodium infection of erythrocytes induces clinical malaria. Parasite-specific CD4+ T cells correlate with reduced parasite burdens and severity of human malaria, and are required to control blood-stage infection in mice. However, the characteristics of CD4+ T cells that determine protection or parasite persistence remain unknown. Here we show that P. falciparum infection of humans increased expression of an inhibitory receptor (PD-1) associated with T cell dysfunction. In vivo blockade of PD-L1 and LAG-3 restored CD4+ T cell function, amplified T follicular helper cell and germinal center B cell and plasmablast numbers, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, which can be rescued to enhance parasite control using inhibitory therapies. PMID:22157630

Mathematical model for HIV dynamics in HIV-specific helper cells

NASA Astrophysics Data System (ADS)

Pinto, Carla M. A.; Carvalho, Ana

2014-03-01

In this paper we study a delay mathematical model for the dynamics of HIV in HIV-specific CD4 + T helper cells. We modify the model presented by Roy and Wodarz in 2012, where the HIV dynamics is studied, considering a single CD4 + T cell population. Non-specific helper cells are included as alternative target cell population, to account for macrophages and dendritic cells. In this paper, we include two types of delay: (1) a latent period between the time target cells are contacted by the virus particles and the time the virions enter the cells and; (2) virus production period for new virions to be produced within and released from the infected cells. We compute the reproduction number of the model, R0, and the local stability of the disease free equilibrium and of the endemic equilibrium. We find that for values of R0<1, the model approaches asymptotically the disease free equilibrium. For values of R0>1, the model approximates asymptotically the endemic equilibrium. We observe numerically the phenomenon of backward bifurcation for values of R0⪅1. This statement will be proved in future work. We also vary the values of the latent period and the production period of infected cells and free virus. We conclude that increasing these values translates in a decrease of the reproduction number. Thus, a good strategy to control the HIV virus should focus on drugs to prolong the latent period and/or slow down the virus production. These results suggest that the model is mathematically and epidemiologically well-posed.

Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression

PubMed Central

Vaeth, Martin; Müller, Gerd; Stauss, Dennis; Dietz, Lena; Klein-Hessling, Stefan; Serfling, Edgar; Lipp, Martin

2014-01-01

Maturation of high-affinity B lymphocytes is precisely controlled during the germinal center reaction. This is dependent on CD4+CXCR5+ follicular helper T cells (TFH) and inhibited by CD4+CXCR5+Foxp3+ follicular regulatory T cells (TFR). Because NFAT2 was found to be highly expressed and activated in follicular T cells, we addressed its function herein. Unexpectedly, ablation of NFAT2 in T cells caused an augmented GC reaction upon immunization. Consistently, however, TFR cells were clearly reduced in the follicular T cell population due to impaired homing to B cell follicles. This was TFR-intrinsic because only in these cells NFAT2 was essential to up-regulate CXCR5. The physiological relevance for humoral (auto-)immunity was corroborated by exacerbated lupuslike disease in the presence of NFAT2-deficient TFR cells. PMID:24590764

Enterocolitis induced by autoimmune targeting of enteric glial cells: A possible mechanism in Crohn's disease?

NASA Astrophysics Data System (ADS)

Cornet, Anne; Savidge, Tor C.; Cabarrocas, Julie; Deng, Wen-Lin; Colombel, Jean-Frederic; Lassmann, Hans; Desreumaux, Pierre; Liblau, Roland S.

2001-11-01

Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8+ T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and/or the progression of human inflammatory bowel disease.

Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells

PubMed Central

Tone, Masahide; Tone, Yukiko; Adams, Elizabeth; Yates, Stephen F.; Frewin, Mark R.; Cobbold, Stephen P.; Waldmann, Herman

2003-01-01

Recently, agonist antibodies to glucocorticoid-induced tumor necrosis factor receptor (GITR) (tumor necrosis factor receptor superfamily 18) have been shown to neutralize the suppressive activity of CD4+CD25+ regulatory T cells. It was anticipated that this would be the role of the physiological ligand. We have identified and expressed the gene for mouse GITR ligand and have confirmed that its interaction with GITR reverses suppression by CD4+CD25+ T cells. It also, however, provides a costimulatory signal for the antigen-driven proliferation of naïve T cells and polarized T helper 1 and T helper 2 clones. RT-PCR and mAb staining revealed mouse GITR ligand expression in dendritic cells, macrophages, and B cells. Expression was controlled by the transcription factor NF-1 and potentially by alternative splicing of mRNA destabilization sequences. PMID:14608036

Epigenomic Views of Innate Lymphoid Cells.

PubMed

Sciumè, Giuseppe; Shih, Han-Yu; Mikami, Yohei; O'Shea, John J

2017-01-01

The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity.

Epigenomic Views of Innate Lymphoid Cells

PubMed Central

Sciumè, Giuseppe; Shih, Han-Yu; Mikami, Yohei; O’Shea, John J.

2017-01-01

The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity. PMID:29250060

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

Adeno-associated virus type 2 enhances goose parvovirus replication in embryonated goose eggs

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

Malkinson, Mertyn; Winocour, Ernest

The autonomous goose parvovirus (GPV) and the human helper-dependent adeno-associated virus type 2 (AAV2) share a high degree of homology. To determine if this evolutionary relationship has a biological impact, we studied viral replication in human 293 cells and in embryonated goose eggs coinfected with both viruses. Similar experiments were performed with the minute virus of mice (MVM), an autonomous murine parvovirus with less homology to AAV2. In human 293 cells, both GPV and MVM augmented AAV2 replication. In contrast, AAV2 markedly enhanced GPV replication in embryonated goose eggs under conditions where a similar effect was not observed with MVM.more » AAV2 did not replicate in embryonated goose eggs and AAV2 inactivated by UV-irradiation also enhanced GPV replication. To our knowledge, this is the first report that a human helper-dependent member of the Parvoviridae can provide helper activity for an autonomous parvovirus in a natural host.« less

Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.

PubMed

Choi, Yoon Seok; Jung, Min Kyung; Lee, Jeewon; Choi, Seong Jin; Choi, Sung Hoon; Lee, Hyun Woong; Lee, Jong-Joo; Kim, Hyung Joon; Ahn, Sang Hoon; Lee, Dong Hyeon; Kim, Won; Park, Su-Hyung; Huh, Jun R; Kim, Hyoung-Pyo; Park, Jun Yong; Shin, Eui-Cheol

2018-03-01

CD4 + CD25 + Foxp3 + T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4 + CD25 + Foxp3 + ) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patterns. Phenotypes of Treg cells were analyzed by flow cytometry and an RORγt inhibitor, ML-209, was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted peripheral blood mononuclear cells s and isolated Treg cells. A higher proportion of CD4 + CD25 + Foxp3 + Treg cells from patients with AHA compared with controls produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients' blood correlated with their serum level of alanine aminotransferase. Treg cells from patients with AHA have altered functions compared with Treg cells from healthy individuals. Treg cells from patients with AHA produce higher levels of TNF, gain features of T-helper 17 cells, and have reduced suppressive activity. The presence of these cells is associated with severe liver injury in patients with AHA. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Impaired selection of IgA and intestinal dysbiosis associated with PD-1-deficiency

PubMed Central

Maruya, Mikako; Kawamoto, Shimpei; Kato, Lucia M.; Fagarasan, Sidonia

2013-01-01

A major function of immunoglobulin A (IgA) is to maintain balanced bacterial communities in the gut. We have previously shown that diversification of IgA upon somatic hypermutation (SHM) is critical for IgA function yet the principles governing the selection of IgA in the gut have remained elusive. Here we discuss recent progress in understanding this process as revealed by our studies in mice that lack the inhibitory co-receptor programmed cell death–1 (PD-1). We found that PD-1 affects the dynamics of germinal center (GC) B cells by controlling the number and the nature of T helper cells in the Peyer’s patches (PPs). Deregulation of the T cell compartment impacts the selection of IgA plasma cells leading to gut dysbiosis. When the PD-1-dependent checkpoint is missing, gut bacteria go beyond the mucosal barrier and induce systemic GCs that can generate antibodies with auto-reactive properties. PMID:23333864

Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System.

PubMed

Spath, Sabine; Komuczki, Juliana; Hermann, Mario; Pelczar, Pawel; Mair, Florian; Schreiner, Bettina; Becher, Burkhard

2017-02-21

Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits. CNS-invading phagocytes produced reactive oxygen species and exhibited a distinct genetic signature compared to myeloid cells invading other organs. We propose that the CNS is particularly vulnerable to the attack of monocyte-derived phagocytes and that the effector functions of GM-CSF-expanded myeloid cells are in turn guided by the tissue microenvironment. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

CD8 down-regulation on cytotoxic T lymphocytes of patients with endometrioid endometrial carcinomas.

PubMed

Pascual-García, Mónica; Bértolo, Cristina; Nieto, Juan C; Serrat, Neus; Espinosa, Íñigo; D'Angelo, Emanuela; Muñoz, Raquel; Rovira, Ramón; Vidal, Silvia; Prat, Jaime

2016-10-01

Carcinogenesis is a multistep process in which cancer cells and tumor stroma cells play important roles. T lymphocytes are immune constituents of tumor stroma and play a crucial function in anti-tumor response. By immunohistochemistry and flow cytometry, we studied T cytotoxic (CTLs) and T helper lymphocyte distribution and percentage in the tumor microenvironment and peripheral blood from 35 patients with endometrioid endometrial carcinomas (EEC). We also studied 23 healthy donors' blood samples as a control group. Tumor and non-tumoral endometrium samples were obtained. Immunohistochemistry revealed a high number of CTLs and T helper lymphocytes in the tumor stroma of myoinvasive EECs. T lymphocytes were mostly located in the invasive front. By flow cytometry, the percentages of CTLs and T helper lymphocytes were significantly higher in the tumor compared with the non-neoplastic endometrium (P = .0492 and P = .002). The mean fluorescence intensity of CD8 staining was lower in the tumor compared to the non-neoplastic endometrium (P = .001). There was also reduction of the mean fluorescence intensity of CD8 staining on peripheral blood from patients with grade 3 EECs compare to the peripheral blood from healthy donors (P = .0093). No alterations in the expression of granzymes A and B were found in the CTLs from the EEC cases. Finally, in a proteome profiler cytokine array we found that the growth differentiation factor 15 (GDF15) increased in blood in parallel to the tumor grade. EECs are capable of down-regulating CD8 expression of CTLs. Most likely, this effect is mediated by a soluble molecule present in plasma and is not a result of anergy or exhaustion state. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Effects of Inteferons on Human B-cell Differentiation in vitro

PubMed Central

Kim, Samyong; Stoetter, Hans; Heimpel, Herrman

1987-01-01

The effects of interferons (IFN) on in vitro differentiation of B-lymphocytes were studied. Peripheral lymphocytes from normal subjects were cultivated under polyclonal activator pokeweed mitogen (PWN) or Epstein-Barr virus (EBV) stimulation. The secreted Ig in the culture supernatants were measured for IgM by ELISA method. To determine the cellular level of IFN action T-cell enriched fraction (Te) or B-cell enriched fraction (Be) were preincubated with IFN prior to recombination culture. IFN had modulatory activities on Ig production; at low to moderately high doses (10–1000 U/ml of IFN-alpha or 12–120 U/ml of IFN-gamma) stimulating when IFN was added until 48 hr after the start of the culture, while after 72 hr from culture start IFN suppressed Ig production. Preincubation of Be-cells with moderately high doses of IFN (120 U/ml of IFN-gamma or 1000 U/ml of IFN-alpha) prior to PWM-stimulation suppressed Ig production. Likewise, in EBV-stimulated culture, high dose IFN suppressed Ig production. But low dose of IFN enhanced ig production in EBV-stimulated culture. Preincubation of Te-cells with IFN prior to PWM-stimulation with Be-cells enhanced the Ig production. The T-cell subset analysis at the end of these culture showed enhanced ratio of T-helper cell relative to T-suppressor cells, suggesting increased T-helper cell proliferation after incubation with IFN. Thus, it is concluded that IFNs have modulatory activities on B-cell differentiation. The mechanism seems to be direct effects on B-cells (in PWM and EBV system) as well as through T-helper cell mediation (PWM system). The IFN-gamma showed more potent (2-to 6-fold) stimulatory activities than IFN-alpha. PMID:2484953

Suppression of unprimed T and B cells in antibody responses by irradiation-resistant and plastic-adherent suppressor cells in Toxoplasma gondii-infected mice

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

Suzuki, Y.; Kobayashi, A.

1983-04-01

In the acute phase of Toxoplasma infection, the function of both helper T and B cells was suppressed in primary antibody responses to dinitrophenol (DNP)-conjugated protein antigens. During the course of infection, the suppressive effect on T cells seems to continue longer than that on B cells, since suppression in responses to sheep erythrocytes, a T-dependent antigen, persisted longer than those to DNP-Ficoll, a T-independent antigen. Plastic-adherent cells from the spleens of Toxoplasma-infected and X-irradiated (400 rads) mice had strong suppressor activity in primary anti-sheep erythrocyte antibody responses of normal mouse spleen cells in vitro. These data suggest that themore » activation of irradiation-resistant and plastic-adherent suppressor cells causes the suppression of both T and B cells in Toxoplasma-infected mice.« less

Interleukin-22: immunobiology and pathology

PubMed Central

Dudakov, Jarrod A.; Hanash, Alan M.; van den Brink, Marcel R.M.

2015-01-01

Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T-helper (Th)-17 cells, γδ T cells, NKT cells and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has rapidly evolved since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues including the intestines, lung, liver, kidney, thymus, pancreas and skin. IL-22 primarily targets non-hematopoietic epithelial and stromal cells where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we will assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function. PMID:25706098

Retinoic Acid as a Modulator of T Cell Immunity

PubMed Central

Bono, Maria Rosa; Tejon, Gabriela; Flores-Santibañez, Felipe; Fernandez, Dominique; Rosemblatt, Mario; Sauma, Daniela

2016-01-01

Vitamin A, a generic designation for an array of organic molecules that includes retinal, retinol and retinoic acid, is an essential nutrient needed in a wide array of aspects including the proper functioning of the visual system, maintenance of cell function and differentiation, epithelial surface integrity, erythrocyte production, reproduction, and normal immune function. Vitamin A deficiency is one of the most common micronutrient deficiencies worldwide and is associated with defects in adaptive immunity. Reports from epidemiological studies, clinical trials and experimental studies have clearly demonstrated that vitamin A plays a central role in immunity and that its deficiency is the cause of broad immune alterations including decreased humoral and cellular responses, inadequate immune regulation, weak response to vaccines and poor lymphoid organ development. In this review, we will examine the role of vitamin A in immunity and focus on several aspects of T cell biology such as T helper cell differentiation, function and homing, as well as lymphoid organ development. Further, we will provide an overview of the effects of vitamin A deficiency in the adaptive immune responses and how retinoic acid, through its effect on T cells can fine-tune the balance between tolerance and immunity. PMID:27304965

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

Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.

Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted inmore » autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.« less

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.

Association of a NOD2 Gene Polymorphism and T-Helper 17 Cells With Presumed Ocular Toxoplasmosis

PubMed Central

Dutra, Míriam S.; Béla, Samantha R.; Peixoto-Rangel, Alba L.; Fakiola, Michaela; Cruz, Ariane G.; Gazzinelli, Andrea; Quites, Humberto F.; Bahia-Oliveira, Lilian M. G.; Peixe, Ricardo G.; Campos, Wesley R.; Higino-Rocha, Anna C.; Miller, Nancy E.; Blackwell, Jenefer M.; Antonelli, Lis R.; Gazzinelli, Ricardo T.

2013-01-01

Retinochoroiditis manifests in patients infected with Toxoplasma gondii. Here, we assessed 30 sibships and 89 parent/case trios of presumed ocular toxoplasmosis (POT) to evaluate associations with polymorphisms in the NOD2 gene. Three haplotype-tagging single-nucleotide polymorphisms (tag-SNPs) within the NOD2 gene were genotyped. The family-based association test showed that the tag-SNP rs3135499 is associated with retinochoroiditis (P = .039). We then characterized the cellular immune response of 59 cases of POT and 4 cases of active ocular toxoplasmosis (AOT). We found no differences in levels of interferon γ (IFN-γ) and interleukin 2 produced by T-helper 1 cells when comparing patients with AOT or POT to asymptomatic individuals. Unexpectedly, we found an increased interleukin 17A (IL-17A) production in patients with POT or OAT. In patients with POT or AOT, the main cellular source of IL-17A was CD4+CD45RO+T-bet−IFN-γ− T-helper 17 cells. Altogether, our results suggest that NOD2 influences the production of IL-17A by CD4+ T lymphocytes and might contribute to the development of ocular toxoplasmosis. PMID:23100559

Association of a NOD2 gene polymorphism and T-helper 17 cells with presumed ocular toxoplasmosis.

PubMed

Dutra, Míriam S; Béla, Samantha R; Peixoto-Rangel, Alba L; Fakiola, Michaela; Cruz, Ariane G; Gazzinelli, Andrea; Quites, Humberto F; Bahia-Oliveira, Lilian M G; Peixe, Ricardo G; Campos, Wesley R; Higino-Rocha, Anna C; Miller, Nancy E; Blackwell, Jenefer M; Antonelli, Lis R; Gazzinelli, Ricardo T

2013-01-01

Retinochoroiditis manifests in patients infected with Toxoplasma gondii. Here, we assessed 30 sibships and 89 parent/case trios of presumed ocular toxoplasmosis (POT) to evaluate associations with polymorphisms in the NOD2 gene. Three haplotype-tagging single-nucleotide polymorphisms (tag-SNPs) within the NOD2 gene were genotyped. The family-based association test showed that the tag-SNP rs3135499 is associated with retinochoroiditis (P = .039). We then characterized the cellular immune response of 59 cases of POT and 4 cases of active ocular toxoplasmosis (AOT). We found no differences in levels of interferon γ (IFN-γ) and interleukin 2 produced by T-helper 1 cells when comparing patients with AOT or POT to asymptomatic individuals. Unexpectedly, we found an increased interleukin 17A (IL-17A) production in patients with POT or OAT. In patients with POT or AOT, the main cellular source of IL-17A was CD4(+)CD45RO(+)T-bet(-)IFN-γ(-) T-helper 17 cells. Altogether, our results suggest that NOD2 influences the production of IL-17A by CD4(+) T lymphocytes and might contribute to the development of ocular toxoplasmosis.

CHARACTERIZATION OF NORMAL HUMAN LUNG LYMPHOCYTES AND INTERLEUKIN-2-INDUCED LUNG T CELL LINES

EPA Science Inventory

Lymphocytes from the lower respiratory tract were obtained by bronchoalveolar lavage of healthy, non-smoking individuals. arious monoclonal antibodies characterizing activated T cells, helper-inducer and suppressor-inducer T cell subsets, and naive versus memory cells were used t...

Helper signals in the plaque-forming cell response to protein-bound haptens.

PubMed

Roehm, N W; Marrack, P; Kappler, J W

1983-08-01

We have demonstrated the ability of a series of murine T cell hybridomas to deliver an antigen-specific, B cell I-region-restricted helper signal in the generation of specific PFC responses to protein-bound haptens. With some hybridomas the elicitation of optimal PFC responses required the addition of nonspecific factors provided by culture supernatants of concanavalin A-stimulated (Con A SN) spleen cells. Using hapten-primed B cells depleted of both T cells and macrophages (Mphi) we have now demonstrated a requirement for three nonspecific factor preparations to substitute for spleen Con A SN in the elicitation of optimal PFC responses. The first preparation was the interleukin 1 containing culture supernatant of the Mphi tumor cell line P388D1, the second the interleukin 2 (IL-2) and B cell growth factor containing Con A SN of the T cell hybridoma FS6-14.13, and the third, the gamma interferon containing Con A SN of the T cell hybridoma FS7-20.6.18. The P388D1 and FS6-14.13 factor preparations were most effective when added at the initiation of culture, while the FS7-20.6.18 factor preparation was most effective when added at 24 h of culture. The activity of FS6-14.13 Con A SN was depleted by incubation with the IL-2-dependent T cell line HT-2. The activity of FS7-20.6.18 Con A SN was abrogated by incubation at pH 2. The results suggest that the generation of PFC responses to protein-bound haptens require at least three nonspecific factors in addition to an antigen/Ia specific helper signal.

Interleukin (IL)-23 Stimulates IFN-γ Secretion by CD56bright Natural Killer Cells and Enhances IL-18-Driven Dendritic Cells Activation.

PubMed

Ziblat, Andrea; Nuñez, Sol Y; Raffo Iraolagoitia, Ximena Lucía; Spallanzani, Raúl German; Torres, Nicolás I; Sierra, Jessica M; Secchiari, Florencia; Domaica, Carolina I; Fuertes, Mercedes B; Zwirner, Norberto W

2017-01-01

Interleukin (IL)-23 is a member of the IL-12 family of cytokines that, as the other members of this family, is secreted by monocytes, macrophages, and dendritic cells (DC) upon recognition of bacterial, viral, and fungal components. IL-23 is critical during immunity against acute infections, and it is also involved in the development of autoimmune diseases. Although immunoregulatory effects of IL-23 on mouse natural killer (NK) cells have been described, the effect of IL-23 on human NK cells remains ill-defined. In this study, we observed that monocytes stimulated with LPS secreted IL-23 and that blockade of this cytokine during monocyte and NK cell coculture led to a diminished production of IFN-γ by NK cells. Accordingly, rIL-23-induced NK cell activation and stimulated IFN-γ production by CD56 bright NK cells. This effect involved MEK1/MEK2, JNK, PI3K, mammalian target of rapamycin, and NF-κB, but not STAT-1, STAT-3, nor p38 MAPK pathways. Moreover, while NK cell-mediated cytotoxicity remained unaltered, antibody-dependent cellular cytotoxicity (ADCC) was enhanced after IL-23 stimulation. In addition, IL-23 displayed a synergistic effect with IL-18 for IFN-γ production by both CD56 bright and CD56 dim NK cells, and this effect was due to a priming effect of IL-23 for IL-18 responsiveness. Furthermore, NK cells pre-stimulated with IL-18 promoted an increase in CD86 expression and IL-12 secretion by DC treated with LPS, and IL-23 potentiated these effects. Moreover, IL-23-driven enhancement of NK cell "helper" function was dependent on NK cell-derived IFN-γ. Therefore, our results suggest that IL-23 may trigger NK cell-mediated "helper" effects on adaptive immunity, shaping T cell responses during different pathological situations through the regulation of DC maturation.

Innate lymphoid cells in atherosclerosis.

PubMed

Engelbertsen, Daniel; Lichtman, Andrew H

2017-12-05

The family of innate lymphoid cells (ILCs) consisting of NK cells, lymphoid tissue inducer cells and the 'helper'-like ILC subsets ILC1, ILC2 and ILC3 have been shown to have important roles in protection against microbes, regulation of inflammatory diseases and involved in allergic reactions. ILC1s produce IFN-γ upon stimulation with IL-12 and IL-18, ILC2s produce IL-5 and IL-13 responding to IL-33 and IL-25 while ILC3s produce IL-17 and IL-22 after stimulation with IL-23 or IL-1. Although few studies have directly investigated the role for ILCs in atherosclerosis, several studies have investigated transcription factors and cytokines shared by ILCs and T helper cells. In this review we summarize our current understanding of the role of ILC in atherosclerosis and discuss future directions. Copyright © 2017. Published by Elsevier B.V.

The Function of Herpes Simplex Virus Genes: A Primer for Genetic Engineering of Novel Vectors

NASA Astrophysics Data System (ADS)

Roizman, Bernard

1996-10-01

Herpes simplex virus vectors are being developed for delivery and expression of human genes to the central nervous system, selective destruction of cancer cells, and as carriers for genes encoding antigens that induce protective immunity against infectious agents. Vectors constructed to meet these objectives must differ from wild-type virus with respect to host range, reactivation from latency, and expression of viral genes. The vectors currently being developed are (i) helper free amplicons, (ii) replication defective viruses, and (iii) genetically engineered replication competent viruses with restricted host range. Whereas the former two types of vectors require stable, continuous cell lines expressing viral genes for their replication, the replication competent viruses will replicate on approved primary human cell strains.

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.

The effects of ALG on the murine immune response to sheep erythrocytes

PubMed Central

Anderson, Hilary R.; Dresser, D. W.; Iverson, G. M.; Lance, E. M.; Wortis, H. H.; Zebra, J.

1972-01-01

Antilymphocyte globulin (ALG), and to a lesser extent normal rabbit globulin (NRG), when given to mice prior to immunization with sheep-RBC suppress both the γM and γG2a responses. Globulin injected after the antigen suppresses the γG2a response, augments the γG1 response and has little effect on the γM response. These effects are also observed in mice partially paralysed to rabbit γ globulin. In another system—the response to hapten—protein conjugates precursors of antibody producing cells were found to be more resistant to ALS treatment in vivo than were helper cells. It is concluded that the suppressive effects of ALG treatment are largely due to the direct action of ALG on helper cells (T-cells). The mechanism of the adjuvant-like effect is unclear. PMID:4550853

Compound heterozygosity for Pten and SHIP augments T-dependent humoral immune responses and cytokine production by CD4+ T cells

PubMed Central

Moody, J L; Jirik, F R

2004-01-01

Tight regulation of the phosphatidylinositiol 3-kinase (PI3K) pathway is essential not only for normal immune system development and responsiveness, but also in the prevention of immunopathology. Indeed, unchecked activation of the PI3K pathway in T cells induces lymphoproliferation and systemic autoimmunity. Evaluating the importance of threshold levels of two key PI3K pathway phosphoinositol phosphatases, we previously reported that mice heterozygous for both Pten and SHIP develop a more rapid progression of a lymphoproliferative autoimmune syndrome than do Pten+\\− mice. Investigating the basis for this difference, we now describe a quantitative and qualitative difference in the antibody responses of C57BL\\6 Pten+\\− SHIP+\\− mice upon challenge with a T-dependent antigen. Suspecting that this phenotypic difference might be the result, at least in part, of a T-helper cell defect, an in vitro analysis of anti-CD3/interleukin (IL)-2-expanded CD4+ T cells was performed. After stimulation with anti-CD3, cells from mice heterozygous for both Pten and SHIP exhibited a striking increase in IL-4 secretion (> 10-fold), without a corresponding increase in T helper 2 (Th2) cell numbers being evident by intracellular staining for this cytokine. Modest increases were also seen for both IL-13 and IFN-γ. Perhaps in keeping with this abnormal in vitro cytokine profile, IgG1 serum levels were significantly elevated in young C57BL\\6 Pten+\\− SHIP+\\− mice. Thus, the relative levels of Pten and SHIP appear to be key variables in CD4+ T-cell function, primarily via their ability to regulate IL-4 production. PMID:15196208

Distinctive profiles of tumor-infiltrating immune cells and association with intensity of infiltration in colorectal cancer.

PubMed

Wu, Yugang; Yuan, Lei; Lu, Qicheng; Xu, Haiyan; He, Xiaozhou

2018-03-01

Tumor-infiltrating immune cells are heterogeneous and consist of characteristic compartments, including T helper (Th)1 and regulatory T (Treg) cells that exhibit distinctive biological functions. The present study investigated the profile of infiltrating immune cells from surgically removed tumor tissues from patients with colorectal cancer. The characteristic transcription factors of Th1 and Th2 cells, Treg cells, Th17 cells and T follicular helper (Tfh) cells were analyzed. The results demonstrated that a marked increased number of Treg cells presented in tumor infiltrates when compared with non-tumor adjacent tissues. An increased number of Th1 and Tfh cells existed in tumor infiltrates compared with non-tumorous adjacent tissues, while the infiltration of Th17 and Th2 cells was similar between tumor and non-tumor adjacent tissues. Furthermore, there were an increased number of Treg cells in tumors with low infiltration compared with those with high infiltration. The expression of CXC motif chemokine (CXC) receptor 3, CXC ligand (CXCL)L9 and CXCL10 was significantly increased on infiltrating T cells in tumors with high infiltration as compared with those with low infiltration. Macrophages exhibited a dominant M2 phenotype in tumor infiltrates of colorectal cancer, whereas a balanced M1 and M2 phenotype presented in macrophages from the peripheral blood. In vitro stimulation of macrophages isolated from tumor tissue of colorectal cancer with granulocyte macrophage colony-stimulating factor and lipopolysaccharide did not drive to an inflammatory phenotype. The results provide insights into the pattern of immune cell infiltration in Chinese patients with colorectal cancer. It may be beneficial that patients with colorectal cancer are screened for the defined profile along with the expression of CXCL9 and CXCL10 in order to achieve better efficacy in clinical applications of immune-based therapy, including anti-programmed cell death protein 1 therapy.

The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells

PubMed Central

Xiao, Nengming; Eto, Danelle; Elly, Chris; Peng, Guiying; Crotty, Shane; Liu, Yun-Cai

2014-01-01

Follicular helper T cells (TFH cells) are responsible for effective B cell–mediated immunity, and Bcl-6 is a central factor for the differentiation of TFH cells. However, the molecular mechanisms that regulate the induction of TFH cells remain unclear. Here we found that the E3 ubiquitin ligase Itch was essential for the differentiation of TFH cells, germinal center responses and immunoglobulin G (IgG) responses to acute viral infection. Itch acted intrinsically in CD4+ T cells at early stages of TFH cell development. Itch seemed to act upstream of Bcl-6 expression, as Bcl-6 expression was substantially impaired in Itch−/− cells, and the differentiation of Itch−/− T cells into TFH cells was restored by enforced expression of Bcl-6. Itch associated with the transcription factor Foxo1 and promoted its ubiquitination and degradation. The defective TFH differentiation of Itch−/− T cells was rectified by deletion of Foxo1. Thus, our results indicate that Itch acts as an essential positive regulator in the differentiation of TFH cells. PMID:24859451

Circulating CXCR5+CD4+ T Follicular-Like Helper Cell and Memory B Cell Responses to Human Papillomavirus Vaccines

PubMed Central

Matsui, Ken; Adelsberger, Joseph W.; Kemp, Troy J.; Baseler, Michael W.; Ledgerwood, Julie E.; Pinto, Ligia A.

2015-01-01

Through the interaction of T follicular helper (Tfh) cells and B cells, efficacious vaccines can generate high-affinity, pathogen-neutralizing antibodies, and memory B cells. Using CXCR5, CXCR3, CCR6, CCR7, PD1, and ICOS as markers, Tfh-like cells can be identified in the circulation and be classified into three functionally distinct subsets that are PD1+ICOS+, PD1+ ICOS-, or PD1-ICOS-. We used these markers to identify different subsets of CXCR5+CD4+ Tfh-like cells in response to highly immunogenic and efficacious vaccines for human papillomaviruses (HPV): Cervarix and Gardasil. In this small study, we used PBMC samples from 11 Gardasil recipients, and 8 Cervarix recipients from the Vaccine Research Center 902 Study to examine the induction of circulating Tfh-like cells and IgD-CD38HiCD27+ memory B cells by flow cytometry. PD1+ICOS+ CXCR3+CCR6-CXCR5+CD4+ (Tfh1-like) cells were induced and peaked on Day (D) 7 post-first vaccination, but not as much on D7 post-third vaccination. We also observed a trend toward increase in PD1+ICOS+ CXCR3-CCR6-CXCR5+CD4+ (Tfh2-like) cells for both vaccines, and PD1+ICOS+ CXCR3-CCR6+CXCR5+CD4+ (Tfh17-like) subset was induced by Cervarix post-first vaccination. There were also minimal changes in the other cellular subsets. In addition, Cervarix recipients had more memory B cells post-first vaccination than did Gardasil recipients at D14 and D30. We found frequencies of memory B cells at D30 correlated with anti-HPV16 and 18 antibody titers from D30, and the induction levels of memory B cells at D30 and PD1+ICOS+Tfh1-like cells at D7 post-first vaccination correlated for Cervarix. Our study showed that induction of circulating CXCR5+CD4+ Tfh-like subsets can be detected following immunization with HPV vaccines, and potentially be useful as a marker of immunogenicity of vaccines. However, further investigations should be extended to different cohorts with larger sample size to better understand the functions of these T cells, as well as their relationship with B cells and antibodies. PMID:26333070

Effector T Helper Cell Subsets in Inflammatory Bowel Diseases

PubMed Central

Imam, Tanbeena; Park, Sungtae; Kaplan, Mark H.; Olson, Matthew R.

2018-01-01

The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.

Fas-Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis.

PubMed

Volpe, Elisabetta; Sambucci, Manolo; Battistini, Luca; Borsellino, Giovanna

2016-01-01

Fas and Fas Ligand (FasL) are two molecules involved in the regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor (TCR) genes and of those that recognize self-antigens, a process called negative selection; moreover, Fas-FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens. This concept is well demonstrated by the development of autoimmune diseases in mice and humans with defects in Fas or FasL. In recent years, several new aspects of T cell functions in MS have been elucidated, such as the pathogenic role of T helper (Th) 17 cells and the protective role of T regulatory (Treg) cells. Thus, in this review, we summarize the role of the Fas-FasL pathway, with particular focus on its involvement in MS. We then discuss recent advances concerning the role of Fas-FasL in regulating Th17 and Treg cells' functions, in the context of MS.

Regulation of Innate Lymphoid Cells by Aryl Hydrocarbon Receptor

PubMed Central

Li, Shiyang; Bostick, John W.; Zhou, Liang

2018-01-01

With striking similarity to their adaptive T helper cell counterparts, innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer cells, T-bet+ Eomes− group 1 ILCs, GATA3+ group 2 ILCs, RORγt+ group 3 ILCs, and newly identified Id3+ regulatory ILC. ILCs are abundantly present in barrier tissues of the host (e.g., the lung, gut, and skin) at the interface of host–environment interactions. Active research has been conducted to elucidate molecular mechanisms underlying the development and function of ILCs. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. Here, we review recent progresses regarding Ahr function in ILCs. We focus on the Ahr-mediated cross talk between ILCs and other immune/non-immune cells in host tissues especially in the gut. We discuss the molecular mechanisms of the action of Ahr expression and activity in regulation of ILCs in immunity and inflammation, and the interaction between Ahr and other pathways/transcription factors in ILC development and function with their implication in disease. PMID:29354125

A novel Minimalist Cell-Free MHC Class II Antigen Processing System Identifies Immunodominant Epitopes

PubMed Central

Hartman, Isamu Z.; Kim, AeRyon; Cotter, Robert J.; Walter, Kimberly; Dalai, Sarat K.; Boronina, Tatiana; Griffith, Wendell; Schwenk, Robert; Lanar, David E.; Krzych, Urszula; Cole, Robert N.; Sadegh-Nasseri, Scheherazade

2010-01-01

Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4+ T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: MHC class II, cathepsins, and HLA-DM. Our minimalist system successfully identified the physiologically selected immunodominant epitopes of model antigens, HA1 from influenza virus (A/Texas/1/77) and type II collagen. When applied for de novo epitope identification to a malaria antigen, or HA1 from H5N1 virus (Avian Flu), the system selected a single epitope from each protein that were confirmed to be immunodominant by their capacity to activate CD4+ T cells in HLA-DR1 positive human volunteers or transgenic mice immunized with the corresponding proteins. Thus, we provide a powerful new tool for the identification of physiologically relevant helper T cell epitopes from antigens. PMID:21037588

T Lymphocyte Activation Threshold is Increased in Reduced Gravity

NASA Technical Reports Server (NTRS)

Adams, Charley L.; Gonzalez, M.; Sams, C. F.

2000-01-01

There have been substantial advances in molecular and cellular biology that have provided new insight into the biochemical and genetic basis of lymphocyte recognition, activation and expression of distinct functional phenotypes. It has now become evident that for both T and B cells, stimuli delivered through their receptors can result in either clonal expansion or apoptosis. In the case of T cells, clonal expansion of helper cells is accompanied by differentiation into two major functional subsets which regulate the immune response. The pathways between the membrane and the nucleus and their molecular components are an area of very active investigation. This meeting will draw together scientists working on diverse aspects of this problem, including receptor ligand interactions, intracellular pathways that transmit receptor mediated signals and the effect of such signal transduction pathways on gene regulation. The aim of this meeting is to integrate the information from these various experimental approaches into a new synthesis and molecular explanation of T cell activation, differentiation and death.

Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells

PubMed Central

Tokita, Daisuke; Sumpter, Tina L.; Raimondi, Giorgio; Zahorchak, Alan F.; Wang, Zhiliang; Nakao, Atsunori; Mazariegos, George V.; Abe, Masanori; Thomson, Angus W.

2008-01-01

Background/Aims The liver is comparatively rich in plasmacytoid (p) dendritic cells (DC),- innate immune effector cells that are also thought to play key roles in the induction and regulation of adaptive immunity. Methods Liver and spleen pDC were purified from fms-like tyrosine kinase ligand-reated control or lipopolysaccharide-injected C57BL/10 mice. Flow cytometric and molecular biologic assays were used to characterize their function and interaction with naturally-occurring regulatory T cells (Treg). Results While IL-10 production was greater for freshly-isolated liver compared with splenic pDC, the former produced less bioactive IL-12p70. Moreover, liver pDC expressed a low Delta4/Jagged1 Notch ligand ratio, skewed towards T helper 2 cell differentiation/cytokine production, and promoted allogeneic CD4+ T cell apoptosis. T cell proliferation in response to liver pDC was, however, enhanced by blocking IL-10 function at the initiation of cultures. In the absence of naturally occurring CD4+CD25+ regulatory T cells, similar levels of T cell proliferation were induced by liver and spleen pDC and the pro-apoptotic activity of liver pDC was reversed. Conclusion The inferior T cell allostimulatory activity of in vivo-stimulated liver pDC may depend on the presence and function of Treg, a property that may contribute to inherent liver tolerogenicity. PMID:18926588

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

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells.

PubMed

Myers, Darienne R; Lau, Tannia; Markegard, Evan; Lim, Hyung W; Kasler, Herbert; Zhu, Minghua; Barczak, Andrea; Huizar, John P; Zikherman, Julie; Erle, David J; Zhang, Weiguo; Verdin, Eric; Roose, Jeroen P

2017-05-23

CD4 + T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4 + T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (T H 2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4 + T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4 + T cell proliferation and uncover a suppressive role for Irf4 in T H 2 polarization; halving Irf4 gene-dosage leads to increases in GATA3 + and IL-4 + cells. Our studies reveal that naive CD4 + T cells are dynamically tuned by tonic LAT-HDAC7 signals. Published by Elsevier Inc.

The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus

PubMed Central

Massaro, Laura; Barbati, Cristiana; Vomero, Marta; Ceccarelli, Fulvia; Spinelli, Francesca Romana; Riccieri, Valeria; Spagnoli, Alessandra; Alessandri, Cristiano; Desideri, Giovambattista; Conti, Fabrizio

2017-01-01

We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients. PMID:28877244

The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus.

PubMed

Scrivo, Rossana; Massaro, Laura; Barbati, Cristiana; Vomero, Marta; Ceccarelli, Fulvia; Spinelli, Francesca Romana; Riccieri, Valeria; Spagnoli, Alessandra; Alessandri, Cristiano; Desideri, Giovambattista; Conti, Fabrizio; Valesini, Guido

2017-01-01

We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients.

Fas–Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis

PubMed Central

Volpe, Elisabetta; Sambucci, Manolo; Battistini, Luca; Borsellino, Giovanna

2016-01-01

Fas and Fas Ligand (FasL) are two molecules involved in the regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor (TCR) genes and of those that recognize self-antigens, a process called negative selection; moreover, Fas–FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens. This concept is well demonstrated by the development of autoimmune diseases in mice and humans with defects in Fas or FasL. In recent years, several new aspects of T cell functions in MS have been elucidated, such as the pathogenic role of T helper (Th) 17 cells and the protective role of T regulatory (Treg) cells. Thus, in this review, we summarize the role of the Fas–FasL pathway, with particular focus on its involvement in MS. We then discuss recent advances concerning the role of Fas–FasL in regulating Th17 and Treg cells’ functions, in the context of MS. PMID:27729910

Perfluorooctanoic Acid Exposure Suppresses T-independent Antibody Responses

EPA Science Inventory

Exposure to  3.75mg/kg of perfluoroocatnoic acid (PFOA) for 15d suppresses T-dependent antibody responses (TDAR), suggesting that T helper cells and/or B cells/plasma cells may be impacted. This study evaluated effects of PFOA exposure on the T cell-independent antibody response...

Inhibition of T cell-mediated functions by MVM(i), a parvovirus closely related to minute virus of mice.

PubMed

Engers, H D; Louis, J A; Zubler, R H; Hirt, B

1981-12-01

A purified preparation of MVM(i), a murine parvovirus closely related to minute virus of mice (MVM), was found to inhibit various functions mediated by murine T cells in vitro. Addition of MVM(i) virus to secondary allogeneic mixed leukocyte cultures resulted in the inhibition of both lymphocyte proliferation (3H-thymidine incorporation) and the generation of cytolytic T lymphocyte activity but not interferon production. MVM(i) virus also inhibited the growth and cytolytic activity of several cloned, long-term Lyt-2+ cytolytic T cell lines. Furthermore, the antigen-induced proliferative responses of parasite- (Leishmania) specific Lyt-1+ T cells in vitro was abrogated by the addition of MVM(i) virus to the culture. Finally, the suppression of an in vitro antibody response to SRBC by MVM(i) virus was the result of the inhibition of T helper cells required for the B cell response. These suppressive effects were specific for MVM(i); parallel studies in which the prototype MVM parvovirus was used showed no significant inhibition in the various systems tested.

[THE EFFECTIVENESS OF THE MODERN IMMUNOACTIVE PREPARATION IMMUNOFAN FOR MEDICAL REHABILITATION OF PATIENTS WITH NONALCOHOLIC STEATOHEPATITISIS AGAINST NEUROCIRCULATORY DYSTONIA, AFTER INFECTIOUS MONONUCLEOSIS].

PubMed

Yugan, Y L; Sotskaya, Y A; Chabarova, A B

2015-01-01

The presence of the expressed changes of cellular immunity, namely T-lymphopenia, disbalance of subpopulation structure of T-lymphocytes with primary downstroke T-helpers/inductor (CD4+), decrease immunoregulatory index CD4/CD8, and functional activity of T-cells is characteristic for the patients with nonalcoholic steatohepatitis, against neurocirculatory dystonia, after infectious mononucleosis. Including in a medical rehabilitation of such patients immunofan promoted practically full correction of the revealed infringements on the part of a cellular link of immunity.

Treatment of lupus nephritis with total lymphoid irradiation. Observations during a 12-79-month followup

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

Strober, S.; Farinas, M.C.; Field, E.H.

1988-07-01

Seventeen patients with intractable lupus nephritis and nephrotic syndrome were treated with total lymphoid irradiation. Statistically significant improvement in mean renal disease and serologic activity parameters occurred within 3 months and persisted for at least 3 years. Although there was a marked reduction of T helper cell numbers and function after total lymphoid irradiation, recovery of these parameters was not associated with a return of disease activity. Risks of sterility, severe infections, and hematologic malignancy appeared to be lower than with alkylating agents.

Beyond NK cells: the expanding universe of innate lymphoid cells.

PubMed

Cella, Marina; Miller, Hannah; Song, Christina

2014-01-01

For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development.

A theory of germinal center B cell selection, division, and exit.

PubMed

Meyer-Hermann, Michael; Mohr, Elodie; Pelletier, Nadége; Zhang, Yang; Victora, Gabriel D; Toellner, Kai-Michael

2012-07-26

High-affinity antibodies are generated in germinal centers in a process involving mutation and selection of B cells. Information processing in germinal center reactions has been investigated in a number of recent experiments. These have revealed cell migration patterns, asymmetric cell divisions, and cell-cell interaction characteristics, used here to develop a theory of germinal center B cell selection, division, and exit (the LEDA model). According to this model, B cells selected by T follicular helper cells on the basis of successful antigen processing always return to the dark zone for asymmetric division, and acquired antigen is inherited by one daughter cell only. Antigen-retaining B cells differentiate to plasma cells and leave the germinal center through the dark zone. This theory has implications for the functioning of germinal centers because compared to previous models, high-affinity antibodies appear one day earlier and the amount of derived plasma cells is considerably larger. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells.

PubMed

Wang, Yifeng; Shi, Jingwen; Yan, Jiacong; Xiao, Zhengtao; Hou, Xiaoxiao; Lu, Peiwen; Hou, Shiyue; Mao, Tianyang; Liu, Wanli; Ma, Yuanwu; Zhang, Lianfeng; Yang, Xuerui; Qi, Hai

2017-08-01

Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells. GC-MP cells expressed the interleukin 9 (IL-9) receptor and responded to IL-9. Acute treatment with IL-9 or antibody to IL-9 accelerated or retarded the positioning of GC-MP cells toward the GC edge and exit from the GC, and enhanced or inhibited the development of memory B cells, which required B cell-intrinsic responsiveness to IL-9. Follicular helper T cells (T FH cells) produced IL-9, and deletion of IL-9 from T cells or, more specifically, from GC T FH cells led to impaired memory formation of B cells. Therefore, the GC development of memory B cells is promoted by T FH cell-derived IL-9.

T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate.

PubMed

Ise, Wataru; Fujii, Kentaro; Shiroguchi, Katsuyuki; Ito, Ayako; Kometani, Kohei; Takeda, Kiyoshi; Kawakami, Eiryo; Yamashita, Kazuo; Suzuki, Kazuhiro; Okada, Takaharu; Kurosaki, Tomohiro

2018-04-17

Higher- or lower-affinity germinal center (GC) B cells are directed either to plasma cell or GC recycling, respectively; however, how commitment to the plasma cell fate takes place is unclear. We found that a population of light zone (LZ) GC cells, Bcl6 lo CD69 hi expressing a transcription factor IRF4 and higher-affinity B cell receptors (BCRs) or Bcl6 hi CD69 hi with lower-affinity BCRs, favored the plasma cell or recycling GC cell fate, respectively. Mechanistically, CD40 acted as a dose-dependent regulator for Bcl6 lo CD69 hi cell formation. Furthermore, we found that expression of intercellular adhesion molecule 1 (ICAM-1) and signaling lymphocytic activation molecule (SLAM) in Bcl6 lo CD69 hi cells was higher than in Bcl6 hi CD69 hi cells, thereby affording more stable T follicular helper (Tfh)-GC B cell contacts. These data support a model whereby commitment to the plasma cell begins in the GC and suggest that stability of Tfh-GC B cell contacts is key for plasma cell-prone GC cell formation. Copyright © 2018. Published by Elsevier Inc.

Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity.

PubMed

Torri, Anna; Carpi, Donatella; Bulgheroni, Elisabetta; Crosti, Maria-Cristina; Moro, Monica; Gruarin, Paola; Rossi, Riccardo L; Rossetti, Grazisa; Di Vizio, Dolores; Hoxha, Mirjam; Bollati, Valentina; Gagliani, Cristina; Tacchetti, Carlo; Paroni, Moira; Geginat, Jens; Corti, Laura; Venegoni, Luigia; Berti, Emilio; Pagani, Massimiliano; Matarese, Giuseppe; Abrignani, Sergio; de Candia, Paola

2017-02-17

Upon T cell receptor stimulation, CD4 + T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4 + T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4 + T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4 + T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity*

PubMed Central

Torri, Anna; Carpi, Donatella; Bulgheroni, Elisabetta; Crosti, Maria-Cristina; Moro, Monica; Gruarin, Paola; Rossi, Riccardo L.; Rossetti, Grazisa; Di Vizio, Dolores; Hoxha, Mirjam; Bollati, Valentina; Gagliani, Cristina; Tacchetti, Carlo; Paroni, Moira; Geginat, Jens; Corti, Laura; Venegoni, Luigia; Berti, Emilio; Pagani, Massimiliano; Matarese, Giuseppe; Abrignani, Sergio; de Candia, Paola

2017-01-01

Upon T cell receptor stimulation, CD4+ T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4+ T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4+ T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4+ T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response. PMID:28077577

Endocrine regulation of the immune response to influenza virus infection with a metabolite of DHEA-androstenediol.

PubMed

Padgett, D A; Loria, R M; Sheridan, J F

1997-09-01

In these studies the influence of androstenediol on the course of an experimental virus infection was examined. Pretreatment with 320 mg/kg AED protected male mice from lethal influenza virus infection. In addition, AED enhanced antigen-induced trafficking of mononuclear cells into the draining lymph node and augmented antigen-specific activation of helper-T cells, which are important for control of viral pathogenesis. Furthermore, AED prevented the characteristic increase in serum corticosterone noted during influenza A virus infection. Although steroid hormones, at least corticosteroids, typically suppress host immune and inflammatory responses in vivo, these data suggest that AED may function to augment host immune and inflammatory responses in contrast to corticosteroids.

[Effects of radiotherapy on lymphocyte populations in lung cancer].

PubMed

Gava, A; Moro, L; De Angeli, S; Coghetto, F; Marazzato, G; Fantin, P; Patrese, P

1988-11-01

The authors report on the results of the immune monitoring of a study population of 31 patients with lung cancer who were treated with radiotherapy. A synthetic thymic pentapeptide, thymopentin, was employed whose effect was evaluated on the immunological parameters analyzed. After radiotherapy, a considerable and homogeneous decrement was observed in several lymphocytic subsets (less sensible in activated T-cells), together with a progressive decrement in the helper/suppressor ratio, in the long run. Monocytes and null cells showed more radioresistance. Thymopentin had no influence on the tested immunological parameters up to 6 months after radiotherapy; later on, a slightly more balanced helper/suppressor ratio could be noticed in the surviving patients who had been treated with thymopentin.

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.

Transcription factor interplay in T helper cell differentiation.

PubMed

Evans, Catherine M; Jenner, Richard G

2013-11-01

The differentiation of CD4 helper T cells into specialized effector lineages has provided a powerful model for understanding immune cell differentiation. Distinct lineages have been defined by differential expression of signature cytokines and the lineage-specifying transcription factors necessary and sufficient for their production. The traditional paradigm of differentiation towards Th1 and Th2 subtypes driven by T-bet and GATA3, respectively, has been extended to incorporate additional T cell lineages and transcriptional regulators. Technological advances have expanded our view of these lineage-specifying transcription factors to the whole genome and revealed unexpected interplay between them. From these data, it is becoming clear that lineage specification is more complex and plastic than previous models might have suggested. Here, we present an overview of the different forms of transcription factor interplay that have been identified and how T cell phenotypes arise as a product of this interplay within complex regulatory networks. We also suggest experimental strategies that will provide further insight into the mechanisms that underlie T cell lineage specification and plasticity.

Structural and Nonstructural Viral Proteins Are Targets of T-Helper Immune Response against Human Respiratory Syncytial Virus.

PubMed

Lorente, Elena; Barriga, Alejandro; Barnea, Eilon; Mir, Carmen; Gebe, John A; Admon, Arie; López, Daniel

2016-06-01

Proper antiviral humoral and cellular immune responses require previous recognition of viral antigenic peptides that are bound to HLA class II molecules, which are exposed on the surface of antigen-presenting cells. The helper immune response is critical for the control and the clearance of human respiratory syncytial virus (HRSV) infection, a virus with severe health risk in infected pediatric, immunocompromised, and elderly populations. In this study, using a mass spectrometry analysis of complex HLA class II-bound peptide pools that were isolated from large amounts of HRSV-infected cells, 19 naturally processed HLA-DR ligands, most of them included in a complex nested set of peptides, were identified. Both the immunoprevalence and the immunodominance of the HLA class II response to HRSV were focused on one nonstructural (NS1) and two structural (matrix and mainly fusion) proteins of the infective virus. These findings have clear implications for analysis of the helper immune response as well as for antiviral vaccine design. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Single-cell mass cytometry and transcriptome profiling reveal the impact of graphene on human immune cells.

PubMed

Orecchioni, Marco; Bedognetti, Davide; Newman, Leon; Fuoco, Claudia; Spada, Filomena; Hendrickx, Wouter; Marincola, Francesco M; Sgarrella, Francesco; Rodrigues, Artur Filipe; Ménard-Moyon, Cécilia; Cesareni, Gianni; Kostarelos, Kostas; Bianco, Alberto; Delogu, Lucia G

2017-10-24

Understanding the biomolecular interactions between graphene and human immune cells is a prerequisite for its utilization as a diagnostic or therapeutic tool. To characterize the complex interactions between graphene and immune cells, we propose an integrative analytical pipeline encompassing the evaluation of molecular and cellular parameters. Herein, we use single-cell mass cytometry to dissect the effects of graphene oxide (GO) and GO functionalized with amino groups (GONH 2 ) on 15 immune cell populations, interrogating 30 markers at the single-cell level. Next, the integration of single-cell mass cytometry with genome-wide transcriptome analysis shows that the amine groups reduce the perturbations caused by GO on cell metabolism and increase biocompatibility. Moreover, GONH 2 polarizes T-cell and monocyte activation toward a T helper-1/M1 immune response. This study describes an innovative approach for the analysis of the effects of nanomaterials on distinct immune cells, laying the foundation for the incorporation of single-cell mass cytometry on the experimental pipeline.

Mimicry of molecular pretenders: the terminal structures of satellites associated with plant RNA viruses.

PubMed

Huang, Ying-Wen; Hu, Chung-Chi; Lin, Na-Sheng; Hsu, Yau-Heiu

2010-01-01

Satellite RNAs (satRNAs) and satellite viruses depend on the replicase complexes provided by their cognate helper viruses and host plants for replication, pretending that they are part of the viral genomes. Although satRNAs and satellite viruses do not share significant nucleotide sequence similarity with the helper viruses, the essential cis-acting elements recognized by the replicase complexes must reside on their genomes, acting as the mimicry for the molecular pretenders. By understanding how this molecular mimicry deceives the helper viruses into supporting the satellites, a significant amount of knowledge of the basic requirements and mechanisms for replication of viruses and satellites has been obtained. Here we review the recent advances in understanding the effects of the cis elements at the termini of satRNAs and satellite viruses on their accumulation. Several well-characterized satellite/helper virus systems, representing the non-coding short satRNAs, mRNA-type long satRNAs, circular satRNAs and satellite viruses, are compared and contrasted. It is concluded that different satellites may adopt different strategies to exploit the replication/transcription/translation machineries of their helper viruses, and different mimicries may be implemented by the same molecular pretender for different biological functions.

The virus–receptor interaction in the replication of feline immunodeficiency virus (FIV)☆

PubMed Central

Willett, Brian J; Hosie, Margaret J

2013-01-01

The feline and human immunodeficiency viruses (FIV and HIV) target helper T cells selectively, and in doing so they induce a profound immune dysfunction. The primary determinant of HIV cell tropism is the expression pattern of the primary viral receptor CD4 and co-receptor(s), such as CXCR4 and CCR5. FIV employs a distinct strategy to target helper T cells; a high affinity interaction with CD134 (OX40) is followed by binding of the virus to its sole co-receptor, CXCR4. Recent studies have demonstrated that the way in which FIV interacts with its primary receptor, CD134, alters as infection progresses, changing the cell tropism of the virus. This review examines the contribution of the virus–receptor interaction to replication in vivo as well as the significance of these findings to the development of vaccines and therapeutics. PMID:23992667

PD-1HIGH Follicular CD4 T Helper Cell Subsets Residing in Lymph Node Germinal Centers Correlate with B Cell Maturation and IgG Production in Rhesus Macaques

PubMed Central

Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A.; Veazey, Ronald S.

2014-01-01

CD4+ T follicular helper (TFH) cells guide development and maturation of B cells and are crucial for effective antibody responses. Here we found rhesus macaque TFH cells, defined as CXCR5+CD4 T cells, contain two major populations: PD-1INT and PD-1HIGH cells. Of these, PD-1HIGHCD4+ T cells highly co-express ICOS but little CCR7, and reside in lymph node germinal centers (GCs), but not in blood. These cells secrete IL-21 and express transcriptional factor Bcl-6 at higher levels than CXCR5+PD-1INTCD4+ T cells. In addition, the frequency of PD-1HIGHCD4+ T cells is low in lymph nodes of newborns, but increases with age. Levels of PD-1HIGHCD4+ T cells correlate with mature B cells in lymph nodes, and PD-1 blockade in PD-1HIGHCD4+ T and B cell co-cultures significantly inhibits IgG production. In summary, PD-1HIGHCD4+ T cells residing in GC represent a specific TFH subset that contributes to maturation of B cells and IgG production. PMID:24678309

Induction and function of virus-specific CD4+ T cell responses

PubMed Central

Whitmire, Jason K.

2010-01-01

CD4+ T cells -- often referred to as T-helper cells -- play a central role in immune defense and pathogenesis. Virus infections and vaccines stimulate and expand populations of antigen-specific CD4+ T cells in mice and in man. These virus-specific CD4+ T cells are extremely important in antiviral protection: deficiencies in CD4+ T cells are associated with virus reactivation, generalized susceptibility to opportunistic infections, and poor vaccine efficacy. As described below, CD4+ T cells influence effector and memory CD8+ T cell responses, humoral immunity, and the antimicrobial activity of macrophages and are involved in recruiting cells to sites of infection. This review summarizes a few key points about the dynamics of the CD4+ T cell response to virus infection, the positive role of pro-inflammatory cytokines in the differentiation of virus-specific CD4+ T cells, and new areas of investigation to improve vaccines against virus infection. PMID:21236461

Antigen-specific and nonspecific mediators of T cell/B cell cooperation. III. Characterization of the nonspecific mediator(s) from different sources.

PubMed

Harwell, L; Kappler, J W; Marrack, P

1976-05-01

T cell-containing lymphoid populations produce a nonantigen-specific mediator(s) (NSM) which can replace T cell helper function in vitro in the response of B cells to sheep red blood cells (SRBC), but not to the hapten-protein conjugate, trinitrophenyl-keyhole limpet hemocyanin, (TNP-KLH). NSM produced under three conditions: 1) stimulation of KLH-primed cells with KLH; 2) allogeneic stimulation of normal spleen cells; and 3) stimulation of normal spleen cells with Con A (but not PHA) are indistinguishable on the basis of their biologic activity and m.w., estimated as 30 to 40,000 daltons by G-200 chromatography. Production of NSM is dependent on the presence of T cells. The action of NSM on B cells responding to SRBC in the presence of 2-mercaptoethanol is unaffected by severe macrophage depletion. Extensive absorption of NSM with SRBC failed to remove its activity, confirming its nonantigen-specific nature.

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

PubMed Central

Matarese, Giuseppe; Procaccini, Claudio; Menale, Ciro; Kim, Jae Geun; Kim, Jung Dae; Diano, Sabrina; Diano, Nadia; De Rosa, Veronica; Dietrich, Marcelo O.; Horvath, Tamas L.

2013-01-01

Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4+ T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3+) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response. PMID:23530205

Curcumin: A natural modulator of immune cells in systemic lupus erythematosus.

PubMed

Momtazi-Borojeni, Amir Abbas; Haftcheshmeh, Saeed Mohammadian; Esmaeili, Seyed-Alireza; Johnston, Thomas P; Abdollahi, Elham; Sahebkar, Amirhossein

2018-02-01

Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE. Copyright © 2017 Elsevier B.V. All rights reserved.

Aryl Hydrocarbon Receptor Promotes RORγt+ ILCs and Controls Intestinal Immunity and Inflammation

PubMed Central

Qiu, Ju; Zhou, Liang

2013-01-01

Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptors (RORγt)+ ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt+ ILCs (e.g., lymphoid tissue inducer-LTi cells) are required for lymphoid organogenesis. In adult mice, RORγt+ ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt+ ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt+ ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells (APCs). In this review, we will focus on the development and function of RORγt+ ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. Better understanding the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases. PMID:23975386

IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

USDA-ARS?s Scientific Manuscript database

CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal...

Promiscuous survivin peptide induces robust CD4+ T-cell responses in the majority of vaccinated cancer patients.

PubMed

Widenmeyer, Melanie; Griesemann, Heinrich; Stevanović, Stefan; Feyerabend, Susan; Klein, Reinhild; Attig, Sebastian; Hennenlotter, Jörg; Wernet, Dorothee; Kuprash, Dmitri V; Sazykin, Alexei Y; Pascolo, Steve; Stenzl, Arnulf; Gouttefangeas, Cécile; Rammensee, Hans-Georg

2012-07-01

CD4(+) T cells have been shown to be crucial for the induction and maintenance of cytotoxic T cell responses and to be also capable of mediating direct tumor rejection. Therefore, the anticancer therapeutic efficacy of peptide-based vaccines may be improved by addition of HLA class II epitopes to stimulate T helper cells. Survivin is an apoptosis inhibiting protein frequently overexpressed in tumors. Here we describe the first immunological evaluation of a survivin-derived CD4(+) T cell epitope in a multipeptide immunotherapy trial for prostate carcinoma patients. The survivin peptide is promiscuously presented by several human HLA-DRB1 molecules and, most importantly, is naturally processed by dendritic cells. In vaccinated patients, it was able to induce frequent, robust and multifunctional CD4(+) T cell responses, as monitored by IFN-γ ELISPOT and intracellular cytokine staining. Thus, this HLA-DR restricted epitope is broadly immunogenic and should be valuable for stimulating T helper cells in patients suffering from a wide range of tumors. Copyright © 2011 UICC.

Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses.

PubMed

Pardi, Norbert; Hogan, Michael J; Naradikian, Martin S; Parkhouse, Kaela; Cain, Derek W; Jones, Letitia; Moody, M Anthony; Verkerke, Hans P; Myles, Arpita; Willis, Elinor; LaBranche, Celia C; Montefiori, David C; Lobby, Jenna L; Saunders, Kevin O; Liao, Hua-Xin; Korber, Bette T; Sutherland, Laura L; Scearce, Richard M; Hraber, Peter T; Tombácz, István; Muramatsu, Hiromi; Ni, Houping; Balikov, Daniel A; Li, Charles; Mui, Barbara L; Tam, Ying K; Krammer, Florian; Karikó, Katalin; Polacino, Patricia; Eisenlohr, Laurence C; Madden, Thomas D; Hope, Michael J; Lewis, Mark G; Lee, Kelly K; Hu, Shiu-Lok; Hensley, Scott E; Cancro, Michael P; Haynes, Barton F; Weissman, Drew

2018-06-04

T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4 + T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses. © 2018 Pardi et al.

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

PubMed Central

Mukherjee, P.; Pathangey, L.B.; Bradley, J.B.; Tinder, T.L.; Basu, G.D.; Akporiaye, E.T.; Gendler, S.J.

2007-01-01

A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan helper peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-γ-producing CD4+ helper and CD8+ cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced. PMID:17166639

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

PubMed

Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

2007-02-19

A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

Seventeen-Year Journey Working With a Master.

PubMed

Zhu, Jinfang

2018-01-01

It had been a great honor for me to work with the late Dr. William E. Paul for 17 years in the Laboratory of Immunology (LI) from 1998 until his passing in 2015. He was such a master in the immunology field. Under his outstanding guidance, my research has been focusing on transcriptional regulation of T helper (Th) cell differentiation, especially, on the role of a master transcription factor GATA3 during Th2 cell differentiation. Just as enormous scientific contributions of Dr. Paul (we all call him Bill) to the immunology community are far beyond his serving as the Chief of the LI, GATA3 also plays important roles in different lymphocytes at various developmental stages besides its critical functions in Th2 cells. In this special review dedicated to the memory of Bill, I will summarize the research that I have carried out in Bill's lab working on GATA3 in the context of related studies by other groups in the field of T cell differentiation and innate lymphoid cell (ILC) development. These include the essential role of GATA3 in regulating Th2/ILC2 differentiation/development and their functions, the critical role of GATA3 during the development of T cells and innate lymphoid cells, and dynamic and quantitative expression of GATA3 in controlling lymphocyte homeostasis and functions.

The role of T lymphocytes in cancer patients undergoing immunotherapy with autologous dendritic cells.

PubMed

Rodrigues, Cláudia M; Matias, Bruna F; Murta, Eddie F C; Michelin, Márcia A

2011-01-01

Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-γ, IL-12, TNF-α, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-α and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period.

Old and New Lymphocyte Players in Inflammatory Bowel Disease.

PubMed

Giuffrida, Paolo; Corazza, Gino Roberto; Di Sabatino, Antonio

2018-02-01

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.

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

Pathogenesis of thyroid autoimmune disease: the role of cellular mechanisms.

PubMed

Ramos-Leví, Ana Maria; Marazuela, Mónica

2016-10-01

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are two very common organ-specific autoimmune diseases which are characterized by circulating antibodies and lymphocyte infiltration. Although humoral and cellular mechanisms have been classically considered separately in the pathogenesis of autoimmune thyroid diseases (AITD), recent research suggests a close reciprocal relationship between these two immune pathways. Several B- and T-cell activation pathways through antigen-presenting cells (APCs) and cytokine production lead to specific differentiation of T helper (Th) and T regulatory (Treg) cells. This review will focus on the cellular mechanisms involved in the pathogenesis of AITD. Specifically, it will provide reasons for discarding the traditional simplistic dichotomous view of the T helper type 1 and 2 pathways (Th1/Th2) and will focus on the role of the recently characterized T cells, Treg and Th17 lymphocytes, as well as B lymphocytes and APCs, especially dendritic cells (DCs). Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6.

PubMed

Andersson, Karin M E; Brisslert, Mikael; Cavallini, Nicola Filluelo; Svensson, Mattias N D; Welin, Amanda; Erlandsson, Malin C; Ciesielski, Michael J; Katona, Gergely; Bokarewa, Maria I

2015-08-21

Follicular T helper (Tfh) cells are recognized by the expression of CXCR5 and the transcriptional regulator Bcl-6. Tfh cells control B cell maturation and antibody production, and if deregulated, may lead to autoimmunity. Here, we study the role of the proto-oncogene survivin in the formation of Tfh cells. We show that blood Tfh cells of patients with the autoimmune condition rheumatoid arthritis, have intracellular expression of survivin. Survivin was co-localized with Bcl-6 in the nuclei of CXCR5+CD4 lymphocytes and was immunoprecipitated with the Bcl-6 responsive element of the target genes. Inhibition of survivin in arthritic mice led to the reduction of CXCR5+ Tfh cells and to low production of autoantibodies. Exposure to survivin activated STAT3 and induced enrichment of PD-1+Bcl-6+ subset within Tfh cells. Collectively, our study demonstrates that survivin belongs to the Tfh cell phenotype and ensures their optimal function by regulating transcriptional activity of Bcl-6.

IL-17+ γδ T cells as kick-starters of inflammation.

PubMed

Papotto, Pedro H; Ribot, Julie C; Silva-Santos, Bruno

2017-05-18

Shortly after the discovery of interleukin 17 (IL-17)-producing CD4 + helper T cells (T H 17 cells), it was found that γδ T cells can also secrete large amounts of this pro-inflammatory cytokine. A decade later, it is now known that IL-17 + γδ T cells (γδ17 T cells) are often the main providers of IL-17A in various models of inflammatory diseases, while they also contribute to protective immune responses to infectious organisms. Due to an intricate thymic program of differentiation, γδ17 T cells are able to respond faster than T H 17 cells do and thus predominate in the early stages of inflammatory responses. Here we review the current knowledge of the development, activation and pathophysiological functions of γδ17 T cells, aiming to increase the awareness in the community of the therapeutic potential of this 'other side' of IL-17-mediated immune responses.

Type two innate lymphoid cells; the Janus cells in health and disease

PubMed Central

Maazi, Hadi; Akbari, Omid

2017-01-01

Summary Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2 and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by costimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. PMID:28658553

[Quantity and function of T follicular helper cells in the bone marrow of patients with immune thrombocytopenia].

PubMed

Zhang, Yang; Qu, Wen; Ruan, Er-Bao; Fu, Rong; Wang, Guo-Jin; Liu, Hong; Wang, Xiao-Ming; Wu, Yu-Hong; Song, Jia; Xing, Li-Min; Guan, Jing; Li, Li-Juan; Wang, Hua-Quan; Shao, Zong-Hong

2014-06-01

This study was purposed to detect the quantity and function of bone marrow (BM) T follicular helper (Tfh) cells of patients with immune thrombocytopenia, and to explore the role of Tfh cells in the pathogenesis of ITP. Twenty-one newly diagnosed ITP patients, twenty ITP patients in recovery stage and eighteen normal controls were enrolled in this study. The percentages of Tfh cells, Tfh-related molecules ICOS, CD40L, IL-21 in BM were detected by flow cytometry (FCM), and the mRNA expression of BCL-6 in BMMNC was determined by semi-quantitive RT-PCR. Correlation of Tfh cell level with the disease severity of ITP patients was analysed. The results showed that the ratio of CD4(+)CXCR5(+)/CD4(+) cells in newly diagnosed ITP patients [(5.532 ± 2.599)%] was significantly higher than that in ITP patients with recovery stage [(4.064 ± 2.026)%] and controls [(4.048 ± 1.413)%] (P < 0.05). The ratio of CD4(+)CXCR5(+)ICOS(+)/CD4(+) CXCR5(+) cells in newly diagnosed ITP patients [(14.586 ± 8.561)%] was higher than that in recovery stage ITP patients [(12.884 ± 10.161)%] and controls [(7.487 ± 5.176)%]. The differences be-tween newly diagnosed ITP patients and controls were statistically significant (P < 0.05). The ratio of CD4(+)CXCR5(+) CD40L(+)/CD4(+) CXCR5(+) cells in newly diagnosed ITP patients [(15.309 ± 10.756)%] and in ITP patients with recovery stage [(18.242 ± 12.243)%] were significantly higher than that in controls [(8.618 ± 5.719) %] (P < 0.05). The ratio of intracytoplasm CD4(+) CXCR5(+) IL-21(+)/CD4(+)CXCR5(+) cells in newly diagnosed ITP patients [(58.560 ± 26.285)%] and in ITP patients with recovery stage [(57.035 ± 30.936)%] were significantly higher than that in controls [(36.289 ± 24.868)%] (P < 0.05). The relative expression levels of BCL-6 mRNA in BMMNC of three groups were (1.407 ± 0.264), (1.149 ± 0.217) and (0.846 ± 0.157), respectively. The differences between 3 groups were significant(P < 0.05). It is concluded that the quantity and function of Tfh cells in ITP patients increase, which may play an important role in the pathogenesis of ITP.

Histone methylation mediates plasticity of human FOXP3(+) regulatory T cells by modulating signature gene expressions.

PubMed

He, Haiqi; Ni, Bing; Tian, Yi; Tian, Zhiqiang; Chen, Yanke; Liu, Zhengwen; Yang, Xiaomei; Lv, Yi; Zhang, Yong

2014-03-01

CD4(+) FOXP3(+) regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4(+) CD25(high) CD127(low/-) Treg cells convert to two subpopulations with distinctive FOXP3(+) and FOXP3(-) phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. © 2013 John Wiley & Sons Ltd.

Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.

PubMed

Xiao, Sheng; Yosef, Nir; Yang, Jianfei; Wang, Yonghui; Zhou, Ling; Zhu, Chen; Wu, Chuan; Baloglu, Erkan; Schmidt, Darby; Ramesh, Radha; Lobera, Mercedes; Sundrud, Mark S; Tsai, Pei-Yun; Xiang, Zhijun; Wang, Jinsong; Xu, Yan; Lin, Xichen; Kretschmer, Karsten; Rahl, Peter B; Young, Richard A; Zhong, Zhong; Hafler, David A; Regev, Aviv; Ghosh, Shomir; Marson, Alexander; Kuchroo, Vijay K

2014-04-17

We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Copyright © 2014 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.

Ion-conducting membranes

DOEpatents

Masel, Richard I.; Sajjad, Syed Dawar; Gao, Yan; Liu, Zengcai; Chen, Qingmei

2017-12-26

An anion-conducting polymeric membrane comprises a terpolymer of styrene, vinylbenzyl-R.sub.s and vinylbenzyl-R.sub.x. R.sub.s is a positively charged cyclic amine group. R.sub.x is at least one constituent selected from the group consisting Cl, OH and a reaction product between an OH or Cl and a species other than a simple amine or a cyclic amine. The total weight of the vinylbenzyl-R.sub.x groups is greater than 0.3% of the total weight of the membrane. In a preferred embodiment, the membrane is a Helper Membrane that increases the faradaic efficiency of an electrochemical cell into which the membrane is incorporated, and also allows product formation at lower voltages than in cells without the Helper Membrane.

B cell depleting therapy regulates splenic and circulating T follicular helper cells in immune thrombocytopenia.

PubMed

Audia, Sylvain; Rossato, Marzia; Trad, Malika; Samson, Maxime; Santegoets, Kim; Gautheron, Alexandrine; Bekker, Cornelis; Facy, Olivier; Cheynel, Nicolas; Ortega-Deballon, Pablo; Boulin, Mathieu; Berthier, Sabine; Leguy-Seguin, Vanessa; Martin, Laurent; Ciudad, Marion; Janikashvili, Nona; Saas, Philippe; Radstake, Timothy; Bonnotte, Bernard

2017-02-01

B cells are involved in immune thrombocytopenia (ITP) pathophysiology by producing antiplatelet auto-antibodies. However more than a half of ITP patients do not respond to B cell depletion induced by rituximab (RTX). The persistence of splenic T follicular helper cells (TFH) that we demonstrated to be expanded during ITP and to support B cell differentiation and antiplatelet antibody-production may participate to RTX inefficiency. Whereas it is well established that the survival of TFH depends on B cells in animal models, nothing is known in humans yet. To determine the effect of B cell depletion on human TFH, we quantified B cells and TFH in the spleen and in the blood from ITP patients treated or not with RTX. We showed that B cell depletion led to a dramatic decrease in splenic TFH and in CXCL13 and IL-21, two cytokines predominantly produced by TFH. The absolute count of circulating TFH and serum CXCL13 also decreased after RTX treatment, whatever the therapeutic response. Therefore, we showed that the maintenance of TFH required B cells and that TFH are not involved in the inefficiency of RTX in ITP. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cell Type-Specific Immunomodulation Induced by Helminthes: Effect on Metainflammation, Insulin Resistance and Type-2 Diabetes.

PubMed

Aravindhan, Vivekanandhan; Anand, Gowrishankar

2017-12-01

Recent epidemiological studies have documented an inverse relationship between the decreasing prevalence of helminth infections and the increasing prevalence of metabolic diseases ("metabolic hygiene hypothesis"). Chronic inflammation leading to insulin resistance (IR) has now been identified as a major etiological factor for a variety of metabolic diseases other than obesity and Type-2 diabetes (metainflammation). One way by which helminth infections such as filariasis can modulate IR is by inducing a chronic, nonspecific, low-grade, immune suppression mediated by modified T-helper 2 (Th2) response (induction of both Th2 and regulatory T cells) which can in turn suppress the proinflammatory responses and promote insulin sensitivity (IS). This article provides evidence on how the cross talk between the innate and adaptive arms of the immune responses can modulate IR/sensitivity. The cross talk between innate (macrophages, dendritic cells, natural killer cells, natural killer T cells, myeloid derived suppressor cells, innate lymphoid cells, basophils, eosinophils, and neutrophils) and adaptive (helper T [CD4 + ] cells, cytotoxic T [CD8 + ] cells and B cells) immune cells forms two opposing circuits, one associated with IR and the other associated with IS under the conditions of metabolic syndrome and helminth-mediated immunomodulation, respectively.

Of mice and men: how animal models advance our understanding of T-cell function in RA.

PubMed

Kobezda, Tamás; Ghassemi-Nejad, Sheida; Mikecz, Katalin; Glant, Tibor T; Szekanecz, Zoltán

2014-03-01

The involvement of autoreactive T cells in the pathogenesis of rheumatoid arthritis (RA) as well as in autoimmune animal models of arthritis has been well established; however, unanswered questions, such as the role of joint-homing T cells, remain. Animal models of arthritis are superb experimental tools in demonstrating how T cells trigger joint inflammation, and thus can help to further our knowledge of disease mechanisms and potential therapies. In this Review, we discuss the similarities and differences in T-cell subsets and functions between RA and mouse arthritis models. For example, various T-cell subsets are involved in both human and mouse arthritis, but differences might exist in the cytokine regulation and plasticity of these cells. With regard to joint-homing T cells, an abundance of synovial T cells is present in humans compared with mice. On the other hand, local expansion of type 17 T-helper (TH17) cells is observed in some animal models, but not in RA. Finally, whereas T-cell depletion therapy essentially failed in RA, antibody targeting of T cells can work, at least preventatively, in most arthritis models. Clearly, additional human and animal studies are needed to fill the gap in our understanding of the specific contribution of T-cell subsets to arthritis in mice and men.

miR-192 suppresses T follicular helper cell differentiation by targeting CXCR5 in childhood asthma.

PubMed

Zhang, Defeng; Wu, Yuanbo; Sun, Gengyun

2018-05-01

The aim of this study was to investigate the role of miR-192 in differentiation of T follicular helper cells in childhood asthma. Blood samples were taken from eighteen children with acute asthma attacks and fifteen healthy children (HC). Quantitative real-time PCR and Western blotting were used to detect the expression levels of miR-192, C-X-C chemokine receptor type 5 (CXCR5), B-cell lymphoma 6 (BCL-6) and inducible T-cell costimulator (ICOS). The flow cytometry was performed to detect the proportion of CD4 + CXCR5+ Tfh cells on CD4 + T lymphocytes. The enzyme-linked immunosorbent assay (ELISA) was carried out to determine the plasma concentrations of total IgE and IL-21. The effect of miR-192 on the T follicular helper cells differentiation by targeting CXCR5 was determined by dual-luciferase reporter assay. Children with asthma had lower levels of miR-192 than HC. The proportion of CD4 + CXCR + Tfh cells was significantly higher in the acute asthma group than HC. Similarly, the plasma concentration of total IgE and IL-21 in the acute group markedly increased compared with the HC, and IgE concentration was positively correlated with the proportion of CD4 + CXCR5 + Tfh cells. Furthermore, the expression levels of CXCR5, Bcl-6 and ICOS were significantly higher in the acute group than in the HC. While the proportion of CD4 + CXCR5 + Tfh cells, IL-21, CXCR5, Bcl-6 and ICOS were obviously lower in the CD4 + T cells transfected with miR-192 plasmid than that in miR-192 + CXCR5 group and control group. In conclusion, miR-192 blocks the activation pathway of Tfh cells by targeting CXCR5, which is a reasonable cellular target for therapeutic intervention.

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.

STATs shape the active enhancer landscape of T cell populations.

PubMed

Vahedi, Golnaz; Takahashi, Hayato; Nakayamada, Shingo; Sun, Hong-Wei; Sartorelli, Vittorio; Kanno, Yuka; O'Shea, John J

2012-11-21

Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. Although enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4(+) T cells as a model of differentiation, mapping the activity of cell-type-specific enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells. Copyright © 2012 Elsevier Inc. All rights reserved.

STATs Shape the Active Enhancer Landscape of T Cell Populations

PubMed Central

Vahedi, Golnaz; Takahashi, Hayato; Nakayamada, Shingo; Sun, Hong-wei; Sartorelli, Vittorio; Kanno, Yuka; O’Shea, John J.

2012-01-01

SUMMARY Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. While enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the acquisition of cell-type-specific enhancer elements in T-helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the acquisition of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells. PMID:23178119

The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis.

PubMed

Wacleche, Vanessa Sue; Landay, Alan; Routy, Jean-Pierre; Ancuta, Petronela

2017-10-19

The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection.

Resilient help to switch and overlap hierarchical subsystems in a small human group

PubMed Central

Fujii, K.; Yokoyama, K.; Koyama, T.; Rikukawa, A.; Yamada, H.; Yamamoto, Y.

2016-01-01

Groups of social organisms in nature are resilient systems that can overcome unpredicted threats by helping its members. These social organisms are assumed to behave both autonomously and cooperatively as individuals, the helper, the helped and other part of a group depending on the context such as emergencies. However, the structure and function of these resilient actions, such as how helpers help colleagues and how the helper’s action is effective at multiple subsystem scales remain unclear. Here we investigated the behaviour of organised and efficient small human groups in a ballgame defence, and identified three principles of hierarchical resilient help when under attack. First, at a present high emergency level, the helper simply switched the local roles in the attacked subsystem with the helped. Second, at an intermediate emergency level, the helpers effectively acted in overlapping subsystems. Third, for the most critical emergency, the helpers globally switched the action on the overall system. These resilient actions to the benefit of the system were assumed to be observed in only humans, which help colleagues at flexibly switched and overlapped hierarchical subsystem. We suggest that these multi-layered helping behaviours can help to understand resilient cooperation in social organisms and human groups. PMID:27045443

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

PubMed Central

Onishi, Motoyasu; Ozasa, Koji; Kobiyama, Kouji; Ohata, Keiichi; Kitano, Mitsutaka; Taniguchi, Keiichi; Homma, Tomoyuki; Kobayashi, Masanori; Sato, Akihiko; Katakai, Yuko; Yasutomi, Yasuhiro; Wijaya, Edward; Igarashi, Yoshinobu; Nakatsu, Noriyuki; Ise, Wataru; Inoue, Takeshi; Yamada, Hiroshi; Vandenbon, Alexis; Standley, Daron M.; Kurosaki, Tomohiro; Coban, Cevayir; Aoshi, Taiki; Kuroda, Etsushi

2015-01-01

Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO+ macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD–adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines. PMID:25681338

Divergent transcriptional profiles in pediatric asthma patients of low and high socioeconomic status.

PubMed

Miller, Gregory E; Chen, Edith; Shalowitz, Madeleine U; Story, Rachel E; Leigh, Adam K K; Ham, Paula; Arevalo, Jesusa M G; Cole, Steve W

2018-06-01

There are marked socioeconomic disparities in pediatric asthma control, but the molecular origins of these disparities are not well understood. To fill this gap, we performed genome-wide expression profiling of monocytes and T-helper cells from pediatric asthma patients of lower and higher socioeconomic status (SES). Ninety-nine children with asthma participated in a cross-sectional assessment. Out of which 87% were atopic, and most had disease of mild (54%) or moderate (29%) severity. Children were from lower-SES (n = 49; household income <$50 000) or higher-SES (n = 50; household income >$140 000) families. Peripheral blood monocytes and T-helper cells were isolated for genome-wide expression profiling of mRNA. Lower-SES children had worse asthma quality of life relative to higher-SES children, by both their own and their parents' reports. Although the groups had similar disease severity and potential confounds were controlled, their transcriptional profiles differed notably. The monocytes of lower-SES children showed transcriptional indications of up-regulated anti-microbial and pro-inflammatory activity. The T-helper cells of lower-SES children also had comparatively reduced expression of genes encoding γ-interferon and tumor necrosis factor-α, cytokines that orchestrate Type 1 responses. They also showed up-regulated activity of transcription factors that polarize cells towards Type 2 responses and promote Th17 cell maturation. Collectively, these patterns implicate pro-inflammatory monocytes and Type 2 cytokine activity as mechanisms contributing to worse asthma control among lower-SES children. © 2018 Wiley Periodicals, Inc.

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.

Th17 Immune Cells in vivo: Friend or Foe? | Center for Cancer Research

Cancer.gov

Upon encountering an antigen, T cells bearing CD4+ (a helper marker) proliferate and become polarized. During this process, the cells produce specific signaling molecules called cytokines.  This signaling stimulates the T cells to become more specialized.  What results is the production of T cell subsets such as Th1, Th17, or others.

CD4 T Follicular Helper Cells and HIV Infection: Friends or Enemies?

PubMed

Moukambi, Félicien; Rodrigues, Vasco; Fortier, Yasmina; Rabezanahary, Henintsoa; Borde, Chloé; Krust, Bernard; Andreani, Guadalupe; Silvestre, Ricardo; Petrovas, Constantinos; Laforge, Mireille; Estaquier, Jérôme

2017-01-01

Follicular T helper (Tfh) cells, a subset of CD4 T lymphocytes, are essential for memory B cell activation, survival, and differentiation and assist B cells in the production of antigen-specific antibodies. Work performed in recent years pointed out the importance of Tfh cells in the context of HIV and SIV infections. The importance of tissue distribution of Tfh is also an important point since their frequency differs between peripheral blood and lymph nodes compared to the spleen, the primary organ for B cell activation, and differentiation. Our recent observations indicated an early and profound loss of splenic Tfh cells. The role of transcriptional activator and repressor factors that control Tfh differentiation is also discussed in the context of HIV/SIV infection. Because Tfh cells are important for B cell differentiation and antibody production, accelerating the Tfh responses early during HIV/SIV infection could be promising as novel immunotherapeutic approach or alternative vaccine strategies. However, because Tfh cells are infected during the HIV/SIV infection and represent a reservoir, this may interfere with HIV vaccine strategy. Thus, Tfh represent the good and bad guys during HIV infection.

CD4 T Follicular Helper Cells and HIV Infection: Friends or Enemies?

PubMed Central

Moukambi, Félicien; Rodrigues, Vasco; Fortier, Yasmina; Rabezanahary, Henintsoa; Borde, Chloé; Krust, Bernard; Andreani, Guadalupe; Silvestre, Ricardo; Petrovas, Constantinos; Laforge, Mireille; Estaquier, Jérôme

2017-01-01

Follicular T helper (Tfh) cells, a subset of CD4 T lymphocytes, are essential for memory B cell activation, survival, and differentiation and assist B cells in the production of antigen-specific antibodies. Work performed in recent years pointed out the importance of Tfh cells in the context of HIV and SIV infections. The importance of tissue distribution of Tfh is also an important point since their frequency differs between peripheral blood and lymph nodes compared to the spleen, the primary organ for B cell activation, and differentiation. Our recent observations indicated an early and profound loss of splenic Tfh cells. The role of transcriptional activator and repressor factors that control Tfh differentiation is also discussed in the context of HIV/SIV infection. Because Tfh cells are important for B cell differentiation and antibody production, accelerating the Tfh responses early during HIV/SIV infection could be promising as novel immunotherapeutic approach or alternative vaccine strategies. However, because Tfh cells are infected during the HIV/SIV infection and represent a reservoir, this may interfere with HIV vaccine strategy. Thus, Tfh represent the good and bad guys during HIV infection. PMID:28265271

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

Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4+ T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling.

PubMed

Zhang, Hongjun; Ju, Baoling; Zhang, Xiaoli; Zhu, Yanfei; Nie, Ying; Xu, Yuanhong; Lei, Qiuxia

2017-06-01

Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis, which displays anti-inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune-related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo. In response to ConA stimulation, the CD4 + T cells preferred to polarizing towards CD4 + T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA-treated liver in addition to suppressing interleukin (IL)-17A generation. Hepatic stellate cells were activated in fibrotic liver as demonstrated by increased alpha smooth muscle actin (α-SMA) and desmin. More transforming growth factor (TGF)-β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro, the recombinant IL-17A plus TGF-β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up-regulated phospho-Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel antifibrotic effect of magnolol on Th17 cell-mediated fibrosis. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

A critical role of T follicular helper cells in human mucosal anti-influenza response that can be enhanced by immunological adjuvant CpG-DNA.

PubMed

Aljurayyan, A N; Sharma, R; Upile, N; Beer, H; Vaughan, C; Xie, C; Achar, P; Ahmed, M S; McNamara, P S; Gordon, S B; Zhang, Q

2016-08-01

T Follicular helper cells (TFH) are considered critical for B cell antibody response, and recent efforts have focused on promoting TFH in order to enhance vaccine efficacy. We studied the frequency and function of TFH in nasopharynx-associated lymphoid tissues (NALT) from children and adults, and its role in anti-influenza antibody response following stimulation by a live-attenuated influenza vaccine (LAIV) or an inactivated seasonal virus antigen (sH1N1). We further studied whether CpG-DNA promotes TFH and by which enhances anti-influenza response. We showed NALT from children aged 1.5-10 years contained abundant TFH, suggesting efficient priming of TFH during early childhood. Stimulation by LAIV induced a marked increase in TFH that correlated with a strong production of anti-hemagglutinin (HA) IgA/IgG/IgM antibodies in tonsillar cells. Stimulation by the inactivated sH1N1 antigen induced a small increase in TFH which was markedly enhanced by CpG-DNA, accompanied by enhanced anti-HA antibody responses. In B cell co-culture experiment, anti-HA responses were only seen in the presence of TFH, and addition of plasmacytoid dendritic cell to TFH-B cell co-culture enhanced the TFH-mediated antibody production following CpG-DNA and sH1N1 antigen stimulation. Induction of TFH differentiation from naïve T cells was also shown following the stimulation. Our results support a critical role of TFH in human mucosal anti-influenza antibody response. Use of an adjuvant such as CpG-DNA that has the capacity to promote TFH by which to enhance antigen-induced antibody responses in NALT tissue may have important implications for future vaccination strategies against respiratory pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

Thyroid Autoimmunity is Associated with Decreased Cytotoxicity T Cells in Women with Repeated Implantation Failure

PubMed Central

Huang, Chunyu; Liang, Peiyan; Diao, Lianghui; Liu, Cuicui; Chen, Xian; Li, Guangui; Chen, Cong; Zeng, Yong

2015-01-01

Thyroid autoimmunity (TAI), which is defined as the presence of autoantibodies against thyroid peroxidase (TPO) and/or thyroglobulin (TG), is related to repeated implantation failure (RIF). It is reported that TAI was involved in reproductive failure not only through leading thyroid function abnormality, but it can also be accompanied with immune imbalance. Therefore, this study was designed to investigate the association of thyroid function, immune status and TAI in women with RIF. Blood samples were drawn from 72 women with RIF to evaluate the prevalence of TAI, the thyroid function, the absolute numbers and percentages of lymphocytes. The prevalence of thyroid function abnormality in RIF women with TAI was not significantly different from that in RIF women without TAI (χ2 = 0.484, p > 0.05). The absolute number and percentage of T cells, T helper (Th) cells, B cells and natural killer (NK) cells were not significantly different in RIF women with TAI compared to those without TAI (all p > 0.05). The percentage of T cytotoxicity (Tc) cells was significantly decreased in RIF women with TAI compared to those without TAI (p < 0.05). Meanwhile, Th/Tc ratio was significantly increased (p < 0.05). These results indicated that the decreased Tc percentage and increased Th/Tc ratio may be another influential factor of adverse pregnancy outcomes in RIF women with TAI. PMID:26308040

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.

Phytosterols isolated from Clinacanthus nutans induce immunosuppressive activity in murine cells.

PubMed

Le, Cheng-Foh; Kailaivasan, Thina Hareesh; Chow, Sek-Chuen; Abdullah, Zunoliza; Ling, Sui-Kiong; Fang, Chee-Mun

2017-03-01

Clinacanthus nutans (Burm. f.) Lindau is a traditional medicinal plant belonging to the Acanthaceae family. Its therapeutic potentials have been increasingly documented particularly the antiviral activity against Herpes Simplex Virus (HSV), anti-cancer, anti-oxidant, anti-inflammatory and immunomodulatory activities. However, majority of these studies used crude or fractionated extracts and not much is known about individual compounds from these extracts and their biological activities. In the present study, we have isolated four compounds (CN1, CN2, CN3 and CN4) from the hexane fractions of C. nutans leaves. Using NMR spectroscopic analysis, these compounds were identified to be shaftoside (CN1), stigmasterol (CN2), β-sitosterol (CN3) and a triterpenoid lupeol (CN4). To determine the immunosuppressive potential of these compounds, their effects on mitogens induced T and B lymphocyte proliferation and the secretion of helper T cell cytokines were examined. Among the four compounds, stigmasterol (CN2) and β-sitosterol (CN3) were shown to readily inhibit T cell proliferation mediated by Concanavalin A (ConA). However, only β-sitosterol (CN3) and not stigmasterol (CN2) blocks the secretion of T helper 2 (Th2) cytokines (IL-4 and IL-10). Both compounds have no effect on the secretion of Th1 cytokines (IL-2 and IFN-γ), suggesting that β-sitosterol treatment selectively suppresses Th2 activity and promotes a Th1 bias. CN3 was also found to significantly reduce the proliferation of both T helper cells (CD4 + CD25 + ) and cytotoxic T cells (CD8 + CD25 + ) following T cell activation induced by ConA. These results suggested that phytosterols isolated from C. nutans possess immunomodulatory effects with potential development as immunotherapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

Co-stimulatory function in primary germinal center responses: CD40 and B7 are required on distinct antigen-presenting cells.

PubMed

Watanabe, Masashi; Fujihara, Chiharu; Radtke, Andrea J; Chiang, Y Jeffrey; Bhatia, Sumeena; Germain, Ronald N; Hodes, Richard J

2017-09-04

T cell-dependent germinal center (GC) responses require coordinated interactions of T cells with two antigen-presenting cell (APC) populations, B cells and dendritic cells (DCs), in the presence of B7- and CD40-dependent co-stimulatory pathways. Contrary to the prevailing paradigm, we found unique cellular requirements for B7 and CD40 expression in primary GC responses to vaccine immunization with protein antigen and adjuvant: B7 was required on DCs but was not required on B cells, whereas CD40 was required on B cells but not on DCs in the generation of antigen-specific follicular helper T cells, antigen-specific GC B cells, and high-affinity class-switched antibody production. There was, in fact, no requirement for coexpression of B7 and CD40 on the same cell in these responses. Our findings support a substantially revised model for co-stimulatory function in the primary GC response, with crucial and distinct contributions of B7- and CD40-dependent pathways expressed by different APC populations and with important implications for understanding how to optimize vaccine responses or limit autoimmunity. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

PD-1(HIGH) Follicular CD4 T Helper Cell Subsets Residing in Lymph Node Germinal Centers Correlate with B Cell Maturation and IgG Production in Rhesus Macaques.

PubMed

Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A; Veazey, Ronald S

2014-01-01

CD4+ T follicular helper (TFH) cells guide development and maturation of B cells and are crucial for effective antibody responses. Here we found rhesus macaque TFH cells, defined as CXCR5+CD4 T cells, contain two major populations: PD-1(INT) and PD-1(HIGH) cells. Of these, PD-1(HIGH)CD4+ T cells highly co-express ICOS but little CCR7, and reside in lymph node germinal centers (GCs), but not in blood. These cells secrete IL-21 and express transcriptional factor Bcl-6 at higher levels than CXCR5+PD-1(INT)CD4+ T cells. In addition, the frequency of PD-1(HIGH)CD4+ T cells is low in lymph nodes of newborns, but increases with age. Levels of PD-1(HIGH)CD4+ T cells correlate with mature B cells in lymph nodes, and PD-1 blockade in PD-1(HIGH)CD4+ T and B cell co-cultures significantly inhibits IgG production. In summary, PD-1(HIGH)CD4+ T cells residing in GC represent a specific TFH subset that contributes to maturation of B cells and IgG production.

Syntheses and Immunological Evaluation of Self-Adjuvanting Clustered N-Acetyl and N-Propionyl Sialyl-Tn Combined with A T-helper Cell Epitope as Antitumor Vaccine Candidates.

PubMed

Chang, Tsung-Che; Manabe, Yoshiyuki; Fujimoto, Yukari; Ohshima, Shino; Kametani, Yoshie; Kabayama, Kazuya; Nimura, Yuka; Lin, Chun-Cheng; Fukase, Koichi

2018-05-16

Sialyl-Tn (STn) is a tumor-associated carbohydrate antigen (TACA) rarely observed on healthy tissues. We synthesized two fully synthetic N-acetyl and N-propionyl STn trimer (triSTn) vaccines possessing a T-helper epitope and a TLR2 agonist, since the clustered STn antigens are highly expressed on many cancer cells. Immunization of both vaccines in mice induced the anti-triSTn IgG antibodies, which recognized triSTn-expressing cell lines PANC-1 and HepG2. The N-propionyl triSTn vaccine induced the triSTn-specific IgGs, while IgGs induced by the N-acetyl triSTn vaccine were less specific. These results illustrated that N-propionyl triSTn is a valuable unnatural TACA for anticancer vaccines. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cell Fate Reprogramming by Control of Intracellular Network Dynamics

PubMed Central

Zañudo, Jorge G. T.; Albert, Réka

2015-01-01

Identifying control strategies for biological networks is paramount for practical applications that involve reprogramming a cell’s fate, such as disease therapeutics and stem cell reprogramming. Here we develop a novel network control framework that integrates the structural and functional information available for intracellular networks to predict control targets. Formulated in a logical dynamic scheme, our approach drives any initial state to the target state with 100% effectiveness and needs to be applied only transiently for the network to reach and stay in the desired state. We illustrate our method’s potential to find intervention targets for cancer treatment and cell differentiation by applying it to a leukemia signaling network and to the network controlling the differentiation of helper T cells. We find that the predicted control targets are effective in a broad dynamic framework. Moreover, several of the predicted interventions are supported by experiments. PMID:25849586

A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers.

PubMed

Claireaux, M; Galperin, M; Benati, D; Nouël, A; Mukhopadhyay, M; Klingler, J; de Truchis, P; Zucman, D; Hendou, S; Boufassa, F; Moog, C; Lambotte, O; Chakrabarti, L A

2018-05-08

Follicular helper T cells (Tfh) play an essential role in the affinity maturation of the antibody response by providing help to B cells. To determine whether this CD4 + T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to undetectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet + ), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA - CXCR5 + CD4 + T cell population, proved more frequent in the controller group ( P = 0.002). The frequency of PD-1 expression in Tet + cTfh was increased in both groups (median, >75%) compared to total cTfh (<30%), but the intensity of PD-1 expression per cell remained higher in the treated patient group ( P = 0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells, did not show major differences between groups in terms of total IgG production but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet + cTfh correlated with HIV-specific IgG production ( R = 0.71 for Gag-specific and R = 0.79 for Env-specific IgG, respectively). Taken together, our findings indicate that key cTfh-B cell interactions are preserved in controlled HIV infection, resulting in potent memory B cell responses that may play an underappreciated role in HIV control. IMPORTANCE The rare patients who spontaneously control HIV replication in the absence of therapy provide a unique model to identify determinants of an effective anti-HIV immune response. HIV controllers show signs of particularly efficient antiviral T cell responses, while their humoral response was until recently considered to play only a minor role in viral control. However, emerging evidence suggests that HIV controllers maintain a significant but "silent" antiviral memory B cell population that can be reactivated upon antigenic stimulation. We report that cTfh help likely contributes to the persistence of controller memory B cell responses, as the frequency of HIV-specific cTfh correlated with the induction of HIV-specific antibodies in functional assays. These findings suggest that T follicular help may contribute to HIV control and highlight the need for inducing such help in HIV vaccine strategies that aim at eliciting persistent B cell responses. Copyright © 2018 Claireaux et al.

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells.

PubMed

Raykova, Ana; Carrega, Paolo; Lehmann, Frank M; Ivanek, Robert; Landtwing, Vanessa; Quast, Isaak; Lünemann, Jan D; Finke, Daniela; Ferlazzo, Guido; Chijioke, Obinna; Münz, Christian

2017-12-26

Type 3 innate lymphoid cells (ILC3s) fulfill protective functions at mucosal surfaces via cytokine production. Although their plasticity to become ILC1s, the innate counterparts of type 1 helper T cells, has been described previously, we report that they can differentiate into cytotoxic lymphocytes with many characteristics of early differentiated natural killer (NK) cells. This transition is promoted by the proinflammatory cytokines interleukin 12 (IL-12) and IL-15, and correlates with expression of the master transcription factor of cytotoxicity, eomesodermin (Eomes). As revealed by transcriptome analysis and flow cytometric profiling, differentiated ILC3s express CD94, NKG2A, NKG2C, CD56, and CD16 among other NK-cell receptors, and possess all components of the cytotoxic machinery. These characteristics allow them to recognize and kill leukemic cells with perforin and granzymes. Therefore, ILC3s can be harnessed for cytotoxic responses via differentiation under the influence of proinflammatory cytokines.

The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery.

PubMed

Cheng, Xinwei; Lee, Robert J

2016-04-01

Lipid nanoparticles (LNPs) have shown promise as delivery vehicles for therapeutic oligonucleotides, including antisense oligos (ONs), siRNA, and microRNA mimics and inhibitors. In addition to a cationic lipid, LNPs are typically composed of helper lipids that contribute to their stability and delivery efficiency. Helper lipids with cone-shape geometry favoring the formation hexagonal II phase, such as dioleoylphosphatidylethanolamine (DOPE), can promote endosomal release of ONs. Meanwhile, cylindrical-shaped lipid phosphatidylcholine can provide greater bilayer stability, which is important for in vivo application of LNPs. Cholesterol is often included as a helper that improves intracellular delivery as well as LNP stability in vivo. Inclusion of a PEGylating lipid can enhance LNP colloidal stability in vitro and circulation time in vivo but may reduce uptake and inhibit endosomal release at the cellular level. This problem can be addressed by choosing reversible PEGylation in which the PEG moiety is gradually released in blood circulation. pH-sensitive anionic helper lipids, such as fatty acids and cholesteryl hemisuccinate (CHEMS), can trigger low-pH-induced changes in LNP surface charge and destabilization that can facilitate endosomal release of ONs. Generally speaking, there is no correlation between LNP activity in vitro and in vivo because of differences in factors limiting the efficiency of delivery. Designing LNPs requires the striking of a proper balance between the need for particle stability, long systemic circulation time, and the need for LNP destabilization inside the target cell to release the oligonucleotide cargo, which requires the proper selection of both the cationic and helper lipids. Customized design and empirical optimization is needed for specific applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Transcription factor interplay in T helper cell differentiation

PubMed Central

Evans, Catherine M.

2013-01-01

The differentiation of CD4 helper T cells into specialized effector lineages has provided a powerful model for understanding immune cell differentiation. Distinct lineages have been defined by differential expression of signature cytokines and the lineage-specifying transcription factors necessary and sufficient for their production. The traditional paradigm of differentiation towards Th1 and Th2 subtypes driven by T-bet and GATA3, respectively, has been extended to incorporate additional T cell lineages and transcriptional regulators. Technological advances have expanded our view of these lineage-specifying transcription factors to the whole genome and revealed unexpected interplay between them. From these data, it is becoming clear that lineage specification is more complex and plastic than previous models might have suggested. Here, we present an overview of the different forms of transcription factor interplay that have been identified and how T cell phenotypes arise as a product of this interplay within complex regulatory networks. We also suggest experimental strategies that will provide further insight into the mechanisms that underlie T cell lineage specification and plasticity. PMID:23878131

Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation.

PubMed

Ryg-Cornejo, Victoria; Ioannidis, Lisa Julia; Ly, Ann; Chiu, Chris Yu; Tellier, Julie; Hill, Danika Lea; Preston, Simon Peter; Pellegrini, Marc; Yu, Di; Nutt, Stephen Laurence; Kallies, Axel; Hansen, Diana Silvia

2016-01-05

Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Dual Roles of IFN-γ and IL-4 in the Natural History of Murine Autoimmune Cholangitis: IL-30 and Implications for Precision Medicine

PubMed Central

Syu, Bi-Jhen; Loh, Chia-En; Hsueh, Yu-Hsin; Gershwin, M. Eric; Chuang, Ya-Hui

2016-01-01

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease with a long natural history. The pathogenesis of PBC is thought to be orchestrated by Th1 and/or Th17. In this study, we investigated the role of CD4+ helper T subsets and their cytokines on PBC using our previous established murine model of 2-OA-OVA immunization. We prepared adeno-associated virus (AAV)-IFN-γ and AAV-IL-4 and studied their individual influences on the natural history of autoimmune cholangitis in this model. Administration of IFN-γ significantly promotes recruitment and lymphocyte activation in the earliest phases of autoimmune cholangitis but subsequently leads to downregulation of chronic inflammation through induction of the immunosuppressive molecule IL-30. In contrast, the administration of IL-4 does not alter the initiation of autoimmune cholangitis, but does contribute to the exacerbation of chronic liver inflammation and fibrosis. Thus Th1 cells and IFN-γ are the dominant contributors in the initiation phase of this model but clearly may have different effects as the disease progress. In conclusion, better understanding of the mechanisms by which helper T cells function in the natural history of cholangitis is essential and illustrates that precision medicine may be needed for patients with PBC at various stages of their disease process. PMID:27721424

How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis.

PubMed

McCuaig, Sarah; Martin, James G

2013-04-01

Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine. Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear. A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle. Persistent bacterial infection, especially with Pseudomonas aeruginosa, stimulates interleukin-8 release from the airway epithelium, resulting in neutrophilic inflammation. Increased neutrophilia and skewing of CFTR-deficient T-helper cells to type 2 helper T cells creates an inflammatory environment characterised by high concentrations of tumour necrosis factor α, interleukin-8, and interleukin-13, which might all contribute to increased contractility of airway smooth muscle in cystic fibrosis. An emerging role of interleukin-17, which is raised in patients with cystic fibrosis, in airway smooth muscle proliferation and hyper-responsiveness is apparent. Increased understanding of the molecular mechanisms responsible for the altered smooth muscle physiology in patients with cystic fibrosis might provide insight into airway dysfunction in this disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

PubMed Central

Shinoda, Kenta; Hirahara, Kiyoshi; Iinuma, Tomohisa; Ichikawa, Tomomi; Suzuki, Akane S.; Sugaya, Kaoru; Tumes, Damon J.; Yamamoto, Heizaburo; Hara, Takahiro; Tani-ichi, Shizue; Ikuta, Koichi; Okamoto, Yoshitaka; Nakayama, Toshinori

2016-01-01

Memory CD4+ T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1+IL-7–producing lymphatic endothelial cells (LECs). The Thy1+IL-7–producing LECs express IL-33 and T-cell–attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4+ T cells and IL-7+IL-33+ LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1+IL-7–producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells. PMID:27140620

CD301b⁺ dermal dendritic cells drive T helper 2 cell-mediated immunity.

PubMed

Kumamoto, Yosuke; Linehan, Melissa; Weinstein, Jason S; Laidlaw, Brian J; Craft, Joseph E; Iwasaki, Akiko

2013-10-17

Unlike other types of T helper (Th) responses, whether the development of Th2 cells requires instruction from particular subset of dendritic cells (DCs) remains unclear. By using an in vivo depletion approach, we have shown that DCs expressing CD301b were required for the generation of Th2 cells after subcutaneous immunization with ovalbumin (OVA) along with papain or alum. CD301b⁺ DCs are distinct from epidermal or CD207⁺ dermal DCs (DDCs) and were responsible for transporting antigen injected subcutaneously with Th2-type adjuvants. Transient depletion of CD301b⁺ DCs resulted in less effective accumulation and decreased expression of CD69 by polyclonal CD4⁺ T cells in the lymph node. Moreover, despite intact cell division and interferon-γ production, CD301b⁺ DC depletion led to blunted interleukin-4 production by OVA-specific OT-II transgenic CD4⁺ T cells and significantly impaired Th2 cell development upon infection with Nippostrongylus brasiliensis. These results reveal CD301b⁺ DDCs as the key mediators of Th2 immunity. Copyright © 2013 Elsevier Inc. All rights reserved.

Myeloid hypoxia-inducible factor 1α prevents airway allergy in mice through macrophage-mediated immunoregulation.

PubMed

Toussaint, M; Fievez, L; Drion, P-V; Cataldo, D; Bureau, F; Lekeux, P; Desmet, C J

2013-05-01

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1α in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. By contrast, we report here that mice conditionally deficient for Hif1α in myeloid cells display enhanced sensitivity to the development of airway allergy to experimental allergens and house-dust mite antigens. We support that upon allergen exposure, MyD88-dependent upregulation of Hif1α boosts the expression of the immunosuppressive cytokine interleukin (IL)-10 by lung interstitial macrophages (IMs). Hif1α-dependent IL-10 secretion is required for IMs to block allergen-induced dendritic cell activation and consequently for preventing the development of allergen-specific T-helper cell responses upon allergen exposure. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1α possesses immunoregulatory functions implicated in the prevention of airway allergy.

Lactobacillus johnsonii supplementation attenuates respiratory viral infection via metabolic reprogramming and immune cell modulation.

PubMed

Fonseca, W; Lucey, K; Jang, S; Fujimura, K E; Rasky, A; Ting, H-A; Petersen, J; Johnson, C C; Boushey, H A; Zoratti, E; Ownby, D R; Levine, A M; Bobbit, K R; Lynch, S V; Lukacs, N W

2017-11-01

Regulation of respiratory mucosal immunity by microbial-derived metabolites has been a proposed mechanism that may provide airway protection. Here we examine the effect of oral Lactobacillus johnsonii supplementation on metabolic and immune response dynamics during respiratory syncytial virus (RSV) infection. L. johnsonii supplementation reduced airway T helper type 2 cytokines and dendritic cell (DC) function, increased regulatory T cells, and was associated with a reprogrammed circulating metabolic environment, including docosahexanoic acid (DHA) enrichment. RSV-infected bone marrow-derived DCs (BMDCs) from L. johnsonii-supplemented mice had altered cytokine secretion, reduced expression of co-stimulatory molecules, and modified CD4+ T-cell cytokines. This was replicated upon co-incubation of wild-type BMDCs with either plasma from L. johnsonii-supplemented mice or DHA. Finally, airway transfer of BMDCs from L. johnsonii-supplemented mice or with wild-type derived BMDCs pretreated with plasma from L. johnsonii-supplemented mice reduced airway pathological responses to infection in recipient animals. Thus L. johnsonii supplementation mediates airway mucosal protection via immunomodulatory metabolites and altered immune function.

Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

PubMed Central

Wu, Yuet; Lam, Kwok-Tai; Chow, Kin-Hung; Ho, Pak-Leung; Guan, Yi; Peiris, Joseph S. Malik

2014-01-01

ABSTRACT Secondary Streptococcus pneumoniae infection after influenza is a significant clinical complication resulting in morbidity and sometimes mortality. Prior influenza virus infection has been demonstrated to impair the macrophage and neutrophil response to the subsequent pneumococcal infection. In contrast, how a secondary pneumococcal infection after influenza can affect the adaptive immune response to the initial influenza virus infection is less well understood. Therefore, this study focuses on how secondary pneumococcal infection after influenza may impact the humoral immune response to the initial influenza virus infection in a lethal coinfection mouse model. Compared to mice infected with influenza virus alone, mice coinfected with influenza virus followed by pneumococcus had significant body weight loss and 100% mortality. In the lung, lethal coinfection significantly increased virus titers and bacterial cell counts and decreased the level of virus-specific IgG, IgM, and IgA, as well as the number of B cells, CD4 T cells, and plasma cells. Lethal coinfection significantly reduced the size and weight of spleen, as well as the number of B cells along the follicular developmental lineage. In mediastinal lymph nodes, lethal coinfection significantly decreased germinal center B cells, T follicular helper cells, and plasma cells. Adoptive transfer of influenza virus-specific immune serum to coinfected mice improved survival, suggesting the protective functions of anti-influenza virus antibodies. In conclusion, coinfection reduced the B cell response to influenza virus. This study helps us to understand the modulation of the B cell response to influenza virus during a lethal coinfection. IMPORTANCE Secondary pneumococcal infection after influenza virus infection is an important clinical issue that often results in excess mortality. Since antibodies are key mediators of protection, this study aims to examine the antibody response to influenza virus and demonstrates that lethal coinfection reduced the B cell response to influenza virus. This study helps to highlight the complexity of the modulation of the B cell response in the context of coinfection. PMID:25428873

Cloning and Sequencing of Defective Particles Derived from the Autonomous Parvovirus Minute Virus of Mice for the Construction of Vectors with Minimal cis-Acting Sequences

PubMed Central

Clément, Nathalie; Avalosse, Bernard; El Bakkouri, Karim; Velu, Thierry; Brandenburger, Annick

2001-01-01

The production of wild-type-free stocks of recombinant parvovirus minute virus of mice [MVM(p)] is difficult due to the presence of homologous sequences in vector and helper genomes that cannot easily be eliminated from the overlapping coding sequences. We have therefore cloned and sequenced spontaneously occurring defective particles of MVM(p) with very small genomes to identify the minimal cis-acting sequences required for DNA amplification and virus production. One of them has lost all capsid-coding sequences but is still able to replicate in permissive cells when nonstructural proteins are provided in trans by a helper plasmid. Vectors derived from this particle produce stocks with no detectable wild-type MVM after cotransfection with new, matched, helper plasmids that present no homology downstream from the transgene. PMID:11152501

Characterization of Helper Virus-Independent Cytopathogenic Classical Swine Fever Virus Generated by an In Vivo RNA Recombination System

PubMed Central

Gallei, Andreas; Rümenapf, Till; Thiel, Heinz-Jürgen; Becher, Paul

2005-01-01

Molecular analyses revealed that most cytopathogenic (cp) pestivirus strains evolve from noncytopathogenic (noncp) viruses by nonhomologous RNA recombination. In contrast to bovine viral diarrhea virus (BVDV), cp classical swine fever virus (CSFV) field isolates were rarely detected and always represented helper virus-dependent subgenomes. To investigate RNA recombination in more detail, we recently established an in vivo system allowing the efficient generation of recombinant cp BVDV strains in cell culture after transfecting a synthetic subgenomic and nonreplicatable transcript into cells being infected with noncp BVDV (A. Gallei, A. Pankraz, H.-J. Thiel, and P. Becher, J. Virol. 78:6271-6281, 2004). Using an analogous approach, the first helper virus-independent cp CSFV strain (CP G1) has now been generated by RNA recombination. Accordingly, this study demonstrates the applicability of RNA recombination for designing new viral RNA genomes. The genomic RNA of CP G1 has a calculated size of 18.139 kb, almost 6 kb larger than all previously described CSFV genomes. It contains cellular sequences encoding a polyubiquitin fragment directly upstream of the nonstructural protein NS3 coding gene together with a duplication of viral sequences. CP G1 induces a cytopathic effect on different tissue culture cell lines from pigs and cattle. Subsequent analyses addressed growth kinetics, expression of NS3, and genetic stability of CP G1. PMID:15681445

Mesenchymal stromal cells: main factor or helper in regenerative medicine?

PubMed

Zander, Axel R; Lange, Claudia; Westenfelder, Christof

2011-09-01

Mesenchymal stromal cells (mSCs) are presently studied for the prophylaxis and therapy of a variety of diseases such as acute graft-versus-host disease after allogeneic stem cell transplantation, cardiac indications, bone degeneration, Crohn's disease, and organ rejection, as well as prevention of acute renal failure in high-risk situations. mSCs appear to function through paracrine mechanisms that exert immunosuppressive, anti-inflammatory, anti-apoptotic, mitogenic, and other organ-protective and repair-stimulating actions. mSCs are either cultured in the presence of fetal calf serum (FCS) or platelet lysate (PL). PL lysate-generated mSCs exhibit faster doubling times, different gene expression profiles, and more potent immunosuppressive activity compared with FSC-generated mSCs. The utility of mSCs in the treatment of chronic inflammatory diseases is being evaluated in prospective studies.

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

Improved methods for predicting peptide binding affinity to MHC class II molecules.

PubMed

Jensen, Kamilla Kjaergaard; Andreatta, Massimo; Marcatili, Paolo; Buus, Søren; Greenbaum, Jason A; Yan, Zhen; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

2018-07-01

Major histocompatibility complex class II (MHC-II) molecules are expressed on the surface of professional antigen-presenting cells where they display peptides to T helper cells, which orchestrate the onset and outcome of many host immune responses. Understanding which peptides will be presented by the MHC-II molecule is therefore important for understanding the activation of T helper cells and can be used to identify T-cell epitopes. We here present updated versions of two MHC-II-peptide binding affinity prediction methods, NetMHCII and NetMHCIIpan. These were constructed using an extended data set of quantitative MHC-peptide binding affinity data obtained from the Immune Epitope Database covering HLA-DR, HLA-DQ, HLA-DP and H-2 mouse molecules. We show that training with this extended data set improved the performance for peptide binding predictions for both methods. Both methods are publicly available at www.cbs.dtu.dk/services/NetMHCII-2.3 and www.cbs.dtu.dk/services/NetMHCIIpan-3.2. © 2018 John Wiley & Sons Ltd.

High Efficiency CRISPR/Cas9-mediated Gene Editing in Primary Human T-cells Using Mutant Adenoviral E4orf6/E1b55k "Helper" Proteins.

PubMed

Gwiazda, Kamila S; Grier, Alexandra E; Sahni, Jaya; Burleigh, Stephen M; Martin, Unja; Yang, Julia G; Popp, Nicholas A; Krutein, Michelle C; Khan, Iram F; Jacoby, Kyle; Jensen, Michael C; Rawlings, David J; Scharenberg, Andrew M

2016-09-29

Many future therapeutic applications of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 and related RNA-guided nucleases are likely to require their use to promote gene targeting, thus necessitating development of methods that provide for delivery of three components-Cas9, guide RNAs and recombination templates-to primary cells rendered proficient for homology-directed repair. Here, we demonstrate an electroporation/transduction codelivery method that utilizes mRNA to express both Cas9 and mutant adenoviral E4orf6 and E1b55k helper proteins in association with adeno-associated virus (AAV) vectors expressing guide RNAs and recombination templates. By transiently enhancing target cell permissiveness to AAV transduction and gene editing efficiency, this novel approach promotes efficient gene disruption and/or gene targeting at multiple loci in primary human T-cells, illustrating its broad potential for application in translational gene editing.

Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis

PubMed Central

Rosenthal, Kenneth S.; Mikecz, Katalin; Steiner, Harold L.; Glant, Tibor T.; Finnegan, Alison; Carambula, Roy E.; Zimmerman, Daniel H.

2016-01-01

The current status of therapeutic vaccines for autoimmune diseases is reviewed with rheumatoid arthritis as the focus. Therapeutic vaccines for autoimmune diseases must regulate or subdue responses to common self-antigens. Ideally, such a vaccine would initiate an antigen-specific modulation of the T-cell immune response that drives the inflammatory disease. Appropriate animal models and types of T helper cells and signature cytokine responses that drive autoimmune disease are also discussed. Interpretation of these animal models must be done cautiously because the means of initiation, autoantigens, and even the signature cytokine and T helper cell (Th1 or Th17) responses that are involved in the disease may differ significantly from those in humans. We describe ligand epitope antigen presentation system vaccine modulation of T-cell autoimmune responses as a strategy for the design of therapeutic vaccines for rheumatoid arthritis, which may also be effective in other autoimmune conditions. PMID:25787143

Pediatric precursor B acute lymphoblastic leukemia: are T helper cells the missing link in the infectious etiology theory?

PubMed

Bürgler, Simone; Nadal, David

2017-12-01

Precursor B acute lymphoblastic leukemia (BCP-ALL), the most common childhood malignancy, arises from an expansion of malignant B cell precursors in the bone marrow. Epidemiological studies suggest that infections or immune responses to infections may promote such an expansion and thus BCP-ALL development. Nevertheless, a specific pathogen responsible for this process has not been identified. BCP-ALL cells critically depend on interactions with the bone marrow microenvironment. The bone marrow is also home to memory T helper (Th) cells that have previously expanded during an immune response in the periphery. In secondary lymphoid organs, Th cells can interact with malignant cells of mature B cell origin, while such interactions between Th cells and malignant immature B cell in the bone marrow have not been described yet. Nevertheless, literature supports a model where Th cells-expanded during an infection in early childhood-migrate to the bone marrow and support BCP-ALL cells as they support normal B cells. Further research is required to mechanistically confirm this model and to elucidate the interaction pathways between leukemia cells and cells of the tumor microenvironment. As benefit, targeting these interactions could be included in current treatment regimens to increase therapeutic efficiency and to reduce relapses.

Alteration of Lymphocyte Phenotype and Function in Sickle Cell Anemia: Implications for Vaccine Responses

PubMed Central

Balandya, Emmanuel; Reynolds, Teri; Obaro, Stephen; Makani, Julie

2016-01-01

Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper : CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (Treg), skewing of CD4+ T cells towards Th2 response and loss of IgM-secreting CD27+IgMhighIgDlow memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C-reactive protein and pro-inflammatory cytokines IL-6 and TNF-α, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub-Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. PMID:27237467

Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity.

PubMed

Hrdlickova, Barbara; Kumar, Vinod; Kanduri, Kartiek; Zhernakova, Daria V; Tripathi, Subhash; Karjalainen, Juha; Lund, Riikka J; Li, Yang; Ullah, Ubaid; Modderman, Rutger; Abdulahad, Wayel; Lähdesmäki, Harri; Franke, Lude; Lahesmaa, Riitta; Wijmenga, Cisca; Withoff, Sebo

2014-01-01

Although genome-wide association studies (GWAS) have identified hundreds of variants associated with a risk for autoimmune and immune-related disorders (AID), our understanding of the disease mechanisms is still limited. In particular, more than 90% of the risk variants lie in non-coding regions, and almost 10% of these map to long non-coding RNA transcripts (lncRNAs). lncRNAs are known to show more cell-type specificity than protein-coding genes. We aimed to characterize lncRNAs and protein-coding genes located in loci associated with nine AIDs which have been well-defined by Immunochip analysis and by transcriptome analysis across seven populations of peripheral blood leukocytes (granulocytes, monocytes, natural killer (NK) cells, B cells, memory T cells, naive CD4(+) and naive CD8(+) T cells) and four populations of cord blood-derived T-helper cells (precursor, primary, and polarized (Th1, Th2) T-helper cells). We show that lncRNAs mapping to loci shared between AID are significantly enriched in immune cell types compared to lncRNAs from the whole genome (α <0.005). We were not able to prioritize single cell types relevant for specific diseases, but we observed five different cell types enriched (α <0.005) in five AID (NK cells for inflammatory bowel disease, juvenile idiopathic arthritis, primary biliary cirrhosis, and psoriasis; memory T and CD8(+) T cells in juvenile idiopathic arthritis, primary biliary cirrhosis, psoriasis, and rheumatoid arthritis; Th0 and Th2 cells for inflammatory bowel disease, juvenile idiopathic arthritis, primary biliary cirrhosis, psoriasis, and rheumatoid arthritis). Furthermore, we show that co-expression analyses of lncRNAs and protein-coding genes can predict the signaling pathways in which these AID-associated lncRNAs are involved. The observed enrichment of lncRNA transcripts in AID loci implies lncRNAs play an important role in AID etiology and suggests that lncRNA genes should be studied in more detail to interpret GWAS findings correctly. The co-expression results strongly support a model in which the lncRNA and protein-coding genes function together in the same pathways.

Aryl hydrocarbon receptor promotes RORγt⁺ group 3 ILCs and controls intestinal immunity and inflammation.

PubMed

Qiu, Ju; Zhou, Liang

2013-11-01

Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptor (RORγt)⁺ group 3 ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt⁺ group 3 ILCs (e.g., lymphoid tissue inducer cells) are required for lymphoid organogenesis. In adult mice, RORγt⁺ group 3 ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt⁺ group 3 ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt⁺ group 3 ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells. In this review, we will focus on the development and function of RORγt⁺ group 3 ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. A better understanding of the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases.

Regulation of CD4 T cells and their effects on immunopathological inflammation following viral infection.

PubMed

Bhattacharyya, Mitra; Madden, Patrick; Henning, Nathan; Gregory, Shana; Aid, Malika; Martinot, Amanda J; Barouch, Dan H; Penaloza-MacMaster, Pablo

2017-10-01

CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naive CD4 T cells undergo substantial expansion following infection, but can induce lethal T helper type 1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary CD4 T cells, but does not seem to play a critical role in regulating the expansion of secondary CD4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary CD4 T cells following viral infection, despite that this treatment increased the numbers of primary CD4 T-cell responses. Altogether, these data demonstrate important aspects of how primary and secondary CD4 T cells are regulated in vivo, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T-cell therapies against persistent antigens. © 2017 John Wiley & Sons Ltd.

The Role of T Lymphocytes in Cancer Patients Undergoing Immunotherapy with Autologous Dendritic Cells

PubMed Central

Rodrigues, Cláudia M.; Matias, Bruna F.; Murta, Eddie F.C.; Michelin, Márcia A.

2011-01-01

Introduction: Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. Patients and methods: We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. Results: We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-γ, IL-12, TNF-α, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-α and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. Conclusion: Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period. PMID:21603246

PD-L2 Elbows out PD-L1 to Rescue T Cell Immunity to Malaria.

PubMed

Crompton, Peter D; Pierce, Susan K

2016-08-16

How early interactions between innate and adaptive immune cells influence outcomes of acute infections is incompletely understood. In this issue of Immunity, Karunarathne et al. (2016) show that dendritic cells help CD4(+) T helper 1 cell immunity against malaria through PD-L2's competition with PD-L1. Published by Elsevier Inc.

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.

A Rapid-Response Humoral Vaccine Platform Exploiting Pre-Existing Non-Cognate Populations of Anti-Vaccine or Anti-Viral CD4+ T Helper Cells to Confirm B Cell Activation.

PubMed

Hills, Thomas; Jakeman, Phillip G; Carlisle, Robert C; Klenerman, Paul; Seymour, Leonard W; Cawood, Ryan

2016-01-01

The need for CD4+ T cell responses to arise de novo following vaccination can limit the speed of B cell responses. Populations of pre-existing vaccine-induced or anti-viral CD4+ T cells recognising distinct antigens could be exploited to overcome this limitation. We hypothesise that liposomal vaccine particles encapsulating epitopes that are recognised, after processing and B cell MHCII presentation, by pre-existing CD4+ T cells will exploit this pre-existing T cell help and result in improved antibody responses to distinct target antigens displayed on the particle surface. Liposomal vaccine particles were engineered to display the malaria circumsporozoite (CSP) antigen on their surface, with helper CD4+ epitopes from distinct vaccine or viral antigens contained within the particle core, ensuring the B cell response is raised but focused against CSP. In vivo vaccination studies were then conducted in C57Bl/6 mice as models of either vaccine-induced pre-existing CD4+ T cell immunity (using ovalbumin-OVA) or virus-induced pre-existing CD4+ T cell immunity (murine cytomegalovirus-MCMV). Following the establishment of pre-existing by vaccination (OVA in the adjuvant TiterMax® Gold) or infection with MCMV, mice were administered CSP-coated liposomal vaccines containing the relevant OVA or MCMV core CD4+ T cell epitopes. In mice with pre-existing anti-OVA CD4+ T cell immunity, these vaccine particles elicited rapid, high-titre, isotype-switched CSP-specific antibody responses-consistent with the involvement of anti-OVA T helper cells in confirming activation of anti-CSP B cells. Responses were further improved by entrapping TLR9 agonists, combining humoral vaccination signals 'one', 'two' and 'three' within one particle. Herpes viruses can establish chronic infection and elicit significant, persistent cellular immune responses. We then demonstrate that this principle can be extended to re-purpose pre-existing anti-MCMV immunity to enhance anti-CSP vaccine responses-the first description of a strategy to specifically exploit anti-cytomegalovirus immunity to augment vaccination against a target antigen.

Ion-conducting membranes

DOEpatents

Masel, Richard L.; Chen, Qingmei; Liu, Zengcai; Kutz, Robert

2016-06-21

An ion conducting polymeric composition mixture comprises a copolymer of styrene and vinylbenzyl-R.sub.s. R.sub.s is selected from the group consisting of imidazoliums and pyridiniums. The composition contains 10%-90% by weight of vinylbenzyl-R.sub.s. The composition can further comprise a polyolefin comprising substituted polyolefins, a polymer comprising cyclic amine groups, a polymer comprising at least one of a phenylene group and a phenyl group, a polyamide, and/or the reaction product of a constituent having two carbon-carbon double bonds. The composition can be in the form of a membrane. In a preferred embodiment, the membrane is a Helper Membrane that increases the faradaic efficiency of an electrochemical cell into which the membrane is incorporated, and also allows product formation at lower voltages than in cells without the Helper Membrane.

Generation and functional analysis of T cell lines and clones specific for schistosomula released products (SRP-A).

PubMed

Damonneville, M; Velge, F; Verwaerde, C; Pestel, J; Auriault, C; Capron, A

1987-08-01

Antigens present in the products released by the larval stage of schistosome (SRP-A) were shown to induce a strong cytotoxic and protective IgE response both in the rat and the monkey. T cell lines and clones specific for SRP-A or 26 kD antigens which are the main target of the cytotoxic IgE have been derived. The passive transfer of SRP-A specific T lymphocytes into infected rats led to an increase of the IgE response, conferring a significant level of protection to the rats. In coculture assays in vitro, these cell lines significantly enhanced the production of IgE by SRP-A sensitized rat spleen cells. This helper effect on the IgE response was confirmed with 26 kD T cell clone supernatants. Moreover, supernatants obtained after stimulation with phorbol myristate acetate were able to enhance the IgE production of a hybridoma B cell line (B48-14) producing a monoclonal IgE antibody, cytotoxic for the schistosomula.

A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

PubMed

Wong, Michael Thomas; Ong, David Eng Hui; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Henry Kun Kiaang; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng-Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Curotto de Lafaille, Maria Alicia; Newell, Evan William

2016-08-16

Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of dendritic cells in cancer.

PubMed

Hansen, Morten; Andersen, Mads Hald

2017-04-01

Though present in low numbers, dendritic cells (DCs) are recognized as major players in the control of cancer by adaptive immunity. The roles of cytotoxic CD8 + T-cells and Th1 helper CD4 + T-cells are well-documented in murine models of cancer and associated with a profound prognostic impact when infiltrating human tumors, but less information is known about how these T-cells gain access to the tumor or how they are primed to become tumor-specific. Here, we highlight recent findings that demonstrate a vital role of CD103 + DCs, which have been shown to be experts in cross-priming and the induction of anti-tumor immunity. We also focus on two different mediators that impair the function of tumor-associated DCs: prostaglandin E 2 and β-catenin. Both of these mediators seem to be important for the exclusion of T-cells in the tumor microenvironment and may represent key pathways to target in optimized treatment regimens against cancer.

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation.

PubMed

Molofsky, Ari B; Savage, Adam K; Locksley, Richard M

2015-06-16

Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks. IL-33 can participate in pathologic fibrotic reactions, or, in the setting of microbial invasion, can cooperate with inflammatory cytokines to promote responses by cytotoxic NK cells, Th1 cells, and CD8(+) T cells. Here, we highlight the regulation and function of IL-33 and ST2 and review their roles in homeostasis, damage, and inflammation, suggesting a conceptual framework for future studies. Copyright © 2015 Elsevier Inc. All rights reserved.

[Construction of lentiviral mediated CyPA siRNA and its functions in non-small cell lung cancer].

PubMed

FENG, Yan-ming; WU, Yi-ming; TU, Xin-ming; XU, Zheng-shun; WU, Wei-dong

2010-02-01

To construct a lentiviral-vector-mediated CyPA small interference RNA (siRNA) and study its function in non-small cell lung cancer. First, four target sequences were selected according to CyPA mRNA sequence, the complementary DNA contained both sense and antisense oligonucleotides were designed, synthesized and cloned into the pGCL-GFP vector, which contained U6 promoter and green fluorescent protein (GFP). The resulting lentiviral vector containing CyPA shRNA was named Lv-shCyPA, and it was confirmed by PCR and sequencing. Next, it was cotransfected by Lipofectamine 2000 along with pHelper1.0 and pHelper 2.0 into 293T cells to package lentivirus particles. At the same time, the packed virus infected non-small cell lung cancer cell (A549), the level of CyPA protein at 5 d after infection was detected by Western Blot to screen the target of CyPA. A549 were infected with Lv-shCyPA and grown as xenografts in severe combined immunodeficient mice. Cell cycle and apoptosis were measured by FCM. It was confirmed by PCR and DNA sequencing that lentiviral-vector-mediated CyPA siRNA (Lv-shCyPA) producing CyPA shRNA was constructed successfully. The titer of concentrated virus were 1 x 10(7) TU/ml. Flow cytometric analysis demonstrated G2-M phase (11.40% +/- 0.68%) was decreased relatively in A549/LvshCyPA compared with control groups (14.52% +/- 1.19%) (P<0.05). The apoptosis rate of A549/Lv-shCyPA (5.01% +/- 0.5%) was higher than control groups (0.35% +/- 0.17%) (P<0.05). Visible tumors were only detectable at 6th day after inoculated by A549/Lv-shCyPA. The xenograft tumors of A549/Lv-shCyPA remarkably delayed tumor growth and remained at a similarly small average size at 38th days after inoculation compared with the control group (P < 0.05). Lentiviral-vector-mediated siRNA technique effectively inhibits the expression of CyPA, induces the NSCLC cell apoptosis, inhibits the tumor growth. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for non-small cell lung cancer.

Barrier Epithelial Cells and the Control of Type 2 Immunity.

PubMed

Hammad, Hamida; Lambrecht, Bart N

2015-07-21

Type-2-cell-mediated immunity, rich in eosinophils, basophils, mast cells, CD4(+) T helper 2 (Th2) cells, and type 2 innate lymphoid cells (ILC2s), protects the host from helminth infection but also drives chronic allergic diseases like asthma and atopic dermatitis. Barrier epithelial cells (ECs) represent the very first line of defense and express pattern recognition receptors to recognize type-2-cell-mediated immune insults like proteolytic allergens or helminths. These ECs mount a prototypical response made up of chemokines, innate cytokines such as interleukin-1 (IL-1), IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), as well as the alarmins uric acid, ATP, HMGB1, and S100 proteins. These signals program dendritic cells (DCs) to mount Th2-cell-mediated immunity and in so doing boost ILC2, basophil, and mast cell function. Here we review the general mechanisms of how different stimuli trigger type-2-cell-mediated immunity at mucosal barriers and how this leads to protection or disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin.

PubMed

Mor, Felix; Cohen, Irun R

2013-02-19

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell-mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

Characterization of a hybridoma-derived T cell factor that promotes the production of antibodies bearing a dominant cross-reactive idiotype(s).

PubMed

Wardzala, A M; Bowen, M B; Jendrisak, G S; Bellone, C J

1986-01-01

The participation of postulated subsets of T helper cells in antigen-specific antibody responses has generated both interest and controversy among immunologists. Specifically the import as well as the very existence of multiple populations of T helper cells has led to an intense search in recent years for cloned lines of such subsets that permit unambiguous classification and study. Furthermore, the means by which some of these T cells induce antibody responses may be via the elaboration of soluble factors mandating their characterization both biochemically and mechanistically. We have recently reported the existence of a T helper factor present in a 24-h Con A supernatant that specifically enhances an idiotype-bearing (Id+) response to trinitrophenol (TNP). The unique biochemical properties of this substance, namely, its capacity to bind both antigen and cross-reactive idiotype (CRI), has led to the generation of a cloned T cell hybridoma that constitutively "secretes" a factor which appears identical to the helper activity in Con A Sn. The cloned T cell hybridoma, herein designated LOP 1.4, elaborates a factor which selectively enhances the CRI+ anti-TNP antibody response in vitro. The specificity of the assay employed as well as its sensitivity for detecting significant enhancement of the percent CRI+ anti-TNP PFC response lent itself well as a useful vehicle for subsequent characterization of the factor. The LOP 1.4 factor, which can act at the later stages of the B cell response in a dose-dependent fashion, was characterized by affinity chromatography in order to probe the mechanism of its selective Id enhancement. The factor binds both the idiotype and the ligand for which one of the idiotype-bearing monoclonal antibodies is specific. That the factor binds idiotype and can be eluted selectively with ligand but not with noncross-reacting ligand suggests that the factor possesses separate but not independent binding sites, or alternatively, a single binding site that preferentially binds to a unique composite of antigen-idiotype. In addition, the factor bears I-J determinants, consistent with what we have previously detected on the surface of TH2-like cells. These results, collectively, suggest that the T cell hybridoma LOP 1.4 is a TH2-like cell (supporting the concept of multiple TH subsets) in light of its ability to enhance an idiotypic response to specific antigen through the production of a soluble factor that demonstrates affinity for both antigen and idiotype. In addition, like the I-J+ TH2 cell, the LOP 1.4 factor also bears I-J region determinants.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production

PubMed Central

Sprokholt, Joris K.; Kaptein, Tanja M.; van Hamme, John L.; Overmars, Ronald J.; Gringhuis, Sonja I.

2017-01-01

Follicular T helper cells (TFH) are fundamental in orchestrating effective antibody-mediated responses critical for immunity against viral infections and effective vaccines. However, it is unclear how virus infection leads to TFH induction. We here show that dengue virus (DENV) infection of human dendritic cells (DCs) drives TFH formation via crosstalk of RIG-I-like receptor (RLR) RIG-I and MDA5 with type I Interferon (IFN) signaling. DENV infection leads to RLR-dependent IKKε activation, which phosphorylates IFNα/β receptor-induced STAT1 to drive IL-27 production via the transcriptional complex ISGF3. Inhibiting RLR activation as well as neutralizing antibodies against IL-27 prevented TFH formation. DENV-induced CXCR5+PD-1+Bcl-6+ TFH cells secreted IL-21 and activated B cells to produce IgM and IgG. Notably, RLR activation by synthetic ligands also induced IL-27 secretion and TFH polarization. These results identify an innate mechanism by which antibodies develop during viral disease and identify RLR ligands as potent adjuvants for TFH-promoting vaccination strategies. PMID:29186193

Formation of high-order oligomers is required for functional bioactivity of an African bat henipavirus surface glycoprotein.

PubMed

Behner, Laura; Zimmermann, Louisa; Ringel, Marc; Weis, Michael; Maisner, Andrea

2018-05-01

Hendra virus (HeV) and Nipah virus (NiV) are highly pathogenic henipaviruses originating from fruit bats in Australia and Asia that can cause severe infections in livestock and humans. In recent years, also African bat henipaviruses were identified at the nucleic acid level. To assess their potential to replicate in non-bat species, several studies were performed to characterize the two surface glycoproteins required for virus entry and spread by cell-cell fusion. It has been shown that surface expression and fusion-helper function of the receptor-binding G protein of Kumasi virus (KV), the prototypic Ghanaian bat henipavirus, is reduced compared to other non-African henipavirus G proteins. Immunostainings and pulse-chase analysis revealed a delayed export of KV G from the ER. As defects in oligomerization of viral glycoproteins can be responsible for limited surface transport thereby restricting the bioactivity, we analyzed the oligomerization pattern of KV G. In contrast to HeV and NiV whose G proteins are known to be expressed at a dimer-tetramer ratio of 1:1, KV G almost exclusively formed stable tetramers or higher oligomers. KV G also showed less stringent requirements for defined stalk cysteines to form dimers and tetramers. Interestingly, any changes in the oligomeric forms negatively affected the fusion-helper activity although surface expression and receptor binding was unchanged. This clearly indicates that the formation of mostly higher oligomeric KV G forms is not a deficiency responsible for ER retention, but is rather a basic structural feature essential for the bioactivity of this African bat henipavirus glycoprotein. Copyright © 2018 Elsevier B.V. All rights reserved.

Induction of A. fumigatus-specific CD4-positive T cells in patients recovering from invasive aspergillosis

PubMed Central

Jolink, Hetty; Hagedoorn, Renate S.; Lagendijk, Ellen L.; Drijfhout, Jan W.; van Dissel, Jaap T.; Falkenburg, J.H. Frederik; Heemskerk, Mirjam H.M.

2014-01-01

After allogeneic stem cell transplantation patients are at risk of invasive aspergillosis, especially during the period of neutropenia. Recent data suggest that impaired T-cell immune reconstitution after transplantation plays an important role in this increased risk. In this study we investigated whether Aspergillus-specific T cells are involved in the recovery from invasive aspergillosis by analyzing the Aspergillus-specific T-cell response in patients with invasive aspergillosis. In nine patients whose Aspergillus infection improved, we identified Crf1- or Catalase1-specific T cells on the basis of CD154 expression and interferon-γ production following stimulation with overlapping peptides of the A. fumigatus proteins Crf1 and Catalase1. These Aspergillus-specific T cells were induced at the moment of regression of the aspergillus lesions. Crf1- and Catalase1-specific T cells, sorted on the basis of CD154 expression at the peak of the immune response, had a T helper-1 phenotype and recognized a variety of T-cell epitopes. In contrast, in two patients with progressive invasive aspergillosis, no Crf1- or Catalase1-specific T cells were identified. These data indicate that the presence of Aspergillus-specific T cells with a T helper-1 phenotype correlates with the clearance of aspergillus infection. PMID:24747947

Somatic mutations and affinity maturation are impaired by excessive numbers of T follicular helper cells and restored by Treg cells or memory T cells.

PubMed

Preite, Silvia; Baumjohann, Dirk; Foglierini, Mathilde; Basso, Camilla; Ronchi, Francesca; Fernandez Rodriguez, Blanca M; Corti, Davide; Lanzavecchia, Antonio; Sallusto, Federica

2015-11-01

We previously reported that Cd3e-deficient mice adoptively transferred with CD4(+) T cells generate high numbers of T follicular helper (Tfh) cells, which go on to induce a strong B-cell and germinal center (GC) reaction. Here, we show that in this system, GC B cells display an altered distribution between the dark and light zones, and express low levels of activation-induced cytidine deaminase. Furthermore, GC B cells from Cd3e(-/-) mice accumulate fewer somatic mutations as compared with GC B cells from wild-type mice, and exhibit impaired affinity maturation and reduced differentiation into long-lived plasma cells. Reconstitution of Cd3e(-/-) mice with regulatory T (Treg) cells restored Tfh-cell numbers, GC B-cell numbers and B-cell distribution within dark and light zones, and the rate of antibody somatic mutations. Tfh-cell numbers and GC B-cell numbers and dynamics were also restored by pre-reconstitution of Cd3e(-/-) mice with Cxcr5(-/-) Treg cells or non-regulatory, memory CD4(+) T cells. Taken together, these findings underline the importance of a quantitatively regulated Tfh-cell response for an efficient and long-lasting serological response. © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Crucial Roles of Interleukin-7 in the Development of T Follicular Helper Cells and in the Induction of Humoral Immunity

PubMed Central

Seo, Yong Bok; Im, Se Jin; Namkoong, Hong; Kim, Sae Won; Choi, Young Woo; Kang, Moon Cheol; Lim, Hye Seong; Jin, Hyun Tak; Yang, Se Hwan; Cho, Mi La; Kim, You-Me; Lee, Seung-Woo; Choi, Young Ki; Surh, Charles D.

2014-01-01

ABSTRACT T follicular helper (Tfh) cells are specialized providers of cognate B cell help, which is important in promoting the induction of high-affinity antibody production in germinal centers (GCs). Interleukin-6 (IL-6) and IL-21 have been known to play important roles in Tfh cell differentiation. Here, we demonstrate that IL-7 plays a pivotal role in Tfh generation and GC formation in vivo, as treatment with anti-IL-7 neutralizing antibody markedly impaired the development of Tfh cells and IgG responses. Moreover, codelivery of mouse Fc-fused IL-7 (IL-7-mFc) with a vaccine enhanced the generation of GC B cells as well as Tfh cells but not other lineages of T helper cells, including Th1, Th2, and Th17 cells. Interestingly, a 6-fold-lower dose of an influenza virus vaccine codelivered with Fc-fused IL-7 induced higher antigen-specific and cross-reactive IgG titers than the vaccine alone in both mice and monkeys and led to markedly enhanced protection against heterologous influenza virus challenge in mice. Enhanced generation of Tfh cells by IL-7-mFc treatment was not significantly affected by the neutralization of IL-6 and IL-21, indicating an independent role of IL-7 on Tfh differentiation. Thus, IL-7 holds promise as a critical cytokine for selectively inducing Tfh cell generation and enhancing protective IgG responses. IMPORTANCE Here, we demonstrate for the first time that codelivery of Fc-fused IL-7 significantly increased influenza virus vaccine-induced antibody responses, accompanied by robust expansion of Tfh cells and GC B cells as well as enhanced GC formation. Furthermore, IL-7-mFc induced earlier and cross-reactive IgG responses, leading to striking protection against heterologous influenza virus challenge. These results suggest that Fc-fused IL-7 could be used for inducing strong and cross-protective humoral immunity against highly mutable viruses, such as HIV and hepatitis C virus, as well as influenza viruses. PMID:24899182

Generation of a Kupffer Cell-evading Adenovirus for Systemic and Liver-directed Gene Transfer

PubMed Central

Khare, Reeti; May, Shannon M; Vetrini, Francesco; Weaver, Eric A; Palmer, Donna; Rosewell, Amanda; Grove, Nathan; Ng, Philip; Barry, Michael A

2011-01-01

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vector, Ad5/6 mediated higher luciferase and factor IX transgene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies. PMID:21505422

Generation of a Kupffer cell-evading adenovirus for systemic and liver-directed gene transfer.

PubMed

Khare, Reeti; May, Shannon M; Vetrini, Francesco; Weaver, Eric A; Palmer, Donna; Rosewell, Amanda; Grove, Nathan; Ng, Philip; Barry, Michael A

2011-07-01

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vector, Ad5/6 mediated higher luciferase and factor IX transgene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies.

Blockade of the Kv1.3 K+ Channel Enhances BCG Vaccine Efficacy by Expanding Central Memory T Lymphocytes.

PubMed

Singh, Dhiraj Kumar; Dwivedi, Ved Prakash; Ranganathan, Anand; Bishai, William R; Van Kaer, Luc; Das, Gobardhan

2016-11-01

Tuberculosis is the oldest known infectious disease, yet there is no effective vaccine against adult pulmonary tuberculosis. Emerging evidence indicates that T-helper 1 and T-helper 17 cells play important roles in host protection against tuberculosis. However, tuberculosis vaccine efficacy in mice is critically dependent on the balance between antigen-specific central memory T (Tcm) and effector memory T (Tem) cells. Specifically, a high Tcm/Tem cell ratio is essential for optimal vaccine efficacy. Here, we show that inhibition of Kv1.3, a potassium channel preferentially expressed by Tem cells, by Clofazimine selectively expands Tcm cells during BCG vaccination. Furthermore, mice that received clofazimine after BCG vaccination exhibited significantly enhanced resistance against tuberculosis. This superior activity against tuberculosis could be adoptively transferred to naive, syngeneic mice by CD4 + T cells. Therefore, clofazimine enhances Tcm cell expansion, which in turn provides improved vaccine efficacy. Thus, Kv1.3 blockade is a promising approach for enhancing the efficacy of the BCG vaccine in humans. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Antigen-driven C–C Chemokine-mediated HIV-1 Suppression by CD4+ T Cells from Exposed Uninfected Individuals Expressing the Wild-type CCR-5 Allele

PubMed Central

Furci, Lucinda; Scarlatti, Gabriella; Burastero, Samuele; Tambussi, Giuseppe; Colognesi, Claudia; Quillent, Caroline; Longhi, Renato; Loverro, Patrizia; Borgonovo, Barbara; Gaffi, Davide; Carrow, Emily; Malnati, Mauro; Lusso, Paolo; Siccardi, Antonio G.; Lazzarin, Adriano; Beretta, Alberto

1997-01-01

Despite repeated exposure to HIV-1, certain individuals remain persistently uninfected. Such exposed uninfected (EU) people show evidence of HIV-1–specific T cell immunity and, in rare cases, selective resistance to infection by macrophage-tropic strains of HIV-1. The latter has been associated with a 32–base pair deletion in the C–C chemokine receptor gene CCR-5, the major coreceptor of macrophage-tropic strains of HIV-1. We have undertaken an analysis of the HIV-specific T cell responses in 12 EU individuals who were either homozygous for the wild-type CCR-5 allele or heterozygous for the deletion allele (CCR-5Δ32). We have found evidence of an oligoclonal T cell response mediated by helper T cells specific for a conserved region of the HIV-1 envelope. These cells produce very high levels of C–C chemokines when stimulated by the specific antigen and suppress selectively the replication of macrophage-tropic, but not T cell–tropic, strains of HIV-1. These chemokine-producing helper cells may be part of a protective immune response that could be potentially exploited for vaccine development. PMID:9236198

Studies on the immunopotentiating effects of a streptococcal preparation, OK-432. I. Enhancement of T cell-mediated immune responses of mice.

PubMed Central

Kai, S; Tanaka, J; Nomoto, K; Torisu, M

1979-01-01

The effects of the anti-tumour agent OK-432 on the immune response to hamster erythrocytes (HRBC) and nucleated chicken erythrocytes (CRBC) were studied in inbred SL mice. Mice were treated repeatedly with OK-432 before immunization with erythrocytes in saline. The cytotoxicity of CRBC-primed spleen cells, as demonstrated by 51Cr release from labelled CRBC, was markedly increased by treatment with OD-432. The delayed footpad reaction to CRBC was significantly augmented by treatment with OK-432. These results in mice indicate that OK-432 can enhance the cellular immune responses which require the contribution of T cells. Such an activation of T cells by OK-432 was observed in the humoral immune response to a trinitrophenyl group. Augmentation of anti-hapten antibody production, suggesting the enhancement of helper T cell activity by OK-432, was noticed after immunization with trinitrophenyl conjugated to erythrocytes. Furthermore, this enhancement of helper T cell activity by OK-432 was confirmed by utilizing an adoptive transfer system. These results support the possibility that T cell activation may be one of the important effects of OK-432 as an immunopotentiator. PMID:314874

Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease

PubMed Central

McLane, Laura M.; Steblyanko, Maria; Anikeeva, Nadia; Ablanedo-Terrazas, Yuria; Demers, Korey; Eller, Michael A.; Streeck, Hendrik; Jansson, Marianne; Sönnerborg, Anders; Canaday, David H.; Naji, Ali; Wherry, E. John; Robb, Merlin L.; Reyes-Teran, Gustavo; Sykulev, Yuri; Betts, Michael R.

2018-01-01

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and β-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues. PMID:29652923

An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.

PubMed

Morita, Hideaki; Arae, Ken; Unno, Hirotoshi; Miyauchi, Kousuke; Toyama, Sumika; Nambu, Aya; Oboki, Keisuke; Ohno, Tatsukuni; Motomura, Kenichiro; Matsuda, Akira; Yamaguchi, Sachiko; Narushima, Seiko; Kajiwara, Naoki; Iikura, Motoyasu; Suto, Hajime; McKenzie, Andrew N J; Takahashi, Takao; Karasuyama, Hajime; Okumura, Ko; Azuma, Miyuki; Moro, Kazuyo; Akdis, Cezmi A; Galli, Stephen J; Koyasu, Shigeo; Kubo, Masato; Sudo, Katsuko; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

2015-07-21

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions.

PubMed Central

Eris, J M; Basten, A; Brink, R; Doherty, K; Kehry, M R; Hodgkin, P D

1994-01-01

B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses. Images PMID:7514304

Histone methylation mediates plasticity of human FOXP3+ regulatory T cells by modulating signature gene expressions

PubMed Central

He, Haiqi; Ni, Bing; Tian, Yi; Tian, Zhiqiang; Chen, Yanke; Liu, Zhengwen; Yang, Xiaomei; Lv, Yi; Zhang, Yong

2014-01-01

CD4+ FOXP3+ regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4+ CD25high CD127low/− Treg cells convert to two subpopulations with distinctive FOXP3+ and FOXP3− phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. PMID:24152290

Rat brain xenografts reverse hypogonadism in mice immunosuppressed with anti-CD4 monoclonal antibody.

PubMed

Honey, C R; Charlton, H M; Wood, K J

1991-01-01

This study examines the effect of immunosuppression with monoclonal antibodies (MAb) against the murine CD4 (L3T4), a cell surface glycoprotein expressed primarily on helper T-lymphocytes, on the viability and function of rat neural xenografts placed in the third ventricle of hypogonadal (hpg) mice. The hpg mouse fails to synthesize hypothalamic gonadotrophin releasing hormone (GnRH) and consequently there is a drastic reduction in pituitary gonadotrophic hormone content and a failure of postnatal gonadal development (Cattanach et al. 1977). Three groups of male hpg mice received xenografts of day 1 post natal rat preoptic area (POA) tissue, a source of GnRH neurons, to their third ventricle. Those immunosuppressed with anti-CD4 MAb all showed surviving graft tissue thirty days post-transplant and half of this group had enlarged testes with all stages of spermatogenesis. In those hpg mice which were injected with saline alone, or with an anti-CD8 (Lyt-2) antibody there was no xenograft survival. These results suggest that the injection of monoclonal antibodies against the T-helper subset may provide an alternative means of immunosuppression aimed at the enhancement of survival of tissue grafts in the CNS.

Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study.

PubMed

Vermeij, Renee; Leffers, Ninke; Hoogeboom, Baukje-Nynke; Hamming, Ineke L E; Wolf, Rinze; Reyners, Anna K L; Molmans, Barbara H W; Hollema, Harry; Bart, Joost; Drijfhout, Jan W; Oostendorp, Jaap; van der Zee, Ate G J; Melief, Cornelis J; van der Burg, Sjoerd H; Daemen, Toos; Nijman, Hans W

2012-09-01

The purpose of the current phase II single-arm clinical trial was to evaluate whether pretreatment with low-dose cyclophosphamide improves immunogenicity of a p53-synthetic long peptide (SLP) vaccine in patients with recurrent ovarian cancer. Patients with ovarian cancer with elevated serum levels of CA-125 after primary treatment were immunized four times with the p53-SLP vaccine. Each immunization was preceded by administration of 300 mg/m2 intravenous cyclophosphamide as a means to affect regulatory T cells (Tregs). Vaccine-induced p53-specific interferon-gamma (IFN-γ)-producing T cells evaluated by IFN-γ ELISPOT were observed in 90% (9/10) and 87.5% (7/8) of evaluable patients after two and four immunizations, respectively. Proliferative p53-specific T cells, observed in 80.0% (8/10) and 62.5% (5/8) of patients, produced both T-helper 1 and T-helper-2 cytokines. Cyclophosphamide induced neither a quantitative reduction of Tregs determined by CD4+ FoxP3+ T cell levels nor a demonstrable qualitative difference in Treg function tested in vitro. Nonetheless, the number of vaccine-induced p53-specific IFN-γ-producing T cells was higher in our study compared to a study in which a similar patient group was treated with p53-SLP monotherapy (p≤0.012). Furthermore, the strong reduction in the number of circulating p53-specific T cells observed previously after four immunizations was currently absent. Stable disease was observed in 20.0% (2/10) of patients, and the remainder of patients (80.0%) showed clinical, biochemical and/or radiographic evidence of progressive disease. The outcome of this phase II trial warrants new studies on the use of low-dose cyclophosphamide to potentiate the immunogenicity of the p53-SLP vaccine or other antitumor vaccines. Copyright © 2011 UICC.

Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain.

PubMed

Pichery, Mélanie; Mirey, Emilie; Mercier, Pascale; Lefrancais, Emma; Dujardin, Arnaud; Ortega, Nathalie; Girard, Jean-Philippe

2012-04-01

IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues.

Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.

PubMed

Kehrmann, Jan; Tatura, Roman; Zeschnigk, Michael; Probst-Kepper, Michael; Geffers, Robert; Steinmann, Joerg; Buer, Jan

2014-07-01

The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+)  CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage-specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells. © 2014 John Wiley & Sons Ltd.

The rise and fall of long-lived humoral immunity: terminal differentiation of plasma cells in health and disease

PubMed Central

O'Connor, Brian P.; Gleeson, Michael W.; Noelle, Randolph J.; Erickson, Loren D.

2010-01-01

Summary Long-lived humoral immune responses are a hallmark of thymus-dependent immunity. The cellular basis for enduring antibody-mediated immunity is long-lived memory B cells and plasma cells (PCs). Both of these cell populations acquire longevity as a result of antigen-specific, CD40–dependent, cognate interactions with helper T cells within germinal centers (GCs). At the molecular level, defined functional domains of CD40 control the post-GC fate of B cells. PC precursors that emerge from these GC reactions are highly proliferative and terminally differentiate to end-stage cells within the bone marrow (BM). The striking phenotypic similarities between the PC precursors and the putative malignant cell in multiple myeloma (MM) suggests that MM may result from the transformation of PC precursors. Within the domain of autoimmune disease, recent studies have shown that dysregulated migration of PCs to the BM may impact immune homeostasis and the development of lupus. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of differentiated B-cell disorders. PMID:12846808

Type two innate lymphoid cells: the Janus cells in health and disease.

PubMed

Maazi, Hadi; Akbari, Omid

2017-07-01

Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2, and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity, and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by co-stimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

TERMINATION OF TOLERANCE TO HUMAN GAMMA GLOBULIN IN MICE BY ANTIGEN AND BACTERIAL LIPOPOLYSACCHARIDE (ENDOTOXIN)

PubMed Central

Chiller, Jacques M.; Weigle, William O.

1973-01-01

Bacterial lipopolysaccharides (endotoxin) allowed the circumvention of the thymus-derived (T) cell helper function otherwise required for the antibody response in mice to human gamma globulin (HGG). In an analogous fashion, the state of tolerance to HGG, existing at a time when bone marrow-derived (B) cells had lost their unresponsiveness, could be terminated by the injection of both immunogenic HGG and endotoxin, but by neither given alone. However, no effect on tolerance to HGG could be observed when this regimen was followed at a time when B cells were tolerant. After the spontaneous recovery from tolerance in B cells, it seemed that specific priming was occurring in that population. This phenomenon was observed either by the injection of endotoxin and HGG or by the adoptive transfer of cells into irradiated hosts. These data have been discussed in the light of potential autoimmune manifestations that could theoretically follow a simultaneous gram-negative bacterial infection along with a release of self-antigen. PMID:4120288

Females increase reproductive investment in response to helper-mediated improvements in allo-feeding, nest survival, nestling provisioning and post-fledging survival in the Karoo scrub-robin Cercotrichas coryphaeus

USGS Publications Warehouse

Lloyd, P.; Andrew, Taylor W.; du Plessis, Morné A.; Martin, T.E.

2009-01-01

In many cooperatively-breeding species, the presence of one or more helpers improves the reproductive performance of the breeding pair receiving help. Helper contributions can take many different forms, including allo-feeding, offspring provisioning, and offspring guarding or defence. Yet, most studies have focussed on single forms of helper contribution, particularly offspring provisioning, and few have evaluated the relative importance of a broader range of helper contributions to group reproductive performance. We examined helper contributions to multiple components of breeding performance in the Karoo scrub-robin Cercotrichas coryphaeus, a facultative cooperative breeder. We also tested a prediction of increased female investment in reproduction when helpers improve conditions for rearing young. Helpers assisted the breeding male in allo-feeding the incubating female, increasing allo-feeding rates. Greater allo-feeding correlated with greater female nest attentiveness during incubation. Nest predation was substantially lower among pairs breeding with a helper, resulting in a 74% increase in the probability of nest survival. Helper contributions to offspring provisioning increased nestling feeding rates, resulting in a reduced incidence of nestling starvation and increased nestling mass. Nestling mass had a strong, positive effect on post-fledging survival. Controlling for female age and habitat effects, annual production of fledged young was 130% greater among pairs breeding with a helper, and was influenced most strongly by helper correlates with nest survival, despite important helper effects on offspring provisioning. Females breeding with a helper increased clutch size, supporting the prediction of increased female investment in reproduction in response to helper benefits. ?? 2009 J. Avian Biol.

Citrus juice fermented with Lactobacillus plantarum YIT 0132 alleviates symptoms of perennial allergic rhinitis in a double-blind, placebo-controlled trial.

PubMed

Harima-Mizusawa, N; Kano, M; Nozaki, D; Nonaka, C; Miyazaki, K; Enomoto, T

2016-11-30

This study aimed to examine whether citrus juice fermented with Lactobacillus plantarum YIT 0132 (LP0132), which was pasteurised after fermentation, could alleviate the symptoms of perennial allergic rhinitis in a double-blind, placebo-controlled, parallel-group trial. Subjects with perennial allergic rhinitis consumed LP0132-fermented juice (n=17) or unfermented citrus juice (placebo; n=16) once a day for 8 weeks. During the pre-intervention and intervention periods, the subjects recorded nasal symptoms (number of sneezing attacks, number of nose-blowing incidents, and stuffy nose score). The primary endpoint, nasal symptoms score (NSS), was scored from 0 to 4 according to the 'Practical Guideline for the Management of Allergic Rhinitis in Japan 2009' using a combination of the three nasal symptom items. Blood samples were collected at pre-intervention and at 8 weeks after commencing the intervention. There were several significant improvements not only in the LP0132 group but also in the placebo group because of potential anti-allergic effects of citrus. Compared with the placebo group, the LP0132 group showed a significant reduction in the NSS and stuffy nose score during the intervention period. Also, the LP0132 group, but not the placebo group, showed significant attenuation of type 2 helper T cells (Th2 cells)/helper T cells, serum total immunoglobulin E (IgE), and eosinophil cationic protein (ECP), and showed significant augmentation of type 1 helper T cells (Th1 cells)/Th2 cells at 8 weeks of intervention compared with baseline. It is suggested that daily intake of fermented citrus juice containing heat-killed LP0132 has beneficial effects on symptoms of perennial allergic rhinitis, and these benefits may be associated with the attenuation of Th2 cells, total IgE, and ECP via the immunomodulating activities of LP0132.

Clinical methods of cryopreservation for donor lymphocyte infusions vary in their ability to preserve functional T-cell subpopulations.

PubMed

Worsham, D Nicole; Reems, Jo-Anna; Szczepiorkowski, Zbigniew M; McKenna, David H; Leemhuis, Thomas; Mathew, Aby J; Cancelas, Jose A

2017-06-01

Cryopreserved donor lymphocyte infusion (DLI) products are manufactured and administered to treat relapse after allogeneic hematopoietic stem cell transplantation. Reported clinical responses to DLIs vary broadly, even within the same group of patients. While there is an implicit recognition of the fact that different manufacturing protocols may have specific effects on different cell types, cryopreservation protocols are frequently derived from our experience in the cryopreservation of stem cell products and do not account for the heterogeneous functional nature of DLI T-cell populations. Here, we report the results of a prospective, multicenter trial on the effect of four different cryopreservation solutions that were used to freeze DLIs compared to control DLIs that were refrigerated overnight. Cryopreserved postthawed and refrigerated specimens were analyzed side by side for their T-cell subpopulation content and viability, as well as T-cell proliferation, cytokine secretion, and cytotoxic activities. This study indicates that "homemade" 10% dimethyl sulfoxide (DMSO) results in reduced viability of different CD4+ T-cell populations, including T-helper, T-cytotoxic, and T-regulatory populations, and a decrease in their proliferative and cytotoxic response to immunologically relevant stimuli, while the use of solutions containing 5% DMSO with intracellular-like cryoprotectant stabilizers maintains T-cell function at levels similar to refrigerated control samples. This study has important implications in determining the best cryoprotectant solution for specific clinical applications in allogeneic immunotherapy. © 2017 AABB.

Asthma: T-bet--a master controller?

PubMed

Robinson, Douglas S; Lloyd, Clare M

2002-04-30

The transcription factors T-bet and GATA3 are important reciprocal determinants of Th1 and Th2 T helper cell differentiation. Recent evidence suggests that these factors may affect airway immunopathology in asthma.

Induction of regulatory T cells in Th1-/Th17-driven experimental autoimmune encephalomyelitis by zinc administration.

PubMed

Rosenkranz, Eva; Maywald, Martina; Hilgers, Ralf-Dieter; Brieger, Anne; Clarner, Tim; Kipp, Markus; Plümäkers, Birgit; Meyer, Sören; Schwerdtle, Tanja; Rink, Lothar

2016-03-01

The essential trace element zinc is indispensable for proper immune function as zinc deficiency accompanies immune defects and dysregulations like allergies, autoimmunity and an increased presence of transplant rejection. This point to the importance of the physiological and dietary control of zinc levels for a functioning immune system. This study investigates the capacity of zinc to induce immune tolerance. The beneficial impact of physiological zinc supplementation of 6 μg/day (0.3mg/kg body weight) or 30 μg/day (1.5mg/kg body weight) on murine experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis with a Th1/Th17 (Th, T helper) cell-dominated immunopathogenesis, was analyzed. Zinc administration diminished EAE scores in C57BL/6 mice in vivo (P<.05), reduced Th17 RORγT(+) cells (P<.05) and significantly increased inducible iTreg cells (P<.05). While Th17 cells decreased systemically, iTreg cells accumulated in the central nervous system. Cumulatively, zinc supplementation seems to be capable to induce tolerance in unwanted immune reactions by increasing iTreg cells. This makes zinc a promising future tool for treating autoimmune diseases without suppressing the immune system. Copyright © 2015 Elsevier Inc. All rights reserved.

Helper-dependent adenoviral vectors for liver-directed gene therapy

PubMed Central

Brunetti-Pierri, Nicola; Ng, Philip

2011-01-01

Helper-dependent adenoviral (HDAd) vectors devoid of all viral-coding sequences are promising non-integrating vectors for liver-directed gene therapy because they have a large cloning capacity, can efficiently transduce a wide variety of cell types from various species independent of the cell cycle and can result in long-term transgene expression without chronic toxicity. The main obstacle preventing clinical applications of HDAd for liver-directed gene therapy is the host innate inflammatory response against the vector capsid proteins that occurs shortly after intravascular vector administration resulting in acute toxicity, the severity of which is dependent on vector dose. Intense efforts have been focused on elucidating the factors involved in this acute response and various strategies have been investigated to improve the therapeutic index of HDAd vectors. These strategies have yielded encouraging results with the potential for clinical translation. PMID:21470977

Ion-conducting membranes

DOEpatents

Masel, Richard I.; Chen, Qingmei; Liu, Zengcai; Kutz, Robert

2017-02-28

An ion conducting polymeric composition mixture comprises a copolymer of styrene and vinylbenzyl-R.sub.s. R.sub.s is selected from the group consisting of imidazoliums, pyridiniums, pyrazoliums, pyrrolidiniums, pyrroliums, pyrimidiums, piperidiniums, indoliums, and triaziniums. The composition contains 10%-90% by weight of vinylbenzyl-R.sub.s. The composition can further comprise a polyolefin comprising substituted polyolefins, a polymer comprising cyclic amine groups, a polymer comprising at least one of a phenylene group and a phenyl group, a polyamide, and/or the reaction product of a constituent having two carbon-carbon double bonds. The composition can be in the form of a membrane. In a preferred embodiment, the membrane is a Helper Membrane that increases the faradaic efficiency of an electrochemical cell into which the membrane is incorporated, and also allows product formation at lower voltages than in cells without the Helper Membrane.

Non-tuberculous mycobacteria have diverse effects on BCG efficacy against Mycobacterium tuberculosis.

PubMed

Poyntz, Hazel C; Stylianou, Elena; Griffiths, Kristin L; Marsay, Leanne; Checkley, Anna M; McShane, Helen

2014-05-01

The efficacy of Bacillus Calmette-Guerin (BCG) vaccination in protection against pulmonary tuberculosis (TB) is highly variable between populations. One possible explanation for this variability is increased exposure of certain populations to non-tuberculous mycobacteria (NTM). This study used a murine model to determine the effect that exposure to NTM after BCG vaccination had on the efficacy of BCG against aerosol Mycobacterium tuberculosis challenge. The effects of administering live Mycobacterium avium (MA) by an oral route and killed MA by a systemic route on BCG-induced protection were evaluated. CD4+ and CD8+ T cell responses were profiled to define the immunological mechanisms underlying any effect on BCG efficacy. BCG efficacy was enhanced by exposure to killed MA administered by a systemic route; T helper 1 and T helper 17 responses were associated with increased protection. BCG efficacy was reduced by exposure to live MA administered by the oral route; T helper 2 cells were associated with reduced protection. These findings demonstrate that exposure to NTM can induce opposite effects on BCG efficacy depending on route of exposure and viability of NTM. A reproducible model of NTM exposure would be valuable in the evaluation of novel TB vaccine candidates. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Transducing Airway Basal Cells with a Helper-Dependent Adenoviral Vector for Lung Gene Therapy.

PubMed

Cao, Huibi; Ouyang, Hong; Grasemann, Hartmut; Bartlett, Claire; Du, Kai; Duan, Rongqi; Shi, Fushan; Estrada, Marvin; Seigel, Kyle E; Coates, Allan L; Yeger, Herman; Bear, Christine E; Gonska, Tanja; Moraes, Theo J; Hu, Jim

2018-06-01

A major challenge in developing gene-based therapies for airway diseases such as cystic fibrosis (CF) is sustaining therapeutic levels of transgene expression over time. This is largely due to airway epithelial cell turnover and the host immunogenicity to gene delivery vectors. Modern gene editing tools and delivery vehicles hold great potential for overcoming this challenge. There is currently not much known about how to deliver genes into airway stem cells, of which basal cells are the major type in human airways. In this study, helper-dependent adenoviral (HD-Ad) vectors were delivered to mouse and pig airways via intranasal delivery, and direct bronchoscopic instillation, respectively. Vector transduction was assessed by immunostaining of lung tissue sections, which revealed that airway basal cells of mice and pigs can be targeted in vivo. In addition, efficient transduction of primary human airway basal cells was verified with an HD-Ad vector expressing green fluorescent protein. Furthermore, we successfully delivered the human CFTR gene to airway basal cells from CF patients, and demonstrated restoration of CFTR channel activity following cell differentiation in air-liquid interface culture. Our results provide a strong rationale for utilizing HD-Ad vectors to target airway basal cells for permanent gene correction of genetic airway diseases.

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.

Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths.

PubMed

Pelly, Victoria S; Coomes, Stephanie M; Kannan, Yashaswini; Gialitakis, Manolis; Entwistle, Lewis J; Perez-Lloret, Jimena; Czieso, Stephanie; Okoye, Isobel S; Rückerl, Dominik; Allen, Judith E; Brombacher, Frank; Wilson, Mark S

2017-06-05

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4 + Foxp3 + regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex-T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3 + cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus Through selective deletion of Il4ra on Foxp3 + cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell-mediated suppression. © 2017 Pelly et al.

Angioimmunoblastic T-cell lymphoma: more than a disease of T follicular helper cells.

PubMed

Lemonnier, François; Mak, Tak W

2017-08-01

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most frequent entities of peripheral T-cell lymphoma. An AITL has two components: the AITL tumour cells, which have a T follicular helper (TFH) cell phenotype, and a surrounding and extensive tumour microenvironment that is populated with various reactive cell types, including B cells. Recurrent TET2 mutations have been described in 50-80% of AITLs, possibly occurring in a haematopoietic progenitor cell. An article published recently in the Journal of Pathology describes the use of microdissection to isolate PD1 + AITL tumour cells and CD20 + B cells from the AITL microenvironment, and to show that TET2 mutations are actually more frequent in these diseases than previously thought. Whereas TET2 mutations were detected in only six of 13 AITLs, 12 of 13 samples of microdissected PD1 + AITL tumour cells possessed this mutation. Moreover, TET2 mutations were detected in CD20 + B cells from the AITL microenvironment in six of nine informative cases. These results confirm that TET2 mutation is an early event in the majority of AITL cases, and that the driving molecular anomalies are not restricted to the T lineage tumour cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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.

Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion.

PubMed

Pilkinton, Mark A; Nicholas, Katherine J; Warren, Christian M; Smith, Rita M; Yoder, Sandra M; Talbot, H Keipp; Kalams, Spyros A

2017-01-05

Influenza related morbidity and mortality disproportionately impacts older adults. The serologic response to vaccine is diminished in older adults; however, high dose inactivated influenza vaccine (HD IIV) has shown improved rates of seroconversion compared to standard dose (SD IIV). We hypothesize this may be due to the superior ability of high dose vaccine to activate T follicular helper (Tfh) cells and provide B cell dependent T cell help. We measured peripheral Tfh (pTfh) activation in 50 community dwelling adults 65years or older who were randomly assigned to receive either the HD IIV or SD IIV. The HD vaccination elicited significantly higher levels of ICOS expression on pTfh cells, at day 7 compared to SD vaccination (p=0.02). The magnitude of the increase in ICOS+ pTfh cells from baseline to day 7 was predictive of seroconversion for both influenza A and B vaccination. Strong Tfh activation in response to influenza vaccination forecasts successful seroconversion in older adults, and HD IIV elicits greater Tfh activation than SD IIV. Future vaccine studies should focus on ways to further optimize the Tfh response. Copyright © 2016 Elsevier Ltd. All rights reserved.

Virus Satellites Drive Viral Evolution and Ecology

PubMed Central

Frígols, Belén; Quiles-Puchalt, Nuria; Mir-Sanchis, Ignacio; Donderis, Jorge; Elena, Santiago F.; Buckling, Angus; Novick, Richard P.; Marina, Alberto; Penadés, José R.

2015-01-01

Virus satellites are widespread subcellular entities, present both in eukaryotic and in prokaryotic cells. Their modus vivendi involves parasitism of the life cycle of their inducing helper viruses, which assures their transmission to a new host. However, the evolutionary and ecological implications of satellites on helper viruses remain unclear. Here, using staphylococcal pathogenicity islands (SaPIs) as a model of virus satellites, we experimentally show that helper viruses rapidly evolve resistance to their virus satellites, preventing SaPI proliferation, and SaPIs in turn can readily evolve to overcome phage resistance. Genomic analyses of both these experimentally evolved strains as well as naturally occurring bacteriophages suggest that the SaPIs drive the coexistence of multiple alleles of the phage-coded SaPI inducing genes, as well as sometimes selecting for the absence of the SaPI depressing genes. We report similar (accidental) evolution of resistance to SaPIs in laboratory phages used for Staphylococcus aureus typing and also obtain the same qualitative results in both experimental evolution and phylogenetic studies of Enterococcus faecalis phages and their satellites viruses. In summary, our results suggest that helper and satellite viruses undergo rapid coevolution, which is likely to play a key role in the evolution and ecology of the viruses as well as their prokaryotic hosts. PMID:26495848

Differential requirements of CD4(+) T-cell signals for effector cytotoxic T-lymphocyte (CTL) priming and functional memory CTL development at higher CD8(+) T-cell precursor frequency.

PubMed

Umeshappa, Channakeshava S; Nanjundappa, Roopa H; Xie, Yufeng; Freywald, Andrew; Xu, Qingyong; Xiang, Jim

2013-04-01

Increased CD8(+) T-cell precursor frequency (PF) precludes the requirement of CD4(+) helper T (Th) cells for primary CD8(+) cytotoxic T-lymphocyte (CTL) responses. However, the key questions of whether unhelped CTLs generated at higher PF are functional effectors, and whether unhelped CTLs can differentiate into functional memory cells at higher PF are unclear. In this study, ovalbumin (OVA) -pulsed dendritic cells (DC(OVA)) derived from C57BL/6, CD40 knockout (CD40(-/-)) or CD40 ligand knockout (CD40L(-/-)) mice were used to immunize C57BL/6, Ia(b-/-), CD40(-/-) or CD40L(-/-) mice, whose PF was previously increased with transfer of 1 × 10(6) CD8(+) T cells derived from OVA-specific T-cell receptor (TCR) transgenic OTI, OTI(CD40(-/-)) or OTI(CD40L(-/-)) mice. All the immunized mice were then assessed for effector and memory CTL responses. Following DC immunization, relatively comparable CTL priming occurred without CD4(+) T-cell help and Th-provided CD40/CD40L signalling. In addition, the unhelped CTLs were functional effectors capable of inducing therapeutic immunity against established OVA-expressing tumours. In contrast, the functional memory development of CTLs was severely impaired in the absence of CD4(+) T-cell help and CD40/CD40L signalling. Finally, unhelped memory CTLs failed to protect mice against lethal tumour challenge. Taken together, these results demonstrate that CD4(+) T-cell help at higher PF, is not required for effector CTL priming, but is required for functional memory CTL development against cancer. Our data may impact the development of novel preventive and therapeutic approaches in cancer patients with compromised CD4(+) T-cell functions. © 2012 Blackwell Publishing Ltd.

Prevention of recrudescent malaria in nude mice by thymic grafting or by treatment with hyperimmune serum.

PubMed Central

Roberts, D W; Rank, R G; Weidanz, W P; Finerty, J F

1977-01-01

Nude mice died when infected with the normally avirulent malarial parasite Plasmodium berghei yoelii. Furthermore, malaria recrudesced in Nu/Nu mice after the termination of acute disease by treatment with clindamycin. Recrudescence was not observed in Nu/Nu mice that had been grafted with thymic tissue or treated with hyperimmune serum. Mice mad B cell deficient by treatment with anti-mu-chain serum also died when infected with P. berghei yoelii. The data suggest that a crucial role of the thymus in preventing recrudescent malaria in this model system is to provide a helper function in the production of protective antibody. PMID:330396

Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths

PubMed Central

Coomes, Stephanie M.; Kannan, Yashaswini; Entwistle, Lewis J.; Perez-Lloret, Jimena; Czieso, Stephanie

2017-01-01

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex–T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus. Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell–mediated suppression. PMID:28507062

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

CD28 T-cell costimulatory molecule expression in pemphigus vulgaris.

PubMed

Alecu, M; Ursaciuc, C; Surcel, M; Coman, G; Ciotaru, D; Dobre, M

2009-03-01

CD28 superfamily of immune costimulatory molecules could play an important role in autotolerance control. CD28 costimulation seems to be necessary for regulatory T cell (Treg) activation and successive suppressive activities involved in autoimmunity protection. This study investigates CD28 expression, especially inducible costimulator fraction, on T lymphocytes in pemphigus vulgaris (PV) patients. CD28 expression on T lymphocytes was assessed in 16 PV patients during acute attack. All patients and 10 healthy control subjects were tested for lymphocyte populations, T-cell subpopulations (T-CD4+, T-CD8+), Treg and CD28 expression on T-cell subpopulations. T, B and natural killer cells average values in PV patients were close to the control group values. Compared with control group, PV values showed lower Treg (2.2% compared with 4.7%), slightly decreased CD4+ CD28+ T cells (91% compared with 95%), higher CD4+ CD28- T cells (9% compared with 5%), decreased CD8+ CD28+ T cells (57% and 73%, respectively) and significantly enhanced CD8+ CD28- T cells (43% compared with 27%). These data suggest that Treg-mediated suppressor T-cell effects could be diminished in PV, together with an abnormal or ineffective subsequent helper T-cell suppression. CD28 high expression on helper T cells and low expression on suppressor T cells are arguments for a potential CD28 role in PV autoimmune response mechanism.

The transcription factor Th-POK negatively regulates Th17 differentiation in Vα14i NKT cells

PubMed Central

Engel, Isaac; Zhao, Meng; Kappes, Dietmar; Taniuchi, Ichiro

2012-01-01

The majority of mouse Vα14 invariant natural killer T (Vα14i NKT) cells produce several cytokines, including IFNγ and IL-4, very rapidly after activation. A subset of these cells, known as NKT17 cells, however, differentiates in the thymus to preferentially produce IL-17. Here, we show that the transcription factor—known as T helper, Poxviruses, and Zinc-finger and Krüppel family, (Th-POK)—represses the formation of NKT17 cells. Vα14i NKT cells from Th-POK–mutant helper deficient (hd/hd) mice have increased transcripts of genes normally expressed by Th17 and NKT17 cells, and even heterozygosity for this mutation leads to dramatically increased numbers of Vα14i NKT cells that are poised to express IL-17, especially in the thymus and lymph nodes. In addition, using gene reporter mice, we demonstrate that NKT17 cells from wild-type mice express lower amounts of Th-POK than the majority population of Vα14i NKT cells. We also show that retroviral transduction of Th-POK represses the expression of the Th17 master regulator RORγT in Vα14i NKT-cell lines. Our data suggest that NKT17-cell differentiation is intrinsically regulated by Th-POK activity, with only low levels of Th-POK permissive for the differentiation of NKT17 cells. PMID:23034280

Cell viability of mycorrhiza helper bacteria solid inoculant in different carrier material

NASA Astrophysics Data System (ADS)

Asyiah, Iis Nur; Hindersah, Reginawanti; Harni, Rita

2018-02-01

Roots of food crops are colonized by nonpathogenic mycorrhizal fungi which show natural ability to control plant pathogen. Mycorrhizal establishment in plant roots is affected by rhizobacteria, known as mycorrhiza helper bacteria (MHB), which has synergetic effects on mycorrhizal associations. Laboratory experiment has been conducted to assess the best carrier material to develop well-qualified MHB of Pseudomonas diminuta and Bacillus subtilis solid inoculant. Carrier materials were 100 mesh organic matter of agricultural waste. Different spore concentration of both bacterial liquid inoculants were grown on three kinds of 100-mesh organic matter and stored at room temperature up to 90 days. Cell viability of both MHB were counted by serial dilution plate method by using specific medium. The results showed that sugar cane baggase ash was the best carrier material to maintain cell viability for both MHB. However, the population of Pseudomonas diminuta and Bacillus subtilis in sugar cane baggase ash were slightly decreased after 90 days. The use of sugarcane baggase ash for solid MHB inoculant development could be suggested.

Peripheral helper lymphocytes produce interleukin 12 in cancer patients.

PubMed

Michelin, Márcia A; Abdalla, Douglas R; Aleixo, André A R; Murta, Eddie F C

2013-01-01

The aim of the study was to seek evidence for the production of IL-12 by CD4(+) T lymphocytes in in vitro and ex vivo trials. We performed in vitro trials with spleen cells from mice subjected to carcinogenesis, as well as ex vivo trials with cells obtained from the peripheral blood of healthy individuals and cancer patients. We were able to verify a significantly increased expression of IL-12 in CD4(+) T lymphocytes from mice and patients with tumors, compared to controls. Follow-up studies are needed to clarify whether this difference is related to being in a chronic disease state or whether it is an attempt by the immune system to produce an anti-tumor response, since T lymphocytes from healthy donors were not able to produce IL-12 when in contact with polyclonal stimuli. We concluded that, in cancer, T helper cells are capable of synthesizing IL-12, raising the question of whether we are faced with another profile, Th12.

Peripheral Helper Lymphocytes Produce Interleukin 12 in Cancer Patients

PubMed Central

Michelin, Márcia A.; Abdalla, Douglas R.; Aleixo, André A.R.; Murta, Eddie F.C.

2013-01-01

The aim of the study was to seek evidence for the production of IL-12 by CD4+ T lymphocytes in in vitro and ex vivo trials. We performed in vitro trials with spleen cells from mice subjected to carcinogenesis, as well as ex vivo trials with cells obtained from the peripheral blood of healthy individuals and cancer patients. We were able to verify a significantly increased expression of IL-12 in CD4+ T lymphocytes from mice and patients with tumors, compared to controls. Follow-up studies are needed to clarify whether this difference is related to being in a chronic disease state or whether it is an attempt by the immune system to produce an anti-tumor response, since T lymphocytes from healthy donors were not able to produce IL-12 when in contact with polyclonal stimuli. We concluded that, in cancer, T helper cells are capable of synthesizing IL-12, raising the question of whether we are faced with another profile, Th12. PMID:23515751

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. | Center for Cancer Research

Cancer.gov

The process by which self-reactive CD4+ T cells infiltrate the central nervous system (CNS) and trigger neuroinflammation is not fully understood. Lazarevic and colleagues show that NKp46+innate lymphoid cells dependent on the transcription factor T-bet are critical mediators in facilitating the entry of autoreactive CD4+ cells of the TH17 subset of helper T cells into the

The Initiative in the Human Microbiome and Infectious Diseases

DTIC Science & Technology

2015-12-01

DL. 2014. Interactions between the intestinal microbiota and innate lymphoid cells . Gut Microbes 5:129-140. 14. Erturk-Hasdemir D, Kasper DL. 2013...of intestinal T- cells , and in particular up-regulate Th17 cells in the gastrointestinal tract. In year 3 of the project, we have finished our...affecting the balance of IL-17-producing T helper (Th17) cells (15). Commensal bacteria are required for induction of Th17 cells ; acquisition of