Sample records for normal t-cell development

  1. Intrathymic T Cell Development and Selection Proceeds Normally in the Absence of Glucocorticoid Receptor Signaling

    Microsoft Academic Search

    Jared F Purton; Richard L Boyd; Timothy J Cole; Dale I Godfrey

    2000-01-01

    Glucocorticoids are believed to play a role in T cell development and selection, although their precise function is controversial. Glucocorticoid receptor (GR)-deficient mice were used to directly investigate this problem. GR-deficient thymocytes were resistant to dexamethasone-mediated apoptosis, confirming the absence of glucocorticoid responsiveness. An absence of GR signaling had no impact on thymocyte development either in vivo or in vitro.

  2. Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration

    PubMed Central

    Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M.; Ricciardo, Belinda; Nelson, Delia J.

    2013-01-01

    Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. PMID:24013775

  3. Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration.

    PubMed

    Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M; Ricciardo, Belinda; Nelson, Delia J

    2013-01-01

    Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4(+) T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. PMID:24013775

  4. Human CD4 restores normal T cell development and function in mice deficient in murine CD4

    PubMed Central

    1994-01-01

    The ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4-/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V beta T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positive cells also were found in the periphery and they were shown to restore MHC class II-restricted alloreactive and antigen- specific T cell responses that were deficient in the mCD4 (-/-) mice. In addition, these hCD4 reconstituted mice can generate a secondary immunoglobulin G humoral response matching that of mCD4 wild-type mice. The fact that human CD4 is functional in mice and can be studied in the absence of murine CD4 should facilitate studies of human CD4 activity in general and human immunodeficiency virus 1 gp120-mediated pathogenesis in acquired immune deficiency syndrome specifically. PMID:8145040

  5. T-cell-mediated immune response in murine malaria: differential effects of antigen-specific Lyt T-cell subsets in recovery from Plasmodium yoelii infection in normal and T-cell-deficient mice.

    PubMed Central

    Brinkmann, V; Kaufmann, S H; Simon, M M

    1985-01-01

    For analysis of the role of immune T cells in protective immunity against murine malaria, Plasmodium yoelii-immune Lyt T-cell subsets were functionally characterized in vitro and in vivo. Selected Lyt2- and Lyt2+ T cells from P. yoelii-immune C57BL/10 mice differed in their capability to proliferate in response to P. yoelii antigen in vitro. Only the Lyt2- T-cell population produced T-cell growth factor upon restimulation, and none of the selected T-cell subsets produced detectable amounts of macrophage activating factor. Lyt2- but not Lyt2+ lymphocytes were capable of transferring protection to normal C57BL/10 mice. When transferred into T-cell-deficient C57BL/6-nu/nu mice, adoptive resistance to P. yoelii by Lyt2- lymphocytes was only demonstrable after prior reconstitution of recipients with normal T cells. These results suggest an interaction between P. yoelii-immune Lyt2- T cells and normal T lymphocytes via T-cell growth factor in the development of protective immunity to malaria. PMID:2857683

  6. T Cell Recruitment in the Brain during Normal Aging

    PubMed Central

    Gemechu, Jickssa M.; Bentivoglio, Marina

    2012-01-01

    Aging-related changes in the peripheral immune response are well documented, but less is known about changes of the immune response in the central nervous system. Reactivity of microglia, effectors of the brain innate immunity, is known to increase in the aged brain, but little attention has been hitherto devoted to T cell recruitment. Data in rodents point to a gradual enhancement of T cell homing to the brain in the steady state since the middle age. Experimental findings also point to enhanced transmigration of lymphocytes as part of an amplified response of the aging brain to acute exogenous inflammatory insults. Thus, available data support the capacity of the aged brain to mount a robust immune response, in contrast with peripheral immunity decline, and indicate that such central response involves recruitment of lymphocytes. These findings open many questions, including blood-brain barrier molecular regulation and infiltrated T cell subtypes during normal aging. The crosstalk between T cells, glia, and neurons also remains to be clarified in the aged brain parenchyma. This intercellular dialogue and related signaling could be relevant for both protection of the aged brain and its vulnerability to neurological disease. PMID:23049498

  7. Cbl-b: Roles in T Cell Tolerance, Proallergic T Cell Development, and Cancer Immunity

    PubMed Central

    Zhang, Jian; Liu, Qingjun; Langdon, Wallace Y.

    2015-01-01

    Cbl-b is a member of the Cbl family of RING finger E3 ubiquitin ligases and polymorphisms and mutations in Cbl-b are associated with several autoimmune/inflammatory diseases in humans. Furthermore, gene targeting experiments in mice have provided proof of the in vivo effects of Cbl-b on T cell function and its involvement with these diseases. This brief review updates our understanding of Cbl-b in T cell tolerance, proallergic T cell development, and cancer immunity in light of the most recent advances, and their impact on autoimmune-/inflammatory diseases and cancer immunotherapy. PMID:26082933

  8. Role of diacylglycerol kinases in T cell development and function

    PubMed Central

    Krishna, Sruti

    2013-01-01

    Diacylglycerol (DAG), a second messenger generated by phospholipase C?1 activity upon T cell receptor (TCR) engagement, triggers several signaling cascades that play important roles in T cell development and function. A family of enzymes called diacylglycerol kinases (DGKs) catalyzes the phosphorylation of DAG to phosphatidic acid, acting as a braking mechanism that terminates DAG-mediated signals. Two DGK isoforms, ? and ?, are predominantly expressed in T cells and synergistically regulate the development of both conventional ?? T cells and invariant NKT cells in the thymus. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T cell hyper-activation upon TCR stimulation and by promoting T cell anergy. In CD8 cells, reduced DGK activity is associated with enhanced primary responses against viruses and tumors. Recent work has also established an important role for DGK activity at the immune synapse and identified partners that modulate DGK function. In addition, emerging evidence points to previously unappreciated roles for DGK function in directional secretion and T cell adhesion. In this review, we discuss the multitude of roles played by DGKs in T cell development and function, while emphasizing recent advances in the field. PMID:23582058

  9. Studies on the syngeneic mixed lymphocyte reaction. III. Development of a monoclonal antibody with specificity for autoreactive T cells

    PubMed Central

    1983-01-01

    Monoclonal antibodies with specificity for autoreactive murine T cells have been developed. These antibodies inhibit proliferative response of splenic T cells activated by syngeneic spleen cells. These antibodies have no effect on the proliferative response of T cells activated by allogeneic spleen cells or PHA. The number of splenic T cells that react with these monoclonal antibodies is comparable in several normal mouse strains. PMID:6225824

  10. Novel insights into the development of T-cell acute lymphoblastic leukemia

    Microsoft Academic Search

    Frank J. T. Staal; Jacques J. M. van Dongen; Anton W. Langerak

    2007-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) results from malignant transformation of immature cells of the T-cell lineage.\\u000a T-ALL is a heterogeneous disease both clinically and genetically. It is generally accepted that T-ALL cells are the malignant\\u000a counterpart of normally developing T cells in the thymus (thymocytes). Recent data using genome-wide gene expression profiling\\u000a and assessment of the rearrangement status of the

  11. Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T-cell development and function.

    PubMed

    Ellis, Gavin I; Zhi, Lianteng; Akundi, Ravi; Büeler, Hansruedi; Marti, Francesc

    2013-12-01

    Mutations in PTEN-induced kinase 1 (PINK1), a serine/threonine kinase linked to familial early-onset Parkinsonism, compromise mitochondrial integrity and metabolism and impair AKT signaling. As the activation of a naïve T cell requires an AKT-dependent reorganization of a cell's metabolic machinery, we sought to determine if PINK1-deficient T cells lack the ability to undergo activation and differentiation. We show that CD4(+) T cells from PINK1 knockout mice fail to properly phosphorylate AKT upon activation, resulting in reduced expression of the IL-2 receptor subunit CD25. Following, deficient IL-2 signaling mutes the activation-induced increase in respiratory capacity and mitochondrial membrane potential. Under polarization conditions favoring the development of induced regulatory T cells, PINK1(-/-) T cells exhibit a reduced ability to suppress bystander T-cell proliferation despite normal FoxP3 expression kinetics. Our results describe a critical role for PINK1 in integrating extracellular signals with metabolic state during T-cell fate determination, and may have implications for the understanding of altered T-cell populations and immunity during the progression of active Parkinson's disease or other immunopathologies. PMID:24037540

  12. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential

    PubMed Central

    1993-01-01

    Diabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal gamma irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4+ and CD8+ T cells and macrophages. The CD8+ T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4+ T cell subset, isolated from healthy syngeneic donors, of the phenotype CD45RClow T cell receptor alpha/beta+ RT6+ Thy-1- OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (IL-2) and IL-4, but no interferon gamma, on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells. PMID:8094734

  13. Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection

    PubMed Central

    Chakrabarti, Lisa A.; Lewin, Sharon R.; Zhang, Linqi; Gettie, Agegnehu; Luckay, Amara; Martin, Louis N.; Skulsky, Eva; Ho, David D.; Cheng-Mayer, Cecilia; Marx, Preston A.

    2000-01-01

    Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) remain healthy though they harbor viral loads comparable to those in rhesus macaques that progress to AIDS. To assess the immunologic basis of disease resistance in mangabeys, we compared the effect of SIV infection on T-cell regeneration in both monkey species. Measurement of the proliferation marker Ki-67 by flow cytometry showed that mangabeys harbored proliferating T cells at a level of 3 to 4% in peripheral blood irrespective of their infection status. In contrast, rhesus macaques demonstrated a naturally high fraction of proliferating T cells (7%) that increased two- to threefold following SIV infection. Ki-67+ T cells were predominantly CD45RA?, indicating increased proliferation of memory cells in macaques. Quantitation of an episomal DNA product of T-cell receptor ? rearrangement (termed ?1 circle) showed that the concentration of recent thymic emigrants in blood decreased with age over a 2-log unit range in both monkey species, consistent with age-related thymic involution. SIV infection caused a limited decrease of ?1 circle numbers in mangabeys as well as in macaques. Dilution of ?1 circles by T-cell proliferation likely contributed to this decrease, since ?1 circle numbers and Ki-67+ fractions correlated negatively. These findings are compatible with immune exhaustion mediated by abnormal T-cell proliferation, rather than with early thymic failure, in SIV-infected macaques. Normal T-cell turnover in SIV-infected mangabeys provides an explanation for the long-term maintenance of a functional immune system in these hosts. PMID:10627531

  14. ??T cells regulate chronic airway inflammation and development of airway remodelling

    PubMed Central

    Murdoch, J R; Gregory, L G; Lloyd, C M

    2014-01-01

    Background ??T cells play a crucial immunoregulatory role in the lung, maintaining normal airway tone and preventing hyperresponsiveness to innocuous allergen. During acute inflammatory episodes, ??T cells promote resolution of acute inflammation. However, their contribution to inflammation-associated airway remodelling remains unexplored. Here we investigate the effects of ??T cell blockade on established allergic airway inflammation and development of remodelling. Methods Sensitised mice were exposed to prolonged ovalbumin challenge or continuous house-dust mite exposure to induce chronic inflammation and remodelling. Functional blocking anti-TCR? antibody was administered therapeutically, and parameters of airway inflammation and remodelling were examined. Results Therapeutic blockade of ??T cells prevented the typical resolution of acute airway inflammation characterised by elevated eosinophil and Th2 cell numbers. Moreover, the lung displayed exacerbated airway remodelling, typified by excess peribronchiolar collagen deposition. Conclusions These results demonstrate a unique role for ??T cells in constraining allergen-induced airway remodelling. Manipulating the ??T cell compartment may therefore contribute to strategies to prevent and treat remodelling. PMID:25146585

  15. Immunohistochemical Analysis of Regulatory T Cell Markers FOXP3 and GITR on CD4+CD25+ T Cells in Normal Skin and Inflammatory Dermatoses

    Microsoft Academic Search

    Onno J. de Boer; Chris M. van der Loos; Peter Teeling; Allard C. van der Wal; Marcel B. M. Teunissen

    2007-01-01

    Regulatory T cells (Treg) are a subset of T lymphocytes that play a central role in immunologic tolerance and in the termination of immune responses. The identification of these cells in normal and inflammatory conditions may contribute to a better understanding of underlying pathology. We investigated the expression of FOXP3 and GITR in normal skin and in a panel of

  16. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

    PubMed Central

    McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

    2014-01-01

    Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

  17. A novel addition to the T cell repertory. Cell surface expression of tumor necrosis factor/cachectin by activated normal human T cells.

    PubMed

    Kinkhabwala, M; Sehajpal, P; Skolnik, E; Smith, D; Sharma, V K; Vlassara, H; Cerami, A; Suthanthiran, M

    1990-03-01

    Expression of the pluripotent molecule TNF in a focused and antigen-restricted fashion might provide an advantage to the host organism. Given the central role of T cells in antigen-specific immunity, we examined whether activated T cells express TNF on their cell surface. FACS analysis of highly purified normal human T cells labeled with an anti-TNF mAb revealed that T cells express cell surface TNF when signaled with the synergistic combination of a calcium ionophore, ionomycin, and a protein kinase C activator, 12-o-tetradecanoyl phorbol acetate. Cell surface radioiodination studies of stimulated T cells demonstrated the presence of 26-kD transmembrane protein, a size predicted by TNF cDNA and different from that of the 17-kD secreted TNF molecule. The induced cell surface expression of TNF could be blocked with cyclosporine and/or methylprednisolone, and Northern analysis for TNF-specific transcripts revealed that this inhibitory effect occurs pretranslationally. Our demonstration for the first time that stimulated normal human T cells display cell surface TNF provides a mechanistic basis for the realization of effects of TNF in an antigen-specific fashion. PMID:2307938

  18. A novel addition to the T cell repertory. Cell surface expression of tumor necrosis factor/cachectin by activated normal human T cells

    PubMed Central

    1990-01-01

    Expression of the pluripotent molecule TNF in a focused and antigen- restricted fashion might provide an advantage to the host organism. Given the central role of T cells in antigen-specific immunity, we examined whether activated T cells express TNF on their cell surface. FACS analysis of highly purified normal human T cells labeled with an anti-TNF mAb revealed that T cells express cell surface TNF when signaled with the synergistic combination of a calcium ionophore, ionomycin, and a protein kinase C activator, 12-o-tetradecanoyl phorbol acetate. Cell surface radioiodination studies of stimulated T cells demonstrated the presence of 26-kD transmembrane protein, a size predicted by TNF cDNA and different from that of the 17-kD secreted TNF molecule. The induced cell surface expression of TNF could be blocked with cyclosporine and/or methylprednisolone, and Northern analysis for TNF-specific transcripts revealed that this inhibitory effect occurs pretranslationally. Our demonstration for the first time that stimulated normal human T cells display cell surface TNF provides a mechanistic basis for the realization of effects of TNF in an antigen- specific fashion. PMID:2307938

  19. Essential Role of LAT in T Cell Development

    Microsoft Academic Search

    Weiguo Zhang; Connie L Sommers; Deborah N Burshtyn; Christopher C Stebbins; Jan B DeJarnette; Ronald P Trible; Alexander Grinberg; Henry C Tsay; Helena M Jacobs; Craig M Kessler; Eric O Long; Paul E Love; Lawrence E Samelson

    1999-01-01

    The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement. Phosphorylated LAT binds many critical signaling molecules. The central role of this molecule in TCR-mediated signaling has been demonstrated by experiments in a LAT-deficient cell line. To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting. LAT-deficient mice

  20. 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

  1. The microRNA biogenesis machinery modulates lineage commitment during ?? T cell development.

    PubMed

    Rupp, Levi J; Brady, Brenna L; Carpenter, Andrea C; De Obaldia, Maria Elena; Bhandoola, Avinash; Bosselut, Remy; Muljo, Stefan A; Bassing, Craig H

    2014-10-15

    Differentiation of CD4(+) helper and CD8(+) cytotoxic ?? T cells from CD4(+)CD8(+) thymocytes involves upregulation of lineage-specifying transcription factors and transcriptional silencing of CD8 or CD4 coreceptors, respectively, in MHC class II or I (MHCII or I)-restricted thymocytes. In this study, we demonstrate that inactivation of the Dicer RNA endonuclease in murine thymocytes impairs initiation of Cd4 and Cd8 silencing, leading to development of positively selected MHCI- and MHCII-restricted mature CD4(+)CD8(+) thymocytes. Expression of the antiapoptotic BCL2 protein or inactivation of the p53 proapoptotic protein rescues these thymocytes from apoptosis, increasing their frequency and permitting accumulation of CD4(+)CD8(+) ?? T cells in the periphery. Dicer-deficient MHCI-restricted ?? T cells fail to normally silence Cd4 and display impaired induction of the CD8 lineage-specifying transcription factor Runx3, whereas Dicer-deficient MHCII-restricted ?? T cells show impaired Cd8 silencing and impaired induction of the CD4 lineage-specifying transcription factor Thpok. Finally, we show that the Drosha RNA endonuclease, which functions upstream of Dicer in microRNA biogenesis, also regulates Cd4 and Cd8 silencing. Our data demonstrate a previously dismissed function for the microRNA biogenesis machinery in regulating expression of lineage-specifying transcription factors and silencing of Cd4 and Cd8 during ?? T cell differentiation. PMID:25217159

  2. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells.

    PubMed

    Carretero, Rafael; Sektioglu, Ibrahim M; Garbi, Natalio; Salgado, Oscar C; Beckhove, Philipp; Hämmerling, Günter J

    2015-06-01

    Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies. PMID:25915731

  3. Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy

    PubMed Central

    Haery, Leila; Thompson, Ryan C.; Gilmore, Thomas D.

    2015-01-01

    The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas.

  4. Statistical Physics of T-Cell Development and Pathogen Specificity

    NASA Astrophysics Data System (ADS)

    Košmrlj, Andrej; Kardar, Mehran; Chakraborty, Arup K.

    2013-04-01

    In addition to an innate immune system that battles pathogens in a nonspecific fashion, higher organisms, such as humans, possess an adaptive immune system to combat diverse (and evolving) microbial pathogens. Remarkably, the adaptive immune system mounts pathogen-specific responses, which can be recalled upon reinfection with the same pathogen. It is difficult to see how the adaptive immune system can be preprogrammed to respond specifically to a vast and unknown set of pathogens. Although major advances have been made in understanding pertinent molecular and cellular phenomena, the precise principles that govern many aspects of an immune response are largely unknown. We discuss complementary approaches from statistical mechanics and cell biology that can shed light on how key components of the adaptive immune system, T cells, develop to enable pathogen-specific responses against many diverse pathogens. The mechanistic understanding that emerges has implications for how host genetics may influence the development of T cells with differing responses to the human immunodeficiency virus (HIV) infection.

  5. Sonic hedgehog signalling in T-cell development and activation

    Microsoft Academic Search

    Susan V. Outram; Ariadne L. Hager-Theodorides; Tessa Crompton

    2007-01-01

    The production of mature functional T cells in the thymus requires signals from the thymic epithelium. Here, we review recent experiments showing that one way in which the epithelium controls the production of mature T cells is by the secretion of sonic hedgehog (SHH). We consider the increasing evidence that SHH-induced signalling is not only important for the differentiation and

  6. Metabolic Regulation of Regulatory T Cell Development and Function

    PubMed Central

    Coe, David John; Kishore, Madhav; Marelli-Berg, Federica

    2014-01-01

    It is now well established that the effector T cell (Teff) response is regulated by a series of metabolic switches. Quiescent T cells predominantly require adenosine triphosphate-generating processes, whereas proliferating Teff require high metabolic flux through growth-promoting pathways, such as glycolysis. Pathways that control metabolism and immune cell function are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell effector functions. Furthermore, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. In particular, naturally occurring regulatory T cells (Treg) are characterized by a unique metabolic signature distinct to that of conventional Teff cells. We here briefly review the signaling pathways that control Treg metabolism and how this metabolic phenotype integrates their differentiation and function. Ultimately, these metabolic features may provide new opportunities for the therapeutic modulation of unwanted immune responses. PMID:25477880

  7. FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

    PubMed Central

    Wang, Liqing; Liu, Yujie; Han, Rongxiang; Beier, Ulf H.; Bhatti, Tricia R.; Akimova, Tatiana; Greene, Mark I.; Hiebert, Scott W.; Hancock, Wayne W.

    2015-01-01

    Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4–6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs. PMID:25642770

  8. Regulation of early T cell development by the PHD finger of histone lysine methyltransferase ASH1

    SciTech Connect

    Tanaka, Yujiro [Genome Structure and Expression, School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8610 (Japan)], E-mail: ytanaka.bgen@mri.tmd.ac.jp; Nakayama, Yasuhiro [Department of Genetics, Yale University School of Medicine, 300 Cedar St., New Haven, CT 06510 (United States); Taniguchi, Masaru [Department of Developmental Immunology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Kioussis, Dimitris [Department of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA (United Kingdom)

    2008-01-18

    We have previously isolated a mammalian homologue of Drosophila discsabsent, small, orhomeotic-1 (ash1) from the murine thymus, and recently shown that its SET domain methylates histone H3 lysine 36 (K36). Expression of ASH1 has been reported to be increased in NOD thymocytes in a BDC2.5 clonotype background, but its function in T cell development has remained elusive. Here we report that the ash1 gene is expressed at high levels in thymocytes of mice deficient for rag1 or tcra genes. ASH1 proteins are present at peri-nuclei and as nuclear speckles in thymocytes. Some of the nuclear ASH1 co-localize with RAG2. Expression of the evolutionarily conserved PHD finger of ASH1 impairs T cell development at the DP stage, and causes increased transcription from the HoxA9 promoter in vitro. Moreover, the C-terminal part of ASH1 interacts with HDAC1 repression complexes, suggesting that the PHD finger of ASH1 may be involved in down-regulation of genes for normal development of {alpha}{beta} T cells.

  9. Canine CD4(+)CD8(+) double-positive T cells can develop from CD4(+) and CD8(+) T cells.

    PubMed

    Bismarck, Doris; Moore, Peter F; Alber, Gottfried; von Buttlar, Heiner

    2014-12-15

    For a long time the expression of the CD4 and CD8 receptor on peripheral blood T cells was thought to be mutually exclusive. However, in canine peripheral blood, similar to other species as swine or human for example, mature CD4(+)CD8(+) double-positive (dp) T cells exist which simultaneously express both surface receptors and have features of activated T cells. Canine CD4(+)CD8(+)dp T cells are heterogeneous and can be divided into three subpopulations by their intensity of CD4 and CD8? expression: CD4(bright)CD8?(bright), CD4(dim)CD8?(bright) and CD4(dim)CD8?(dim). The number of CD4(+)CD8?(+)dp T cells increases after in vitro stimulation of canine peripheral blood mononuclear cells (PBMC) raising the question of their progenitor(s). Thus, the aim of our study was to characterize the progenitor(s) of canine CD4(+)CD8?(+)dp T cells. By cell tracing experiments we identified both CD4(+) single-positive (sp) and also CD8?(+)sp T cells as progenitors of canine CD4(+)CD8?(+)dp T cells after in vitro stimulation. CD4(+)sp T cells almost exclusively upregulate a CD8?? homodimer, whereas CD8?(+)sp T cells can become CD4(+)CD8??(+) or CD4(+)CD8??(+). Even in the absence of other cells, highly purified CD4(+)sp T cells can become double-positive upon in vitro stimulation, whereas highly purified CD8?(+)sp T cells fail to do so. However, CD8?(+)sp T cells can additionally express CD4 when stimulated in the presence of CD4(-)CD8?(-) double-negative (dn) cells or more efficiently when stimulated in the presence of CD4(+)sp T cells. Soluble factors secreted by CD4(+)sp T cells are sufficient for the upregulation of CD4 on CD8?(+)sp T cells, but direct cell-cell contact between CD4(+)sp and CD8?(+)sp T cells is more efficient. mRNA analysis shows that additional CD4 expression on CD8?(+)sp T cells results from de novo synthesis. Thus, uptake of soluble CD4 or trogocytosis is less likely as mechanism for generation of canine double-positive T cells. CD4(+)CD8?(+)dp T cells are highly activated independent of their origin except when generated in coculture of CD8?(+)sp T cells with CD4(-)CD8?(-)dn cells. Overall, in dog, CD4(+)sp T cells are the more potent progenitors of CD4(+)CD8?(+)dp T cells compared to CD8?(+)sp T cells. PMID:25454082

  10. Differential Requirement for CCR4 and CCR7 during the Development of Innate and Adaptive ??T Cells in the Adult Thymus

    PubMed Central

    Cowan, Jennifer E.; McCarthy, Nicholas I.; Parnell, Sonia M.; White, Andrea J.; Bacon, Andrea; Serge, Arnauld; Irla, Magali; Lane, Peter J. L.; Jenkinson, Eric J.; Jenkinson, William E.

    2014-01-01

    ??T cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional ??T cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters ??T cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple ??T cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional ??T cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple ??T cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire?/? mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple ??T cell lineages to access the thymic medulla. PMID:24990081

  11. Differential requirement for CCR4 and CCR7 during the development of innate and adaptive ??T cells in the adult thymus.

    PubMed

    Cowan, Jennifer E; McCarthy, Nicholas I; Parnell, Sonia M; White, Andrea J; Bacon, Andrea; Serge, Arnauld; Irla, Magali; Lane, Peter J L; Jenkinson, Eric J; Jenkinson, William E; Anderson, Graham

    2014-08-01

    ??T cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional ??T cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters ??T cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple ??T cell lineages, notably the induction of Foxp3(+) regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional ??T cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple ??T cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire(-/-) mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3(+) regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple ??T cell lineages to access the thymic medulla. PMID:24990081

  12. Role of tumor suppressor genes in the development of adult T cell leukemia\\/lymphoma (ATLL)

    Microsoft Academic Search

    Y Hatta; HP Koeffler

    2002-01-01

    Adult T cell leukemia\\/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL.

  13. Pontin is required for pre-TCR signaling at the ?-selection checkpoint in T cell development.

    PubMed

    Boo, Kyungjin; Baek, Sung Hee; Lee, Ho

    2014-04-25

    Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Based on high expression in lymphoid tissues, we examined whether Pontin has a T cell-specific function. We generated Pontin(f/f);Lck-Cre mice, in which Pontin can be conditionally deleted in T cells and then explored T cell-specific function of Pontin in vivo. Here, we show that specific abrogation of Pontin expression in T cells almost completely blocked development of ?? T cells at the ?-selection checkpoint by inducing cell apoptosis indicating that Pontin is essential for early T cell development. Pontin-deficient thymocytes show a comparable expression level of T cell receptor (TCR)? chain, but have enhanced activation of p53 and Notch signaling compared to wild-type thymocytes. Intriguingly, the developmental block of ?? T cells can be partially rescued by loss of p53. Together, our data demonstrate a novel role of Pontin as a crucial regulator in pre-TCR signaling during T cell development. PMID:24680824

  14. NFAT proteins: key regulators of T-cell development and function

    Microsoft Academic Search

    Fernando Macian

    2005-01-01

    Since the discovery of the first nuclear factor of activated T cells (NFAT) protein more than a decade ago, the NFAT family of transcription factors has grown to include five members. It has also become clear that NFAT proteins have crucial roles in the development and function of the immune system. In T cells, NFAT proteins not only regulate activation

  15. A role for CD44 in T cell development and function during direct competition between CD44+ and CD44- cells.

    PubMed

    Graham, Victoria A; Marzo, Amanda L; Tough, David F

    2007-04-01

    The role of CD44 in T cell biology remains incompletely understood. Although studies using anti-CD44 antibodies have implicated this cell adhesion molecule in a variety of important T cell processes, few T cell defects have been reported in CD44-deficient mice. We have assessed the requirement for CD44 in T cell development and mature T cell function by analyzing mice in which CD44(-/-) and WT cells were produced simultaneously. In mixed (CD44(-/-) + CD44(+/+)) bone marrow chimeras, production of CD44(-/-) T cells was shown to be reduced compared to WT cells due to inefficient intrathymic development. In addition, mature CD44(-/-) CD8(+) T cells generated a substantially lower response than WT T cells after infection of mice with lymphocytic choriomeningitis virus, with the reduction in response apparent in both lymphoid and non-lymphoid tissues. Overall, these results demonstrate a poor capacity of CD44(-/-) T lineage cells to compete with WT cells at multiple levels, implicating CD44 in normal T cell function. PMID:17330818

  16. Metabolic switching and fuel choice during T-cell differentiation and memory development

    PubMed Central

    van der Windt, Gerritje J.W.; Pearce, Erika L.

    2013-01-01

    Summary Clearance or control of pathogens or tumors usually requires T-cell-mediated immunity. As such, understanding the mechanisms that govern the function, maintenance, and persistence of T cells will likely lead to new treatments for controlling disease. During an immune response, T-cell development is marked by striking changes in metabolism. There is a growing appreciation that these metabolic changes underlie the capacity of T cells to perform particular functions, and this has led to a recent focus on the idea that the manipulation of cellular metabolism can be used to shape adaptive immune responses. Although interest in this area has grown in the last few years, a full understanding of the metabolic control of T-cell functions, particularly during an immune response in vivo, is still lacking. In this review, we first provide a basic overview of metabolism in T cells, and then we focus on recent studies providing new or updated insights into the regulation of metabolic pathways and how they underpin T-cell differentiation and memory T-cell development. PMID:22889213

  17. Disruption of alpha beta but not of gamma delta T cell development by overexpression of the helix-loop-helix protein Id3 in committed T cell progenitors.

    PubMed Central

    Blom, B; Heemskerk, M H; Verschuren, M C; van Dongen, J J; Stegmann, A P; Bakker, A Q; Couwenberg, F; Res, P C; Spits, H

    1999-01-01

    Enforced expression of Id3, which has the capacity to inhibit many basic helix-loop-helix (bHLH) transcription factors, in human CD34(+) hematopoietic progenitor cells that have not undergone T cell receptor (TCR) gene rearrangements inhibits development of the transduced cells into TCRalpha beta and gamma delta cells in a fetal thymic organ culture (FTOC). Here we document that overexpression of Id3, in progenitors that have initiated TCR gene rearrangements (pre-T cells), inhibits development into TCRalpha beta but not into TCRgamma delta T cells. Furthermore, Id3 impedes expression of recombination activating genes and downregulates pre-Talpha mRNA. These observations suggest possible mechanisms by which Id3 overexpression can differentially affect development of pre-T cells into TCRalpha beta and gamma delta cells. We also observed that cell surface CD4(-)CD8(-)CD3(-) cells with rearranged TCR genes developed from Id3-transduced but not from control-transduced pre-T cells in an FTOC. These cells had properties of both natural killer (NK) and pre-T cells. These findings suggest that bHLH factors are required to control T cell development after the T/NK developmental checkpoint. PMID:10329625

  18. Regulation of Lipid Signaling by Diacylglycerol Kinases during T Cell Development and Function

    PubMed Central

    Krishna, Sruti; Zhong, Xiao-Ping

    2013-01-01

    Diacylglycerol (DAG) and phosphatidic acid (PA) are bioactive lipids synthesized when the T cell receptor binds to a cognate peptide-MHC complex. DAG triggers signaling by recruiting Ras guanyl-releasing protein 1, PKC?, and other effectors, whereas PA binds to effector molecules that include mechanistic target of rapamycin, Src homology region 2 domain-containing phosphatase 1, and Raf1. While DAG-mediated pathways have been shown to play vital roles in T cell development and function, the importance of PA-mediated signals remains less clear. The diacylglycerol kinase (DGK) family of enzymes phosphorylates DAG to produce PA, serving as a molecular switch that regulates the relative levels of these critical second messengers. Two DGK isoforms, ? and ?, are predominantly expressed in T lineage cells and play an important role in conventional ?? T cell development. In mature T cells, the activity of these DGK isoforms aids in the maintenance of self-tolerance by preventing T cell hyper-activation and promoting T cell anergy. In this review, we discuss the roles of DAG-mediated pathways, PA-effectors, and DGKs in T cell development and function. We also highlight recent work that has uncovered previously unappreciated roles for DGK activity, for instance in invariant NKT cell development, anti-tumor and anti-viral CD8 responses, and the directional secretion of soluble effectors. PMID:23847619

  19. T Cell–specific Inactivation of the Interleukin 10 Gene in Mice Results in Enhanced T Cell Responses but Normal Innate Responses to Lipopolysaccharide or Skin Irritation

    PubMed Central

    Roers, Axel; Siewe, Lisa; Strittmatter, Elke; Deckert, Martina; Schlüter, Dirk; Stenzel, Werner; Gruber, Achim D.; Krieg, Thomas; Rajewsky, Klaus; Müller, Werner

    2004-01-01

    Interleukin (IL)-10 is a regulator of inflammatory responses and is secreted by a variety of different cell types including T cells. T regulatory cells have been shown to suppress immune responses by IL-10–dependent, but also IL-10–independent, mechanisms. Herein, we address the role of T cell–derived IL-10 in mice with an inactivation of the IL-10 gene restricted to T cells generated by Cre/loxP-mediated targeting of the IL-10 gene. Splenocytes from this T cell–specific mutant secrete increased amounts of proinflammatory cytokines after activation in vitro compared with show enhanced contact hypersensitivity reactions, and succumb to severe immunopathology upon infection with Toxoplasma gondii. Despite intact IL-10 genes in other cell types, the dysregulation of T cell responses observed in the T cell–specific IL-10 mutant closely resembles the phenotype in complete IL-10 deficiency. However, in contrast to complete IL-10 deficiency, sensitivity to endotoxic shock and irritant responses of the skin are not enhanced in the T cell–specific IL-10 mutant. Our data highlight the importance of T cell–derived IL-10 in the regulation of T cell responses and demonstrate that endotoxic shock and the irritant response of the skin are controlled by IL-10 from other cell types. PMID:15534372

  20. Recent developments in the management of T-cell precursor acute lymphoblastic leukemia/lymphoma.

    PubMed

    Fielding, Adele K; Banerjee, Lalita; Marks, David I

    2012-06-01

    T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma are uncommon disorders classified together by the World Health Organization classification as "T-lymphoblastic leukemia/lymphoma." This review gives an overview on the treatment of these aggressive but curable T cell malignancies in adult patients, in order to highlight current developments. The most interesting and relevant developments are in our understanding of the genetics of T-ALL/LBL and how the genetics relate to clinical outcome. These studies will inform clinicians as to which targeted novel agents may be of value and how patients may be best risk-stratified to receive them. PMID:22476945

  1. CD28 in thymocyte development and peripheral T cell activation in mice exposed to suspended particulate matter

    SciTech Connect

    Drela, Nadzieja [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland)]. E-mail: ndrela@biol.uw.edu.pl; Zesko, Izabela [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland); Jakubowska, Martyna [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland); Biernacka, Marzena [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland)

    2006-09-01

    The CD28:B7 signaling pathway is very important for the activity of mature peripheral T lymphocytes and thymocyte development. The proper development of thymocytes into mature single positive CD4{sup +}and CD8{sup +} T cells is crucial for almost all immune functions. In naturally occurring conditions, T cells maturation in the thymus is influenced by environmental agents. The expression of CD28 and the distribution of CD28{sup low/high} thymocytes have been examined at various stages of thymocyte development in BALB/c mice exposed to air-suspended particulate matter (ASM). Acute exposure to ASM resulted in the decrease of CD28 expression in the total thymocyte population. The increase of the percentage of CD28{sup low} and the decrease of CD28{sup high} thymocytes were observed, which may account for the acceleration of thymocyte development under the conditions of elevated risk resulting from the exposure of animals to environmental xenobiotics. ASM exposure resulted in the increase of the level of proliferation of lymph node T cells induced by anti-CD3 and anti-CD28 monoclonal antibodies activation despite normal expression of CD28 molecule. In contrast, the level of proliferation of spleen T cells was lowered or normal dependently of the concentration of stimuli used for activation. Results of these studies demonstrate that acute exposure of mice to ASM can result in the progression of two contrasting processes in the immune system: upregulation of thymocyte development, which contributes to the maintenance of peripheral T cell pool, and over-activation of lymph node lymphocytes, which may lead to uncontrolled immunostimulation.

  2. Type I interferons regulate eomesodermin expression and the development of unconventional memory CD8+ T cells

    PubMed Central

    Martinet, Valérie; Tonon, Sandrine; Torres, David; Azouz, Abdulkader; Nguyen, Muriel; Kohler, Arnaud; Flamand, Véronique; Mao, Chai-An; Klein, William H.; Leo, Oberdan; Goriely, Stanislas

    2015-01-01

    CD8+ T-cell memory phenotype and function are acquired after antigen-driven activation. Memory-like cells may also arise in absence of antigenic exposure in the thymus or in the periphery. Eomesodermin (Eomes) is a key transcription factor for the development of these unconventional memory cells. Herein, we show that type I interferon signalling in CD8+ T cells directly activates Eomes gene expression. Consistent with this observation, the phenotype, function and age-dependent expansion of ‘virtual memory' CD8+ T cells are strongly affected in absence of type I interferon signalling. In addition, type I interferons induce a sustained expansion of ‘virtual memory' CD8+ T cells in an Eomes-dependent fashion. We further show that the development of ‘innate thymic' CD8+ T cells is dependent on the same pathway. In conclusion, we demonstrate that type I interferon signalling in CD8+ T cells drives Eomes expression and thereby regulates the function and homeostasis of memory-like CD8+ T cells. PMID:25953241

  3. The Intrahepatic T Cell Compartment Does Not Normalize Years After Therapy-Induced Hepatitis C Virus Eradication.

    PubMed

    Spaan, Michelle; Claassen, Mark A A; Hou, Jun; Janssen, Harry L A; de Knegt, Robert J; Boonstra, Andre

    2015-08-01

    Little is known about the immune status in liver and blood of patients with chronic hepatitis C virus (HCV) infection long after therapy-induced viral clearance. In this study, we demonstrate that, 4 years after clearance, regulation of HCV-specific immunity in blood by regulatory T cells (Tregs) and the immunosuppressive cytokines interleukin 10 and transforming growth factor ? is still ongoing. Importantly, analysis of liver specimens collected 4 years after HCV clearance shows that intrahepatic Tregs are still present in all patients, suggesting that liver T cells remain regulated. Identifying mechanisms that regulate HCV-specific memory T-cell responses after clearance is highly relevant for the development of protective vaccines, especially in patients at high risk of reinfection. PMID:25637348

  4. Induction of T Cell Development from Hematopoietic Progenitor Cells by Delta-like-1 In Vitro

    Microsoft Academic Search

    Thomas M. Schmitt; Juan Carlos Zúñiga-Pflücker

    2002-01-01

    The molecular interactions provided by the thymic microenvironment that predicate T cell development remain obscure. Here, we show that a bone marrow stromal cell line ectopically expressing the Notch ligand Delta-like-1 loses its ability to support B cell lymphopoiesis, but acquires the capacity to induce the differentiation of hematopoietic progenitors into CD4 CD8 double- and single-positive T cells. Both ??-TCR+

  5. Genetic control of T cell receptor BJ gene expression in peripheral lymphocytes of normal and rheumatoid arthritis monozygotic twins.

    PubMed Central

    Nanki, T; Kohsaka, H; Mizushima, N; Ollier, W E; Carson, D A; Miyasaka, N

    1996-01-01

    The amino acids encoded at the junctions of T cell receptor (TCR) V and J genes directly interact with MHC bound peptides. However, the regulation of the human TCRBJ gene repertoire has been difficult to analyze, because of the potentially complex number of BJ gene rearrangements. To overcome this problem, we developed a PCR-ELISA method to study BJ gene expression, and compared peripheral T lymphocytes from 12 pairs of monozygotic twins, including 6 rheumatoid arthritis (RA) discordant pairs, and 5 normals. Analyses of the TCRBV5, 13 and 17 gene families, which have been reported to be increased in RA patients, showed: (a) the three TCRBV transcripts have common features of BJ gene usage; (b) TCR transcripts from each TCRBV family display a distinctive BJ gene profile, which is displayed better by CD4+ than CD8+ lymphocytes; (c) the BJ gene repertoires of monozygotic twins are more similar than those of unrelated individuals; and (d) the inflammation of RA does not induce specific changes in the genetically determined pattern of BJ expression. These results indicate that the frequency of expression particular TCRBV-TCRBJ recombinants in human lymphocytes is controlled genetically, and is maintained despite the presence of a chronic inflammatory disease. PMID:8833908

  6. CD5 instructs extrathymic regulatory T cell development in response to self and tolerizing antigens.

    PubMed

    Henderson, Jacob G; Opejin, Adeleye; Jones, Andrew; Gross, Cindy; Hawiger, Daniel

    2015-03-17

    Self-reactive T cells can escape thymic deletion and therefore some of these potentially autoaggressive T cells need to convert into regulatory T (Treg) cells to help control responses against self. However, it remains unknown how peripheral self-reactive T cells are specifically instructed to become Treg cells. We report that CD5, whose expression is upregulated in T cells by self and tolerizing antigens in the thymus and periphery, governed extrathymic Treg cell development. CD5 modified effector cell-differentiating signals that inhibit Treg cell induction. Treg cell conversion of Cd5(-/-) and CD5(lo) T cells was inhibited by even small amounts of interleukin-4 (IL-4), IL-6, and interferon-? (IFN-?) produced by bystander lymphocytes, while CD5(hi) T cells resisted this inhibition of Treg cell induction. Our findings further revealed that CD5 promoted Treg cell induction by blocking mechanistic target of rapamycin (mTOR) activation. Therefore CD5 instructs extrathymic Treg cell development in response to self and tolerizing antigens. PMID:25786177

  7. Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development

    PubMed Central

    Kurtulus, Sema; Tripathi, Pulak; Hildeman, David A.

    2013-01-01

    Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïve T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8+ T cells. For example, the effector CD8+ T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8+ T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8+ T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8+ T cell memory. Effector to memory transition of CD4+ T cells is less well characterized than CD8+ T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells. PMID:23346085

  8. Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin

    Microsoft Academic Search

    J. D. Bos; C. Hagenaars; P. K. Das; S. R. Krieg; W. J. Voorn; M. L. Kapsenberg

    1989-01-01

    Absolute numbers of CD3+ T lymphocytes and their subpopulations were determined and statistically evaluated in the lesional skin of psoriasis, atopic dermatitis, nummular dermatitis, pityriasis rosea, and lichen planus. Skin sections were divided into horizontal layers and the numbers of CD3+ T cells as well as CD4+ inducer and CD8+ suppressor-cytotoxic T-cell subsets were counted. In addition, absolute numbers of

  9. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells

    Microsoft Academic Search

    Isao Miyoshi; Ichiro Kubonishi; Shizuo Yoshimoto; Tadaatsu Akagi; Yuji Ohtsuki; Yukimasa Shiraishi; Kinya Nagata; Yorio Hinuma

    1981-01-01

    A recent nationwide survey of the lymphocyte subpopulations of leukaemia and lymphoma in Japan has disclosed a high incidence of adult T-cell leukaemia (ATL)1. One of the striking features of this disease is the clustering of patients in the southwestern part of Japan1,2. We have established a continuous culture line of leukaemic T cells from a patient with ATL3,4. This

  10. HIV Infection in Uncircumcised Men Is Associated With Altered CD8 T-cell Function But Normal CD4 T-cell Numbers in the Foreskin

    PubMed Central

    Prodger, Jessica L.; Hirbod, Taha; Gray, Ronald; Kigozi, Godfrey; Nalugoda, Fred; Galiwango, Ronald; Reynolds, Steven J.; Huibner, Sanja; Wawer, Maria J.; Serwadda, David; Kaul, Rupert; Nehemiah, Kighoma; Denis, Tumuramye; Emma, Mbagiira; John-Bosco, Kubaawo; Yahaya, Isabirye; Patrick, Mulema; James, Teba; Boru, Atukunda; Herbert, Mayengo; Mary, Nakafeero; Stephen, Mugamba; Mary, Nakyeyune; Margaret, Anyokorit; Deo, Male; Dan, Kayiwa; Sarah, Kalibbala; Lawrence, Lubyayi; Joseph, Otobi Ouma; Moses, Kakanga; Baptist, Okech John; Grace, Okello; Gerald, Aluma; Ivan, Ssebugenyi; Ambrose, Balikudembe

    2014-01-01

    Background.?Human immunodeficiency virus (HIV)–infected (HIV+) men are more susceptible to sexually transmitted infections, and may be superinfected by HIV. We hypothesized that HIV induces immune alterations in the foreskin that may impact the subsequent acquisition/clearance of genital coinfections. Methods.?Foreskin tissue and blood were obtained from 70 HIV-uninfected and 20 HIV+ men undergoing circumcision. T cells were characterized by flow cytometry, immunohistochemistry, and polymerase chain reaction. Results.?There was substantial influx of CD8 T-cells into the foreskins of HIV+ men (108.8 vs 23.1 cells/mm2; P < .001); but foreskin CD4 T-cell density was unchanged (43.0 vs 33.7/mm2; P = .67), despite substantial blood depletion (409.0 vs 877.8 cells/µL; P < .001). While frequencies of foreskin C-C chemokine receptor type 5+ (CCR5+) T cells, T regulatory cells, and T-helper 17 cells were unaltered in HIV+ men, CD8 T-cell production of tumor necrosis factor ? (TNF?) was decreased. HIV-specific CD8 T cells were present in the foreskins of HIV+ men, although their frequency and function was reduced compared to the blood. Conclusions.?Foreskin CD4 T-cell density and CCR5 expression were not reduced during HIV infection, perhaps explaining susceptibility to HIV superinfection. Foreskin CD8 T-cell density was increased, but decreased production of TNF? may enhance susceptibility to genital coinfections in HIV+ men. PMID:24277744

  11. Viral FLIP impairs survival of activated T cells and generation of CD8+ T cell memory.

    PubMed

    Wu, Zhengqi; Roberts, Margaret; Porter, Melissa; Walker, Fabianne; Wherry, E John; Kelly, John; Gadina, Massimo; Silva, Elisabeth M; DosReis, George A; Lopes, Marcela F; O'Shea, John; Leonard, Warren J; Ahmed, Rafi; Siegel, Richard M

    2004-05-15

    Viral FLIPs (vFLIPs) interfere with apoptosis signaling by death-domain-containing receptors in the TNFR superfamily (death receptors). In this study, we show that T cell-specific transgenic expression of MC159-vFLIP from the human Molluscum contagiosum virus blocks CD95-induced apoptosis in thymocytes and peripheral T cells, but also impairs postactivation survival of in vitro activated primary T cells despite normal early activation parameters. MC159 vFLIP impairs T cell development to a lesser extent than does Fas-associated death domain protein deficiency or another viral FLIP, E8. In the periphery, vFLIP expression leads to a specific deficit of functional memory CD8(+) T cells. After immunization with a protein Ag, Ag-specific CD8(+) T cells initially proliferate, but quickly disappear and fail to produce Ag-specific memory CD8(+) T cells. Viral FLIP transgenic mice exhibit impaired CD8(+) T cell responses to lymphocytic choriomeningitis virus and Trypanosoma cruzi infections, and a specific defect in CD8(+) T cell recall responses to influenza virus was seen. These results suggest that vFLIP expression in T cells blocks signals necessary for the sustained survival of CD8(+) T cells and the generation of CD8(+) T cell memory. Through this mechanism, vFLIP proteins expressed by T cell tropic viruses may impair the CD8(+) T cell immune responses directed against them. PMID:15128821

  12. The Ets-1 transcription factor controls the development and function of natural regulatory T cells

    PubMed Central

    Mouly, Enguerran; Chemin, Karine; Nguyen, Hai Vu; Chopin, Martine; Mesnard, Laurent; Leite-de-Moraes, Maria; Burlen-defranoux, Odile; Bandeira, Antonio

    2010-01-01

    Regulatory T cells (T reg cells) constitute a population of CD4+ T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1?/?) developed T cell–mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1?/? mice contained mostly activated T cells, including Th2-polarized CD4+ cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1?/? T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1?/? T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1?/? T reg cells showed decreased in vitro suppression activity and did not protect Rag2?/? hosts from naive T cell–induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression. PMID:20855499

  13. SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors

    PubMed Central

    De Calisto, Jaime; Wang, Ninghai; Wang, Guoxing; Yigit, Burcu; Engel, Pablo; Terhorst, Cox

    2014-01-01

    Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8+ T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1?+?6]?/? and Slamf[1?+?5?+?6]?/?B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8+ T cells slightly increased in the Slamf[1?+?5?+?6]?/?, but not in the Slamf[1?+?6]?/? strain, suggesting that Slamf5 may function as a negative regulator of innate CD8+ T cell development. Accordingly, Slamf5?/? B6 mice showed an exclusive expansion of innate CD8+ T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7?/? strain showed an expansion of both splenic innate CD8+ T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3?/? BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZFhi) NKT cells and innate CD8+ T cells significantly increased in the SAP-independent Slamf8?/? BALB/c strain. In summary, these results show that NKT and innate CD8+ T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8+ T cells. PMID:24795728

  14. SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors.

    PubMed

    De Calisto, Jaime; Wang, Ninghai; Wang, Guoxing; Yigit, Burcu; Engel, Pablo; Terhorst, Cox

    2014-01-01

    Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8(+) T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1?+?6](-/-) and Slamf[1?+?5?+?6](-/-) B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8(+) T cells slightly increased in the Slamf[1?+?5?+?6](-/-) , but not in the Slamf[1?+?6](-/-) strain, suggesting that Slamf5 may function as a negative regulator of innate CD8(+) T cell development. Accordingly, Slamf5(-/-) B6 mice showed an exclusive expansion of innate CD8(+) T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7(-/-) strain showed an expansion of both splenic innate CD8(+) T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3(-/-) BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZF(hi)) NKT cells and innate CD8(+) T cells significantly increased in the SAP-independent Slamf8(-/-) BALB/c strain. In summary, these results show that NKT and innate CD8(+) T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8(+) T cells. PMID:24795728

  15. Activation requirements for normal T cells: accessory cell-dependent and -independent stimulation by anti-receptor antibodies.

    PubMed

    Bekoff, M; Kubo, R; Grey, H M

    1986-09-01

    We have examined the requirements for the activation of normal T cells by two anti-T cell receptor antibody preparations, including a rabbit antiserum, R3497, which binds to all normal T cells, and a rat monoclonal antibody, KJ16-133, which binds to about 20% of T cells. The requirements for stimulation of T cells by both antibodies were similar. Soluble antibodies in the absence of accessory cells (AC) failed to induce either proliferation or the expression of IL 2 receptors, and the addition of either IL 2 or PMA failed to synergize with these soluble antibodies for an AC-independent proliferative response. Activation could only be achieved in the presence of Fc receptor-positive AC, although Fc receptor expression alone appeared not to be sufficient for AC activity because some Fc receptor-positive cells did not function in this capacity. Activation with anti-receptor antibody conjugated to Sepharose 4B beads could be demonstrated in the presence of some exogenous cofactors, such as IL 2 and PMA, but not in the presence of recombinant IL 1. When activation by soluble antibody plus AC was compared to activation by bead-conjugated antibody + recombinant IL 2, it was found that the former favored the stimulation of Lyt-2+ cells. The effects of the addition of anti-L3T4 monoclonal antibody was also examined in this system. Anti-L3T4 inhibited the response of L3T4+ cells when used in the presence of Ia+ as well as Ia- AC, and it also inhibited activation in a system in which KJ16-133 conjugated to Sepharose was used in the absence of AC. Because anti-L3T4 had an inhibitory effect in the presence of Ia- AC as well as in the absence of any AC, it is concluded that L3T4 does not necessarily function by interacting with Ia on the surface of AC, and may directly transmit down-regulatory signals when bound by anti-L3T4. PMID:3489033

  16. Oligoclonality in the human CD8+ T cell repertoire in normal subjects and monozygotic twins: implications for studies of infectious and autoimmune diseases.

    PubMed Central

    Monteiro, J.; Hingorani, R.; Choi, I. H.; Silver, J.; Pergolizzi, R.; Gregersen, P. K.

    1995-01-01

    BACKGROUND: We have previously demonstrated CD8+ T cell clonal dominance using a PCR assay for the CDR3 length of T cell receptors belonging to a limited number of TCRBV segments/families. In this study, we have modified this approach in order to analyze more comprehensively the frequency of oligoclonality in the CD8+ T cell subset in 25 known TCRBV segments/families. In order to assess the relative roles of genes and environment in the shaping of a clonally restricted CD8+ T cell repertoire, we have analyzed clonal dominance in the CD8+ T cell population of monozygotic twins, related siblings, and adoptees. MATERIALS AND METHODS: Oligoclonality was assessed in the CD8+ T cell subsets using a multiplex PCR approach to assay for CDR3 length variation across 25 different TCRBV segments/families. Specific criteria for oligoclonality were established, and confirmed by direct sequence analysis of the PCR products. This assay was used to investigate the CD8+ T cell repertoire of 56 normal subjects, as well as six sets of monozygotic (MZ) twins. RESULTS: Seventy-two percent of normal subjects (n = 56) had evidence of oligoclonality in the CD8+ T cell subset, using well-defined criteria. Although MZ twins frequently displayed CD8+ T cell clonal dominance, the overall pattern of oligoclonality was very diverse within each twin pair. However, we occasionally observed dominant CD8+ T cell clones that were highly similar in sequence in both members of some twin pairs. Not a single example of such similarity was observed in normal controls or siblings. CONCLUSIONS: Oligoclonality of circulating CD8+ T cells is a characteristic feature of the human immune system; both host genetic factors and environment shape the pattern of oligoclonality in this T cell subset. The high frequency of this phenomenon in normal subjects provides a background with which to evaluate CD8+ T cell oligoclonality in the setting of infection or autoimmune disease. Further phenotypic and functional characterization of these clonally expanded T cells should provide insight into normal immune homeostasis. Images FIG. 2 FIG. 4 FIG. 5 PMID:8529128

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2012-10-18

    Immune thrombocytopenia (ITP) results from decreased platelet production and accelerated platelet destruction. Impaired CD4(+) regulatory T-cell (Treg) compartment and skewed Th1 and possibly Th17 responses have been described in ITP patients. The trigger for aberrant T-cell polarization remains unknown. Because monocytes have a critical role in development and polarization of T-cell subsets, we explored the contribution of monocyte subsets in control of Treg and Th development in patients with ITP. Unlike circulating classic CD14(hi)CD16(-) subpopulation, the CD16(+) monocyte subset was expanded in ITP patients with low platelet counts on thrombopoietic agents and positively correlated with T-cell CD4(+)IFN-?(+) levels, but negatively with circulating CD4(+)CD25(hi)Foxp3(+) and IL-17(+) Th cells. Using a coculture model, we found that CD16(+) ITP monocytes promoted the expansion of IFN-?(+)CD4(+) cells and concomitantly inhibited the proliferation of Tregs and IL-17(+) Th cells. Th-1-polarizing cytokine IL-12, secreted after direct contact of patient T-cell and CD16(+) monocytes, was responsible for the inhibitory effect on Treg and IL-17(+)CD4(+) cell proliferation. Our findings are consistent with ITP CD16(+) monocytes promoting Th1 development, which in turn negatively regulates IL-17 and Treg induction. This underscores the critical role of CD16(+) monocytes in the generation of potentially pathogenic Th responses in ITP. PMID:22915651

  19. RET/GFR? Signals Are Dispensable for Thymic T Cell Development In Vivo

    PubMed Central

    Almeida, Afonso Rocha Martins; Arroz-Madeira, Sílvia; Fonseca-Pereira, Diogo; Ribeiro, Hélder; Lasrado, Reena; Pachnis, Vassilis; Veiga-Fernandes, Henrique

    2012-01-01

    Identification of thymocyte regulators is a central issue in T cell biology. Interestingly, growing evidence indicates that common key molecules control neuronal and immune cell functions. The neurotrophic factor receptor RET mediates critical functions in foetal hematopoietic subsets, thus raising the possibility that RET-related molecules may also control T cell development. We show that Ret, Gfra1 and Gfra2 are abundantly expressed by foetal and adult immature DN thymocytes. Despite the developmentally regulated expression of these genes, analysis of foetal thymi from Gfra1, Gfra2 or Ret deficient embryos revealed that these molecules are dispensable for foetal T cell development. Furthermore, analysis of RET gain of function and Ret conditional knockout mice showed that RET is also unnecessary for adult thymopoiesis. Finally, competitive thymic reconstitution assays indicated that Ret deficient thymocytes maintained their differentiation fitness even in stringent developmental conditions. Thus, our data demonstrate that RET/GFR? signals are dispensable for thymic T cell development in vivo, indicating that pharmacological targeting of RET signalling in tumours is not likely to result in T cell production failure. PMID:23300832

  20. Bystander chronic infection negatively impacts development of CD8(+) T cell memory.

    PubMed

    Stelekati, Erietta; Shin, Haina; Doering, Travis A; Dolfi, Douglas V; Ziegler, Carly G; Beiting, Daniel P; Dawson, Lucas; Liboon, Jennifer; Wolski, David; Ali, Mohammed-Alkhatim A; Katsikis, Peter D; Shen, Hao; Roos, David S; Haining, W Nicholas; Lauer, Georg M; Wherry, E John

    2014-05-15

    Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8(+) T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8(+) T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8(+) T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation. PMID:24837104

  1. Bystander chronic infection negatively impacts development of CD8+ T cell memory

    PubMed Central

    Stelekati, Erietta; Shin, Haina; Doering, Travis A.; Dolfi, Douglas V.; Ziegler, Carly G.; Beiting, Daniel P.; Dawson, Lucas; Liboon, Jennifer; Wolski, David; Ali, Mohammed-Alkhatim A.; Katsikis, Peter D.; Shen, Hao; Roos, David S.; Haining, W. Nicholas; Lauer, Georg M.; Wherry, E. John

    2014-01-01

    Summary Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8+ T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8+ T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8+ T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation. PMID:24837104

  2. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy.

    PubMed

    Wang, S-C; Li, Y-H; Piao, H-L; Hong, X-W; Zhang, D; Xu, Y-Y; Tao, Y; Wang, Y; Yuan, M-M; Li, D-J; Du, M-R

    2015-01-01

    CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-? producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy. PMID:25950468

  3. Kinetics of T-cell receptor-dependent antigen recognition determined in vivo by multi-spectral normalized epifluorescence laser scanning

    NASA Astrophysics Data System (ADS)

    Favicchio, Rosy; Zacharakis, Giannis; Oikonomaki, Katerina; Zacharopoulos, Athanasios; Mamalaki, Clio; Ripoll, Jorge

    2012-07-01

    Detection of multiple fluorophores in conditions of low signal represents a limiting factor for the application of in vivo optical imaging techniques in immunology where fluorescent labels report for different functional characteristics. A noninvasive in vivo Multi-Spectral Normalized Epifluorescence Laser scanning (M-SNELS) method was developed for the simultaneous and quantitative detection of multiple fluorophores in low signal to noise ratios and used to follow T-cell activation and clonal expansion. Colocalized DsRed- and GFP-labeled T cells were followed in tandem during the mounting of an immune response. Spectral unmixing was used to distinguish the overlapping fluorescent emissions representative of the two distinct cell populations and longitudinal data reported the discrete pattern of antigen-driven proliferation. Retrieved values were validated both in vitro and in vivo with flow cytometry and significant correlation between all methodologies was achieved. Noninvasive M-SNELS successfully quantified two colocalized fluorescent populations and provides a valid alternative imaging approach to traditional invasive methods for detecting T cell dynamics.

  4. Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression

    PubMed Central

    Tansiri, Yada; Rowland-Jones, Sarah L.; Ananworanich, Jintanat; Hansasuta, Pokrath

    2015-01-01

    In this cross-sectional study we evaluated T-cell responses using several assays to determine immune correlates of HIV control that distinguish untreated viraemic controllers (VC) from noncontrollers (NC) with similar CD4 counts. Samples were taken from 65 ART-naïve chronically HIV-infected VC and NC from Thailand with matching CD4 counts in the normal range (>450 cells/?l). We determined HIVp24-specific T-cell responses using standard Interferon-gamma (IFN?) ELISpot assays, and compared the functional quality of HIVp24-specific CD8+ T-cell responses using polychromatic flow cytometry. Finally, in vitro HIV suppression assays were performed to evaluate directly the activity of CD8+ T cells in HIV control. Autologous CD4+ T cells were infected with primary patient-derived HIV isolates and the HIV suppressive activity of CD8+ T cells was determined after co-culture, measuring production of HIVp24 Ag by ELISA. The HIVp24-specific T-cell responses of VC and NC could not completely be differentiated through measurement of IFN?-producing cells using ELISpot assays, nor by the absolute cell numbers of polyfunctional HIVp24-specific CD8+ T cells. However, in vitro HIV suppression assays showed clear differences between VC and NC. HIV suppressive activity, mediated by either ex vivo unstimulated CD8+ T cells or HIVp24-specific T-cell lines, was significantly greater using cells from VC than NC cells. Additionally, we were able to demonstrate a significant correlation between the level of HIV suppressive activity mediated by ex vivo unstimulated CD8+ T cells and plasma viral load (pVL) (Spearman r = -0.7345, p = 0.0003). This study provides evidence that in vitro HIV suppression assays are the most informative in the functional evaluation of CD8+ T-cell responses and can distinguish between VC and NC. PMID:25764310

  5. Developing an in vitro model of T cell type of large granular lymphocyte leukemia

    PubMed Central

    Ren, Tong; Yang, Jun; Broeg, Katie; Liu, Xin; Loughran, Thomas P.; Cheng, Hua

    2013-01-01

    We developed a strategy that can prolong in vitro growth of T cell type of large granular lymphocyte (T-LGL) leukemia cells. Primary CD8+ lymphocytes from T-LGL leukemia patients were stably transduced with the retroviral tax gene derived from human T cell leukemia virus type 2. Expression of Tax overrode replicative senescence and promoted clonal expansion of the leukemic CD8+ T cells. These cells exhibit features characteristic of leukemic LGL, including resistance to FasL-mediated apoptosis, sensitivity to the inhibitors of sphingosine-1-phosphate receptor and I?B kinases as well as expression of cytotoxic gene products such as granzyme B, perforin and IFN?. Collectively, these results indicate that this leukemia cell model can duplicate the main phenotype and pathophysiological characteristics of the clinical isolates of T-LGL leukemia. This model should be useful for investigating molecular pathogenesis of the disease and for developing new therapeutics targeting T-LGL leukemia. PMID:24183305

  6. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)V?6(+)?? T cells.

    PubMed

    Akitsu, Aoi; Ishigame, Harumichi; Kakuta, Shigeru; Chung, Soo-Hyun; Ikeda, Satoshi; Shimizu, Kenji; Kubo, Sachiko; Liu, Yang; Umemura, Masayuki; Matsuzaki, Goro; Yoshikai, Yasunobu; Saijo, Shinobu; Iwakura, Yoichiro

    2015-01-01

    Interleukin-17 (IL-17)-producing ?? T (??17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4(+) and ??17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4(+) T cells direct ?? T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the V?6(+) subset of CCR2(+) ?? T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on ?? T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on V?6(+) cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner. PMID:26108163

  7. Regulatory T cell development in the absence of functional Foxp3

    Microsoft Academic Search

    Wen Lin; Dipica Haribhai; Lance M Relland; Nga Truong; Marc R Carlson; Calvin B Williams; Talal A Chatila

    2007-01-01

    Although the development of regulatory T cells (Treg cells) in the thymus is defined by expression of the lineage marker Foxp3, the precise function of Foxp3 in Treg cell lineage commitment is unknown. Here we examined Treg cell development and function in mice with a Foxp3 allele that directs expression of a nonfunctional fusion protein of Foxp3 and enhanced green

  8. The effects of radio-frequency electromagnetic fields on T cell function during development.

    PubMed

    Ohtani, Shin; Ushiyama, Akira; Maeda, Machiko; Ogasawara, Yuki; Wang, Jianqing; Kunugita, Naoki; Ishii, Kazuyuki

    2015-05-01

    With the widespread use of radio-frequency devices, it is increasingly important to understand the biological effects of the associated electromagnetic fields. Thus, we investigated the effects of radio-frequency electromagnetic fields (RF-EMF) on T cell responses during development due to the lack of science-based evidence for RF-EMF effects on developmental immune systems. Sprague Dawley (SD) rats were exposed to 2.14-GHz wideband code division multiple-access (W-CDMA) RF signals at a whole-body specific absorption rate (SAR) of 0.2 W/kg. Exposures were performed for a total of 9 weeks spanning in utero development, lactation and the juvenile period. Rats were continuously exposed to RF-EMF for 20 h/day, 7 days/week. Comparisons of control and exposed rats using flow cytometry revealed no changes in the numbers of CD4/CD8 T cells, activated T cells or regulatory T cells among peripheral blood cells, splenocytes and thymocytes. Expression levels of 16 genes that regulate the immunological Th1/Th2 paradigm were analyzed using real-time PCR in the spleen and thymus tissues of control and RF-EMF-exposed rats. Although only the Il5 gene was significantly regulated in spleen tissues, Il4, Il5 and Il23a genes were significantly upregulated in thymus tissues following exposure to RF-EMF. However, ELISAs showed no changes in serum IL-4 protein concentrations. These data indicate no adverse effects of long-term RF-EMF exposure on immune-like T cell populations, T cell activation, or Th1/Th2 balance in developing rats, although significant transcriptional effects were observed. PMID:25835473

  9. Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.

    PubMed

    Lee, Hyung-Ok; He, Xiao; Mookerjee-Basu, Jayati; Zhongping, Dai; Hua, Xiang; Nicolas, Emmanuelle; Sulis, Maria Luisa; Ferrando, Adolfo A; Testa, Joseph R; Kappes, Dietmar J

    2015-06-23

    The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-??TCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation. PMID:26056302

  10. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy" [published erratum appears in J Exp Med 1994 Mar 1;179(3):1077

    PubMed Central

    1994-01-01

    To determine whether T cells, like B cells, can become clonally expanded in normal individuals as a function of age, we compared the T cell V beta repertoire of cord blood to that of peripheral blood from normal donors over 65 yr of age. T cells from elderly subjects contained expanded subsets (greater than the mean+three standard deviations) of T cell receptor (TCR) V beta populations. These expanded subsets were observed primarily among CD8, but not CD4 cells, represented up to 37.5% of all CD8 cells, and were present in most elderly subjects. An expanded V beta 5.2/3 CD8 subset and a V beta 6.7a CD8 subset from separate donors were analyzed by reverse transcriptase- polymerase chain reaction, cloning and sequencing of the TCR beta chain VDJ junction. In both cases the expanded subsets were mono- or oligoclonal while control CD4 populations were polyclonal. Using two- color flow cytometry it was possible to identify the expanded V beta 6.7a subset as CD8+ CD28-CD11b+ cells. In three of five random old subjects similar expansions of V beta subsets were found specifically in the CD8+ CD28- subpopulation, an interesting subset of cytotoxic T lymphocytes, known to lack proliferative responses to TCR stimuli. It is common practice to use the demonstration of clonality as a diagnostic indicator for T cell lymphoma/leukemia. In view of the high frequency of expanded T clones of T cells in normal elderly subjects the diagnostic usefulness of this test should be reexamined. PMID:8294871

  11. Stress-free T-cell development: glucocorticoids are not obligatory

    Microsoft Academic Search

    Dale I Godfrey; Jared F Purton; Richard L Boyd; Timothy J Cole

    2000-01-01

    A role for glucocorticoids in thymopoiesis has been suggested by studies using glucocorticoid receptor (GR) anti-sense transgenic mice, glucocorticoid synthesis inhibitors and GR antagonists. Unfortunately, no consensus has been reached on exactly how glucocorticoids influence T-cell development. The most recent approach, using GR knockout (GR?\\/?) mice, indicates that GR signaling is, in fact, dispensable in this entire process.

  12. Stat5 Synergizes with T Cell Receptor\\/Antigen Stimulation in the Development of Lymphoblastic Lymphoma

    Microsoft Academic Search

    John A. Kelly; Rosanne Spolski; Panu E. Kovanen; Takeshi Suzuki; Julie Bollenbacher; Cynthia A. Pise-Masison; Michael F. Radonovich; Stephen Lee; Nancy A. Jenkins; Neal G. Copeland; Herbert C. Morse III; Warren J. Leonard

    Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lym- phoma induction was markedly enhanced

  13. BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells.

    PubMed

    Iguchi, Tomohiro; Aoki, Kazuhisa; Ikawa, Tomokatsu; Taoka, Masato; Taya, Choji; Yoshitani, Hiroshi; Toma-Hirano, Makiko; Koiwai, Osamu; Isobe, Toshiaki; Kawamoto, Hiroshi; Masai, Hisao; Miyatake, Shoichiro

    2015-08-01

    Many members of the BTB-ZF family have been shown to play important roles in lymphocyte development and function. The role of zinc finger Znf131 (also known as Zbtb35) in T cell lineage was elucidated through the production of mice with floxed allele to disrupt at different stages of development. In this article, we present that Znf131 is critical for T cell development during double-negative to double-positive stage, with which significant cell expansion triggered by the pre-TCR signal is coupled. In mature T cells, Znf131 is required for the activation of effector genes, as well as robust proliferation induced upon TCR signal. One of the cyclin-dependent kinase inhibitors, p21(Cip1) encoded by cdkn1a gene, is one of the targets of Znf131. The regulation of T cell proliferation by Znf131 is in part attributed to its suppression on the expression of p21(Cip1). PMID:26136427

  14. PP6 controls T cell development and homeostasis by negatively regulating distal TCR signaling.

    PubMed

    Ye, Jian; Shi, Hao; Shen, Ye; Peng, Chao; Liu, Yan; Li, Chenyu; Deng, Kejing; Geng, Jianguo; Xu, Tian; Zhuang, Yuan; Zheng, Biao; Tao, Wufan

    2015-02-15

    T cell development and homeostasis are both regulated by TCR signals. Protein phosphorylation and dephosphorylation, which are catalyzed by protein kinases and phosphatases, respectively, serve as important switches controlling multiple downstream pathways triggered by TCR recognition of Ags. It has been well documented that protein tyrosine phosphatases are involved in negative regulation of proximal TCR signaling. However, how TCR signals are terminated or attenuated in the distal TCR signaling pathways is largely unknown. We investigated the function of Ser/Thr protein phosphatase (PP) 6 in TCR signaling. T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection, and preferential expansion of fetal-derived, IL-17-producing V?6V?1(+) T cells. Both PP6-deficient peripheral CD4(+) helper and CD8(+) cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells. PP6 deficiency led to profound hyperactivation of multiple distal TCR signaling molecules, including MAPKs, AKT, and NF-?B. Our studies demonstrate that PP6 acts as a critical negative regulator, not only controlling both ?? and ?? lineage development, but also maintaining naive T cell homeostasis by preventing their premature activation before Ag stimulation. PMID:25609840

  15. Expression of MUC1 Mucin on Activated Human T Cells: Implications for a Role of MUC1 in Normal Immune Regulation

    Microsoft Academic Search

    Babita Agrawal; Mark J. Krantz; Joanne Parker; B. Michael Longenecker

    MUC1 mucin is expressed by normal and malignant epithelial cells and is thought to function through cell-cell interactions and transmembrane signal transduction events. Secreted cancer-associated MUC1 is immuno- suppressive and inhibits human T-cell proliferation. We report here that newly synthesized MUC1 is expressed on the surface of mitogen-activated human T cells and is also found in soluble form in the

  16. The influence of T cell development on pathogen specificity and autoreactivity

    E-print Network

    Kosmrlj, Andrej

    T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein ...

  17. Evidence that CD8+ Dendritic Cells Enable the Development of ?? T Cells that Modulate Airway Hyperresponsiveness2

    PubMed Central

    Cook, Laura; Miyahara, Nobuaki; Jin, Niyun; Wands, JM; Taube, Christian; Roark, Christina L.; Potter, Terry A.; Gelfand, Erwin W.; O'Brien, Rebecca L.; Born, Willi K.

    2008-01-01

    Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by ?? T cells. In mice sensitized and challenged with ovalbumin, AHR depends on allergen-specific ?? T cells, but V??1+ ?? T cells spontaneously enhance AHR, whereas V?4+ ?? T cells after being induced by airway challenge suppress AHR. The activity of these ?? T cell modulators is allergen-nonspecific, and how they develop is unclear. We now show that CD8 is essential for the development of both the AHR-suppressor and enhancer ?? T cells although neither type needs to express CD8 itself. Both cell types encounter CD8-expressing non-T cells in the spleen, and their functional development in an otherwise CD8-negative environment can be restored with transferred spleen cell preparations containing CD8+ DC, but not CD8+ T cells or CD8? DC. Our findings suggest that CD8+ DC in the lymphoid tissues enable an early step in the development of ?? T cells, through direct cell-contact. DC-expressed CD8 might take part in this interaction. PMID:18566396

  18. Design and development of therapies using chimeric antigen receptor-expressing T cells.

    PubMed

    Dotti, Gianpietro; Gottschalk, Stephen; Savoldo, Barbara; Brenner, Malcolm K

    2014-01-01

    Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR-T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. PMID:24329793

  19. Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells.

    PubMed

    Zhao, Yuan; Croft, Michael

    2012-01-30

    CD8 T cells are strongly induced in response to certain strains of vaccinia virus (VACV) and the generation of this population is tightly regulated by two Tumor Necrosis Factor (TNF)/TNFR superfamily members, OX40 (CD134) and CD27. In this study, we examined the role of another member of the TNFR superfamily, 4-1BB (CD137, TNFRSF9), and its ligand (4-1BBL, CD137L, TNFSF9), that have been described to control the generation of memory CD8 T cell populations elicited by other viruses such as influenza. Expression of 4-1BB and 4-1BBL was observed in wild-type mice during the primary infection, but we found that both 4-1BB and 4-1BBL deficient mice generated normal numbers of VACV-specific effector CD8 T cells that produced IFN-? and TNF. Additionally, CD8 T cells deficient in 4-1BB were able to expand and persist comparably to wild-type T cells in response to VACV infection. Furthermore, the knockout mice also showed no defect in development of VACV-specific CD8 memory T cell populations. Lastly, showing alternate control mechanisms were not active in the gene-deficient environments that masked any activity, blocking 4-1BB/4-1BBL interactions using neutralizing antibody also had no effect on the number of VACV-specific memory CD8 T cells induced. Thus, our data demonstrate that 4-1BB and 4-1BBL do not play a strong or dominant role in driving the generation of high frequencies of VACV-specific CD8 T cells. PMID:22037570

  20. Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia.

    PubMed

    Lubeck, Beth A; Lapinski, Philip E; Oliver, Jennifer A; Ksionda, Olga; Parada, Luis F; Zhu, Yuan; Maillard, Ivan; Chiang, Mark; Roose, Jeroen; King, Philip D

    2015-07-01

    Ras GTPase-activating proteins (RasGAPs) inhibit signal transduction initiated through the Ras small GTP-binding protein. However, which members of the RasGAP family act as negative regulators of T cell responses is not completely understood. In this study, we investigated potential roles for the RasGAPs RASA1 and neurofibromin 1 (NF1) in T cells through the generation and analysis of T cell-specific RASA1 and NF1 double-deficient mice. In contrast to mice lacking either RasGAP alone in T cells, double-deficient mice developed T cell acute lymphoblastic leukemia/lymphoma, which originated at an early point in T cell development and was dependent on activating mutations in the Notch1 gene. These findings highlight RASA1 and NF1 as cotumor suppressors in the T cell lineage. PMID:26002977

  1. Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner1

    PubMed Central

    He, Qiuming; Morillon, Y. Maurice; Spidale, Nicholas A.; Kroger, Charles J.; Liu, Bo; Sartor, R. Balfour; Wang, Bo; Tisch, Roland

    2013-01-01

    Inefficient thymic negative selection of self-specific T cells is associated with several autoimmune diseases, including type 1 diabetes (T1D). The factors that influence the efficacy of thymic negative selection, and the kinetics of thymic output of autoreactive T cells remain ill-defined. We investigated thymic production of ? cell-specific T cells using a thymus transplantation model. Thymi from different aged NOD mice representing distinct stages of T1D, were implanted into NOD.scid recipients and the diabetogenicity of the resulting T cell pool examined. Strikingly, the development of diabetes-inducing ? cell-specific CD4+ and CD8+ T cells was regulated in an age-dependent manner. NOD.scid recipients of newborn NOD thymi developed diabetes. However, recipients of thymi from 7 and 10 d-old NOD donor mice remained diabetes-free, and exhibited a progressive decline in islet infiltration and ? cell-specific CD4+ and CD8+ T cells. A similar temporal decrease in autoimmune infiltration was detected in some but not all tissues of recipient mice implanted with thymi from NOD mice lacking expression of the autoimmune regulator transcription factor, which develop multi-organ T cell-mediated autoimmunity. In contrast, recipients of 10 d or older thymi lacked diabetogenic T cells but developed severe colitis marked by increased effector T cells reactive to intestinal microbiota. These results demonstrate that thymic development of autoreactive T cells is limited to a narrow time-window, and occurs in a reciprocal manner compared to colonic microbiota-responsive T cells in NOD mice. PMID:24198282

  2. Gamma delta T cell responses associated with the development of tuberculosis in health care workers.

    PubMed

    Ordway, Diane J; Pinto, Luisa; Costa, Leonor; Martins, Marta; Leandro, Clara; Viveiros, Miguel; Amaral, Leonard; Arroz, Maria J; Ventura, Fernando A; Dockrell, Hazel M

    2005-03-01

    This study evaluated T cell immune responses to purified protein derivative (PPD) and Mycobacterium tuberculosis (Mtb) in health care workers who remained free of active tuberculosis (HCWs w/o TB), health care workers who went on to develop active TB (HCWs w/TB), non-health care workers who were TB free (Non-HCWs) and tuberculosis patients presenting with minimal (Min TB) or advanced (Adv TB) disease. Peripheral blood mononuclear cells (PBMC) were stimulated with Mtb and PPD and the expression of T cell activation markers CD25+ and HLA-DR+, intracellular IL-4 and IFN-gamma production and cytotoxic responses were evaluated. PBMC from HCWs who developed TB showed decreased percentages of cells expressing CD8+CD25+ in comparison to HCWs who remained healthy. HCWs who developed TB showed increased gammadelta TCR+ cell cytotoxicity and decreased CD3+gammadelta TCR- cell cytotoxicity in comparison to HCWs who remained healthy. PBMC from TB patients with advanced disease showed decreased percentages of CD25+CD4+ and CD25+CD8+ T cells that were associated with increased IL-4 production in CD8+ and gammadelta TCR+ phenotypes, in comparison with TB patients presenting minimal disease. TB patients with advanced disease showed increased gammadelta TCR+ cytotoxicity and reduced CD3+gammadelta TCR- cell cytotoxicity. Our results suggest that HCWs who developed TB show an early compensatory mechanism involving an increase in lytic responses of gammadelta TCR+ cells which did not prevent TB. PMID:15708307

  3. Normalization of tumor microenvironment by neem leaf glycoprotein potentiates effector T cell functions and therapeutically intervenes in the growth of mouse sarcoma.

    PubMed

    Barik, Subhasis; Banerjee, Saptak; Mallick, Atanu; Goswami, Kuntal Kanti; Roy, Soumyabrata; Bose, Anamika; Baral, Rathindranath

    2013-01-01

    We have observed restriction of the murine sarcoma growth by therapeutic intervention of neem leaf glycoprotein (NLGP). In order to evaluate the mechanism of tumor growth restriction, here, we have analyzed tumor microenvironment (TME) from sarcoma bearing mice with NLGP therapy (NLGP-TME, in comparison to PBS-TME). Analysis of cytokine milieu within TME revealed IL-10, TGF?, IL-6 rich type 2 characters was switched to type 1 microenvironment with dominance of IFN? secretion within NLGP-TME. Proportion of CD8(+) T cells was increased within NLGP-TME and these T cells were protected from TME-induced anergy by NLGP, as indicated by higher expression of pNFAT and inhibit related downstream signaling. Moreover, low expression of FasR(+) cells within CD8(+) T cell population denotes prevention from activation induced cell death. Using CFSE as a probe, better migration of T cells was noted within TME from NLGP treated mice than PBS cohort. CD8(+) T cells isolated from NLGP-TME exhibited greater cytotoxicity to sarcoma cells in vitro and these cells show higher expression of cytotoxicity related molecules, perforin and granzyme B. Adoptive transfer of NLGP-TME exposed T cells, but not PBS-TME exposed cells in mice, is able to significantly inhibit the growth of sarcoma in vivo. Such tumor growth inhibition by NLGP-TME exposed T cells was not observed when mice were depleted for CD8(+) T cells. Accumulated evidences strongly suggest NLGP mediated normalization of TME allows T cells to perform optimally to inhibit the tumor growth. PMID:23785504

  4. Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice.

    PubMed

    Zhao, Tiejun; Satou, Yorifumi; Matsuoka, Masao

    2014-07-01

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection. PMID:24818712

  5. A Critical Role for Dnmt1 and DNA Methylation in T Cell Development, Function, and Survival

    Microsoft Academic Search

    Peggy P. Lee; David R. Fitzpatrick; Caroline Beard; Heidi K. Jessup; Sophie Lehar; Karen W. Makar; Mercedes Pérez-Melgosa; Marianne T. Sweetser; Mark S. Schlissel; Suzanne Nguyen; Sara R. Cherry; Jeff H. Tsai; Sean M. Tucker; William M. Weaver; Anne Kelso; Rudolf Jaenisch; Christopher B. Wilson

    2001-01-01

    The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre\\/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led

  6. A normal T cell receptor beta CDR3 length distribution in patients with APECED.

    PubMed

    Niemi, Heikki J; Laakso, Sini; Salminen, Jukka T; Arstila, T Petteri; Tuulasvaara, Anni

    2015-06-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the AIRE gene. Murine studies suggest that AIRE controls thymic expression of tissue-restricted antigens, its absence allowing nonselected autoreactive cells to escape. We tested this in humans using the TCR? CDR3 length repertoire as a surrogate of thymic selection, as it shortens during the process. Analysis of healthy thymuses showed an altogether 1.9 base pair shortening, starting at the CD4(+)CD8(+)CD3(low) stage and continuing until the CD4(+) subset, likely encompassing both the positive and negative selection. Comparison of five APECED patients with eight healthy controls showed a skewed repertoire with oligoclonal expansions in the patients' CD4(+) and CD8(+) populations. The average CDR3 length, however, was normal and unaffected by the skewing. This was also true of the hypothesized autoreactive CD8(+)CD45RA(+) population. We failed to detect a subset with an abnormally long CDR3 repertoire, as would be predicted by a failure in selection. PMID:25880100

  7. Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

    PubMed Central

    Lewis, George K.; DeVico, Anthony L.; Gallo, Robert C.

    2014-01-01

    The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibody-mediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4+ T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Env-based AIDS vaccines regardless of the mechanism of antibody-mediated protection. PMID:25349379

  8. Normal Psychosexual Development

    ERIC Educational Resources Information Center

    Rutter, Michael

    1971-01-01

    Normal sexual development is reviewed with respect to physical maturation, sexual interests, sex drive", psychosexual competence and maturity, gender role, object choice, children's concepts of sexual differences, sex role preference and standards, and psychosexual stages. Biologic, psychoanalytic and psychosocial theories are briefly considered.…

  9. Design and Development of Therapies using Chimeric Antigen Receptor-Expressing T cells

    PubMed Central

    Dotti, Gianpietro; Gottschalk, Stephen; Savoldo, Barbara; Brenner, Malcolm K

    2013-01-01

    Summary Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking and effector functions of a T-cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CART cells. Our review then describes our own and other investigators’ work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. PMID:24329793

  10. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development.

    PubMed

    O'Connell, Ryan M; Kahn, Daniel; Gibson, William S J; Round, June L; Scholz, Rebecca L; Chaudhuri, Aadel A; Kahn, Melissa E; Rao, Dinesh S; Baltimore, David

    2010-10-29

    Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory disease. Consistent with a positive role for miR-155 in mediating inflammatory responses, Mir155(-/-) mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4(+) T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders. PMID:20888269

  11. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development

    PubMed Central

    O’Connell, Ryan M.; Kahn, Daniel; Gibson, William S.J.; Round, June L.; Scholz, Rebecca L.; Chaudhuri, Aadel A.; Kahn, Melissa E.; Rao, Dinesh S.; Baltimore, David

    2010-01-01

    Summary Mammalian non-coding micro RNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory disease. Consistent with a positive role for miR-155 in mediating inflammatory responses, Mir155?/? mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4+ T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders. PMID:20888269

  12. Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells

    SciTech Connect

    Sakaguchi, N.; Sakaguchi, S. (Stanford Univ. School of Medicine, CA (United States) Scripps Research Institute, La Jolla, CA (United States) PRESTO, JRDC, Institute of Phical and Chemical Research, Tsukuba, Ibaraki (Japan)); Miyai, K. (Univ. of California, San Diego, LA Jolla, CA (United States))

    1992-11-01

    Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4[sup +] T cells mediated the autoimmune prevention but CD8[sup +] T cells did not. CD4[sup +] T cells also appeared to mediate the TLI-induced autoimmune disease because CD4[sup +] T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs.

  13. The influence of T cell development on pathogen specificity and autoreactivity

    E-print Network

    Kosmrlj, Andrej; Chakraborty, Arup K

    2012-01-01

    T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.

  14. The Influence of T Cell Development on Pathogen Specificity and Autoreactivity

    NASA Astrophysics Data System (ADS)

    Košmrlj, Andrej; Kardar, Mehran; Chakraborty, Arup K.

    2012-10-01

    T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.

  15. Mice reconstituted with DNA polymerase ?-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally

    PubMed Central

    Esposito, Gloria; Texido, Gemma; Betz, Ulrich A. K.; Gu, Hua; Müller, Werner; Klein, Ulf; Rajewsky, Klaus

    2000-01-01

    The ubiquitously expressed, error-prone DNA polymerase ? (pol?) plays a role in base excision repair, and the involvement of this molecule in the nonhomologous end joining (NHEJ) process of DNA repair has recently been demonstrated in yeast. Pol?-deficient mice are not viable, and studies on conditional mutants revealed a competitive disadvantage of pol??/? vs. wild-type cells. We show here that pol?-deficient mice survive up to day 18.5 postcoitum, but die perinatally; a circumstance that allowed the investigation of a potential role of pol? in lymphocyte development by transfer of fetal liver cells (FLC) derived from pol??/? embryos into lethally irradiated hosts. FLC transfers using mutant cells lead to an almost normal reconstitution of the lymphocyte compartment, indicating that pol?-deficiency does not prevent V(D)J recombination, which is known to employ factors of the NHEJ pathway. Mice reconstituted with pol??/? FLC mount a normal T cell-dependent immune response against the hapten (4-hydroxy-3-nitrophenyl) acetyl (NP). Moreover, germinal center B cells from NP-immunized reconstituted mice show normal levels and patterns of somatic point mutations in their rearranged antibody genes, demonstrating that pol? is not critically involved in somatic hypermutation. PMID:10655502

  16. A genome-wide regulatory network identifies key transcription factors for memory CD8[superscript +] T-cell development

    E-print Network

    Hu, Guangan

    Memory CD8[superscript +] T-cell development is defined by the expression of a specific set of memory signature genes. Despite recent progress, many components of the transcriptional control of memory CD8[superscript +] ...

  17. Agonistic Anti-TIGIT Treatment Inhibits T Cell Responses in LDLr Deficient Mice without Affecting Atherosclerotic Lesion Development

    PubMed Central

    Foks, Amanda C.; Ran, Ingrid A.; Frodermann, Vanessa; Bot, Ilze; van Santbrink, Peter J.; Kuiper, Johan; van Puijvelde, Gijs H. M.

    2013-01-01

    Objective Co-stimulatory and co-inhibitory molecules are mainly expressed on T cells and antigen presenting cells and strongly orchestrate adaptive immune responses. Whereas co-stimulatory molecules enhance immune responses, signaling via co-inhibitory molecules dampens the immune system, thereby showing great therapeutic potential to prevent cardiovascular diseases. Signaling via co-inhibitory T cell immunoglobulin and ITIM domain (TIGIT) directly inhibits T cell activation and proliferation, and therefore represents a novel therapeutic candidate to specifically dampen pro-atherogenic T cell reactivity. In the present study, we used an agonistic anti-TIGIT antibody to determine the effect of excessive TIGIT-signaling on atherosclerosis. Methods and Results TIGIT was upregulated on CD4+ T cells isolated from mice fed a Western-type diet in comparison with mice fed a chow diet. Agonistic anti-TIGIT suppressed T cell activation and proliferation both in vitro and in vivo. However, agonistic anti-TIGIT treatment of LDLr?/? mice fed a Western-type diet for 4 or 8 weeks did not affect atherosclerotic lesion development in comparison with PBS and Armenian Hamster IgG treatment. Furthermore, elevated percentages of dendritic cells were observed in the blood and spleen of agonistic anti-TIGIT-treated mice. Additionally, these cells showed an increased activation status but decreased IL-10 production. Conclusions Despite the inhibition of splenic T cell responses, agonistic anti-TIGIT treatment does not affect initial atherosclerosis development, possibly due to increased activity of dendritic cells. PMID:24376654

  18. T Cell Factor-1 Controls the Lifetime of CD4+ CD8+ Thymocytes In Vivo and Distal T Cell Receptor ?-Chain Rearrangement Required for NKT Cell Development

    PubMed Central

    Sen, Jyoti Misra

    2014-01-01

    Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) V?14-J?18 gene. Temporal regulation and late appearance of V?14-J?18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF)-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR V?14-J?18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits V?14-J?18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of ROR?t, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo. PMID:25536344

  19. HIV-1 transgenic rat CD4+ T cells develop decreased CD28 responsiveness and suboptimal Lck tyrosine dephosphorylation following activation

    SciTech Connect

    Yadav, Anjana [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Pati, Shibani [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Nyugen, Anhthu [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Barabitskaja, Oxana [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Mondal, Prosanta [Department of Epidemiology and Prevention, Institute of Human Virology, University of Maryland, Baltimore, MD 21201 (United States); Anderson, Michael [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Gallo, Robert C. [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Huso, David L. [Division of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Reid, William [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States)]. E-mail: reid@umbi.umd.edu

    2006-09-30

    Impaired CD4+ T cell responses, resulting in dysregulated T-helper 1 (Th1) effector and memory responses, are a common result of HIV-1 infection. These defects are often preceded by decreased expression and function of the {alpha}/{beta} T cell receptor (TCR)-CD3 complex and of co-stimulatory molecules including CD28, resulting in altered T cell proliferation, cytokine secretion and cell survival. We have previously shown that HIV Tg rats have defective development of T cell effector function and generation of specific effector/memory T cell subsets. Here we identify abnormalities in activated HIV-1 Tg rat CD4+ T cells that include decreased pY505 dephosphorylation of Lck (required for Lck activation), decreased CD28 function, reduced expression of the anti-apoptotic molecule Bcl-xL, decreased secretion of the mitogenic lympokine interleukin-2 (IL-2) and increased activation induced apoptosis. These events likely lead to defects in antigen-specific signaling and may help explain the disruption of Th1 responses and the generation of specific effector/memory subsets in transgenic CD4+ T cells.

  20. Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages.

    PubMed

    Sellars, MacLean; Huh, Jun R; Day, Kenneth; Issuree, Priya D; Galan, Carolina; Gobeil, Stephane; Absher, Devin; Green, Michael R; Littman, Dan R

    2015-07-01

    During development, progenitor cells with binary potential give rise to daughter cells that have distinct functions. Heritable epigenetic mechanisms then lock in gene-expression programs that define lineage identity. Regulation of the gene encoding the T cell-specific coreceptor CD4 in helper and cytotoxic T cells exemplifies this process, with enhancer- and silencer-regulated establishment of epigenetic memory for stable gene expression and repression, respectively. Using a genetic screen, we identified the DNA-methylation machinery as essential for maintaining silencing of Cd4 in the cytotoxic lineage. Furthermore, we found a requirement for the proximal enhancer in mediating the removal of DNA-methylation marks from Cd4, which allowed stable expression of Cd4 in helper T cells. Our findings suggest that stage-specific methylation and demethylation events in Cd4 regulate its heritable expression in response to the distinct signals that dictate lineage 'choice' during T cell development. PMID:26030024

  1. Osteonecrosis of the Jaw Developed in Mice: DISEASE VARIANTS REGULATED BY ?? T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY.

    PubMed

    Park, Sil; Kanayama, Keiichi; Kaur, Kawaljit; Tseng, Han-Ching Helen; Banankhah, Sina; Quje, Davood Talebi; Sayre, James W; Jewett, Anahid; Nishimura, Ichiro

    2015-07-10

    Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier ?? T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 ?g/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. ?? T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated ?? T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of ?? T cells from human peripheral blood (h-?? T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-?? T cells exhibited rapid expansion and robust IFN-? secretion. When h-?? T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that ?? T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ. PMID:26013832

  2. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas.

    PubMed

    Egen, Jackson G; Rothfuchs, Antonio Gigliotti; Feng, Carl G; Winter, Nathalie; Sher, Alan; Germain, Ronald N

    2008-02-01

    Granulomas play a key role in host protection against mycobacterial pathogens, with their breakdown contributing to exacerbated disease. To better understand the initiation and maintenance of these structures, we employed both high-resolution multiplex static imaging and intravital multiphoton microscopy of Mycobacterium bovis BCG-induced liver granulomas. We found that Kupffer cells directly capture blood-borne bacteria and subsequently nucleate formation of a nascent granuloma by recruiting both uninfected liver-resident macrophages and blood-derived monocytes. Within the mature granuloma, these myeloid cell populations formed a relatively immobile cellular matrix that interacted with a highly dynamic effector T cell population. The efficient recruitment of these T cells was highly dependent on TNF-alpha-derived signals, which also maintained the granuloma structure through preferential effects on uninfected macrophage populations. By characterizing the migration of both innate and adaptive immune cells throughout the process of granuloma development, these studies provide a new perspective on the cellular events involved in mycobacterial containment and escape. PMID:18261937

  3. An islet-homing NOD CD8 +cytotoxic T cell clone recognizes GAD 65and causes insulitis

    Microsoft Academic Search

    Nicoline Videbæk; Silvia Harach; Jenny Phillips; Patricia Hutchings; Patricia Ozegbe; Birgitte K Michelsen; Anne Cooke

    2003-01-01

    T cells play a central role in the development of diabetes both in man and in the non-obese diabetic (NOD) mouse. Both the CD4+and CD8+subsets of T cells are required for the normal development of IDDM in NOD mice. Islet reactive CD4+T cells play a clear pathogenic role as evidenced from the isolation of diabetogenic CD4+T cell clones. CD8+T cells

  4. Molecular mechanisms that control mouse and human TCR-?? and TCR-?? T cell development

    Microsoft Academic Search

    Tom Taghon; Ellen V. Rothenberg

    2008-01-01

    Following specification of hematopoietic precursor cells into the T cell lineage, several developmental options remain available\\u000a to the immature thymocytes. The paradigm is that the outcome of the T cell receptor rearrangements and the corresponding T\\u000a cell receptor signaling events will be predominant to determine the first of these choices: the ?? versus ?? T cell pathways.\\u000a Here, we review

  5. Development and characterization of Histoplasma capsulatum-reactive murine T-cell lines and clones

    NASA Technical Reports Server (NTRS)

    Deepe, George S., Jr.; Smith, James G.; Denman, David; Bullock, Ward E.; Sonnenfeld, Gerald

    1986-01-01

    Several Histoplasma capsulatum-reactive murine cloned T-cell lines (TCLs) were isolated from spleens of C57BL/6 mice immunized with viable H. capsulatum yeast cells, using the methodology of Kimoto and Fathman (1980). These T-cells were characterized phenotypically as Thy-1.2(+) Lyt-1(+) L3T4(+) Lyt-2(-), that is, as the helper/inducer phenotype. The cloned T cells proliferate in response to histoplasmin and, in some cases, to heterologous fungal anigens. Upon injection of mice with the antigen, the T-cells mediate local delayed-type hypersensitivity responses and, after stimulation, release regulatory lymphokines.

  6. Engineered T Cells Targeting Tumor-Specific Mutations

    Cancer.gov

    Scientists at the National Cancer Institute's Surgery Branch have developed a method to identify and generate T-cell receptor (TCR) engineered T- cells for personalized cancer therapy. The TCR is a complex of integral membrane proteins that recognizes antigens and activates T cells. Human cancers contain genetic mutations that are unique in each patient. The researchers found cancer-specific mutations by sequencing tumors and comparing with normal cells.

  7. The Recognition of Hypothalamo-Neurohypophysial Functions by Developing T Cells

    PubMed Central

    Martens, H.; Cormann, N.; Benhida, A.; Schoenen, J.; Geenen, V.

    1992-01-01

    Neuropeptide signals and specific neuropeptide receptors have been described in the thymus supporting the concept of a close dialogue between the neuroendocrine and the immune systems at the level of early T-cell differentiation. In this paper, we review recent data about neurohypophysial (NHP)-related peptides detected in the thymus from different species. We suggest that we are dealing in fact with other member(s) of the NHP hormone family, which seems to exert its activity locally through a novel model of cell-to-cell signaling, that of cryptocrine communication. This model involves exchange of signals between thymic epithelial cells and developing thymocytes. The NHP-related peptides have been shown to trigger thymocyte proliferation and could induce immune tolerance of this highly conserved neuroendocrine family. PMID:1322752

  8. T Cell-Mediated Maintenance of Natural Self-Tolerance: its Breakdown as a Possible Cause of Various Autoimmune Diseases

    Microsoft Academic Search

    Shimon Sakaguchi; Masaaki Toda; Masanao Asano; Misako Itoh; Stephen S. Morse; Noriko Sakaguchi

    1996-01-01

    This paper shows that elimination of a small subpopulation of peripheral T cells can elicit activation\\/expansion of self-reactive T cells from the remaining T cells and produce a wide spectrum of organ-specific and systemic auto-immune diseases in normal mice; reconstitution of the eliminated T-cell population prevents autoimmune development. This regulatory T-cell population expresses the CD25 molecule, apparently includes ‘activated’ T

  9. Antigen-Bearing Dendritic Cells Regulate the Diverse Pattern of Memory CD8 T Cell Development in Different Tissues

    E-print Network

    Shen, Ching-Hung

    Memory T cells of the effector type (TEM) account for the characteristic rapidity of memory T-cell responses, whereas memory T cells of the central type (TCM) account for long-lasting, vigorously proliferating memory T-cell ...

  10. Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help

    NASA Astrophysics Data System (ADS)

    Sun, Joseph C.; Bevan, Michael J.

    2003-04-01

    The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.

  11. The T cell antigen receptor complex expressed on normal peripheral blood CD4-, CD8- T lymphocytes. A CD3-associated disulfide-linked gamma chain heterodimer

    PubMed Central

    1987-01-01

    IL-2-dependent cell lines were established from normal peripheral blood T lymphocytes that express neither CD4 nor CD8 differentiation antigens. CD3+,4-,8- cell lines from 15 different donors failed to react with WT31, an mAb directed against the T cell antigen receptor alpha/beta heterodimer. Anti-Leu-4 mAb was used to isolate the CD3/T cell antigen receptor complex from 125I-labeled CD3+,4-,8- (WT31-) T cells. Using detergent conditions that preserved the CD3/T cell antigen receptor complex, an approximately 90 kD disulfide-linked heterodimer, composed of approximately 45- and approximately 40- (or approximately 37-) kD subunits, was coimmunoprecipitated with the invariant 20-29-kD CD3 complex. Analysis of these components by nonequilibrium pH gradient electrophoresis indicated that the approximately 40-kD and approximately 37-kD subunits were similar, and quite distinct from the more basic approximately 45-kD subunit. None of these three subunits reacted with an antibody directed against a beta chain framework epitope. Heteroantiserum against a T cell receptor gamma chain peptide specifically reacted with both the approximately 37- and approximately 40-kD CD3-associated proteins, but not with the approximately 45-kD subunit. CD3+,4-,8- cells failed to transcribe substantial amounts of functional 1.3-kb beta or 1.6-kb alpha mRNA, but produced abundant 1.6- kb gamma mRNA. Southern blot analysis revealed that these CD3+,4-,8- cell lines rearranged both gamma and beta genes, and indicated that the populations were polyclonal. The expression of a CD3-associated disulfide-linked heterodimer on CD3+,4-,8- T cell lines established from normal, adult peripheral blood contrasts with prior reports describing a CD3-associated non-disulfide-linked heterodimer on CD3+/WT31- cell lines established from thymus and peripheral blood obtained from patients with immunodeficiency diseases. We propose that this discrepancy may be explained by preferential usage of the two C gamma genes in T lymphocytes. PMID:2435832

  12. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus.

    PubMed

    Zhang, Xiaoming; Mozeleski, Brian; Lemoine, Sebastien; Dériaud, Edith; Lim, Annick; Zhivaki, Dania; Azria, Elie; Le Ray, Camille; Roguet, Gwenaelle; Launay, Odile; Vanet, Anne; Leclerc, Claude; Lo-Man, Richard

    2014-05-28

    The T cell compartment is considered to be naïve and dedicated to the development of tolerance during fetal development. We have identified and characterized a population of fetally developed CD4 T cells with an effector memory phenotype (TEM), which are present in cord blood. This population is polyclonal and has phenotypic features similar to those of conventional adult memory T cells, such as CD45RO expression. These cells express low levels of CD25 but are distinct from regulatory T cells because they lack Foxp3 expression. After T cell receptor activation, neonatal TEM cells readily produced tumor necrosis factor-? (TNF-?) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We also detected interferon-? (IFN-?)-producing T helper 1 (TH1) cells and interleukin-4 (IL-4)/IL-13-producing TH2-like cells, but not IL-17-producing cells. We used chemokine receptor expression patterns to divide this TEM population into different subsets and identified distinct transcriptional programs using whole-genome microarray analysis. IFN-? was found in CXCR3(+) TEM cells, whereas IL-4 was found in both CXCR3(+) TEM cells and CCR4(+) TEM cells. CCR6(+) TEM cells displayed a genetic signature that corresponded to TH17 cells but failed to produce IL-17A. However, the TH17 function of TEM cells was observed in the presence of IL-1? and IL-23. In summary, in the absence of reported pathology or any major infectious history, T cells with a memory-like phenotype develop in an environment thought to be sterile during fetal development and display a large variety of inflammatory effector functions associated with CD4 TH cells at birth. PMID:24871133

  13. Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes

    PubMed Central

    1992-01-01

    We demonstrate that mouse intestinal intraepithelial lymphocytes (IEL) can be divided into subsets based on the differential expression of functional T cell receptor alpha/beta (TCR-alpha/beta) signaling complexes. Two subsets, CD4+ 8 alpha + beta - and CD8 alpha + beta -, are refractory to stimulation with anti-TCR-alpha/beta and contain high frequencies of potentially self-reactive cells. In contrast, the CD4+ and CD8 alpha + beta + IEL subsets are responsive to anti-TCR- alpha/beta and depleted of potentially self-reactive cells. The analysis of fetal liver radiation chimeras using adult thymectomized recipients demonstrates that the four TCR-alpha/beta + IEL subsets are generated in normal numbers in the absence of the thymus. Moreover, expression of the major histocompatibility complex class II-encoded I-E molecule and Mls1a in the gut of the athymic host results in the negative selection of potentially self-reactive T cells expressing V beta 11 and V beta 6, respectively, from those IEL subsets that express functional TCR-alpha/beta signaling complexes. Neither the spleen nor the Peyer's patches of athymic recipients contain T cells of donor origin. In contrast, normal numbers of phenotypically and functionally mature CD4+ and CD8 alpha + beta + T cells of donor origin are found in the lamina propria of chimeric animals. The phenotypic analysis of lymphocytes obtained from Ly5 congenic parabionts reveals that peripheral T cells migrate rapidly to the Peyer's patches and lamina propria, but not to the intestinal epithelium. Taken together, these results demonstrate that the intestinal epithelium is a thymus- independent site of T lymphopoiesis, where selection of the T cell repertoire involves the deletion of potentially self-reactive cells in situ. Moreover, the appearance of donor-derived, phenotypically mature T cells, exclusively in the lamina propria of athymic radiation chimeras, suggests that mature IEL expressing functional TCR-alpha/beta migrate to this site. PMID:1535367

  14. Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells.

    PubMed

    Huijskens, Mirelle J A J; Walczak, Mateusz; Koller, Nicole; Briedé, Jacob J; Senden-Gijsbers, Birgit L M G; Schnijderberg, Melanie C; Bos, Gerard M J; Germeraad, Wilfred T V

    2014-12-01

    The efficacy of donor HSCT is partly reduced as a result of slow post-transplantation immune recovery. In particular, T cell regeneration is generally delayed, resulting in high infection-related mortality in the first years post-transplantation. Adoptive transfer of in vitro-generated human T cell progenitors seems a promising approach to accelerate T cell recovery in immunocompromised patients. AA may enhance T cell proliferation and differentiation in a controlled, feeder-free environment containing Notch ligands and defined growth factors. Our experiments show a pivotal role for AA during human in vitro T cell development. The blocking of NOS diminished this effect, indicating a role for the citrulline/NO cycle. AA promotes the transition of proT1 to proT2 cells and of preT to DP T cells. Furthermore, the addition of AA to feeder cocultures resulted in development of DP and SP T cells, whereas without AA, a preT cell-stage arrest occurred. We conclude that neither DLL4-expressing feeder cells nor feeder cell conditioned media are required for generating DP T cells from CB and G-CSF-mobilized HSCs and that generation and proliferation of proT and DP T cells are greatly improved by AA. This technology could potentially be used to generate T cell progenitors for adoptive therapy. PMID:25157026

  15. Iron Prevents the Development of Experimental Cerebral Malaria by Attenuating CXCR3-Mediated T Cell Chemotaxis

    PubMed Central

    Van Den Ham, Kristin M.; Shio, Marina Tiemi; Rainone, Anthony; Fournier, Sylvie; Krawczyk, Connie M.; Olivier, Martin

    2015-01-01

    Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFN?-responsiveness, as indicated by mitigated expression of IFN?R2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain. PMID:25768944

  16. Dermal ?? T cells - What have we learned?

    PubMed

    O'Brien, Rebecca L; Born, Willi K

    2015-07-01

    Over the last several years, a number of papers have called attention to a distinct population of ?? T cells preferentially found in the dermis of the skin of normal mice. These cells appear to play an important role in promoting the development of psoriasis, but also are critical for host resistance to particular pathogens. They are characterized by the expression of a limited subset of ?? T cell receptors and a strong propensity to secrete IL-17. Perhaps most importantly, humans appear to carry an equivalent dermal ?? T cell population, likewise biased to secrete IL-17 and also implicated as playing a pathogenic role in psoriasis. This review will attempt to summarize and reconcile recent findings concerning the dermal ?? T cells. PMID:25649119

  17. Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.

    PubMed

    Wu, Xuesong; Schulte, Brian C; Zhou, Youwen; Haribhai, Dipica; Mackinnon, Alexander C; Plaza, Jose A; Williams, Calvin B; Hwang, Sam T

    2014-11-01

    Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL. PMID:24780929

  18. Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling.

    PubMed

    Epron, G; Ame-Thomas, P; Le Priol, J; Pangault, C; Dulong, J; Lamy, T; Fest, T; Tarte, K

    2012-01-01

    Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease. PMID:21788945

  19. Insufficient TLR Activation Contributes to the Slow Development of CD8 T Cell Responses in Trypanosoma cruzi

    E-print Network

    in Trypanosoma cruzi Infection1 Angel M. Padilla,* Laura J. Simpson,* and Rick L. Tarleton2 * During experimental infection with Trypanosoma cruzi, mice develop a strong CD8 T cell response focused mainly on a few. cruzi. The Journal of Immunology, 2009, 183: 1245­1252. T he protozoan Trypanosoma cruzi

  20. Depression of T-cell function and normality of B-cell response in protein calorie malnutrition.

    PubMed Central

    Narayanan, R B; Nath, I; Bhuyan, U N; Talwar, G P

    1977-01-01

    Antibody response to a T-cell dependent antigen, sheep erythrocytes and to a B-cell mitogen, purified lipopolysaccharide (LPS), has been studied in mice kept on protein deficient (2 and 4 per cent casein) diets. The number of plaque-forming cells (PFC) to SRBC were 20-5 +/- 7-7 per million spleen cells in protein-deficient animals compared to 261-0 +/- 31-1 in parallel controls maintained on a protein rich diet (18 per cent casein). No difference was observed in number of PFC formed in controls and deficient animals to LPS, values were 161-4 +/- 19-7, 158-5 +/- 14-2, & 162-3 +/- 31-9 in control (18 per cent casein) and deficient groups (4 per cent and 2 per cent casein) respectively. The delayed hypersensitivity skin reaction to SRBC measured in foot pads was significantly lower in mice on 4 per cent casein diet compared to controls. These studies suggest that the effect of protein deficiency is primarily on T-cell function and not on the B-cell response; PMID:403130

  1. Normal psychomotor development.

    PubMed

    Cioni, Giovanni; Sgandurra, Giuseppina

    2013-01-01

    "Psychomotor" development refers to changes in a child's cognitive, emotional, motor, and social capacities from the beginning of life throughout fetal and neonatal periods, infancy, childhood, and adolescence. It occurs in a variety of domains and a wide range of theories makes understanding children's development a challenging undertaking. Different models have tried to interpret the origins of human behavior, the pattern of developmental changes over time, and the individual and contextual factors that could direct child development. No single theory has been able to account for all aspects of child development, but each of them may contribute an important piece to the child development puzzle. Although theories sometimes disagree, much of their information is complementary rather than contradictory. The knowledge of child typical development and related theories and models is greatly useful for clinical practice, leading to recognition of developmental disorders and the ways in which they can be approached and treated. In this chapter, traditional and more modern concepts around functional development of psychomotor abilities are reported, firstly more in general and then specifically in the motor domain. PMID:23622146

  2. Normal Distribution of CD8+ T-Cell-Derived ELISPOT Counts within Replicates Justifies the Reliance on Parametric Statistics for Identifying Positive Responses

    PubMed Central

    Karulin, Alexey Y.; Caspell, Richard; Dittrich, Marcus; Lehmann, Paul V.

    2015-01-01

    Accurate assessment of positive ELISPOT responses for low frequencies of antigen-specific T-cells is controversial. In particular, it is still unknown whether ELISPOT counts within replicate wells follow a theoretical distribution function, and thus whether high power parametric statistics can be used to discriminate between positive and negative wells. We studied experimental distributions of spot counts for up to 120 replicate wells of IFN-? production by CD8+ T-cell responding to EBV LMP2A (426 – 434) peptide in human PBMC. The cells were tested in serial dilutions covering a wide range of average spot counts per condition, from just a few to hundreds of spots per well. Statistical analysis of the data using diagnostic Q-Q plots and the Shapiro-Wilk normality test showed that in the entire dynamic range of ELISPOT spot counts within replicate wells followed a normal distribution. This result implies that the Student t-Test and ANOVA are suited to identify positive responses. We also show experimentally that borderline responses can be reliably detected by involving more replicate wells, plating higher numbers of PBMC, addition of IL-7, or a combination of these. Furthermore, we have experimentally verified that the number of replicates needed for detection of weak responses can be calculated using parametric statistics. PMID:25738924

  3. Development of a Model System for Tick-Borne Flavivirus Persistence in HEK 293T Cells

    PubMed Central

    Mlera, Luwanika; Offerdahl, Danielle K.; Martens, Craig; Porcella, Stephen F.; Melik, Wessam

    2015-01-01

    ABSTRACT We devised a model system to study persistent infection by the tick-borne flavivirus Langat virus (LGTV) in 293T cells. Infection with a molecularly cloned LGTV strain produced an acute lytic crisis that left few surviving cells. The culture was repopulated by cells that were ~90% positive for LGTV E protein, thus initiating a persistent infection that was maintained for at least 35 weeks without additional lytic crises. Staining of cells for viral proteins and ultrastructural analysis revealed only minor differences from the acute phase of infection. Infectious LGTV decreased markedly over the study period, but the number of viral genomes remained relatively constant, suggesting the development of defective interfering particles (DIPs). Viral genome changes were investigated by RNA deep sequencing. At the initiation of persistent infection, levels of DIPs were below the limit of detection at a coverage depth of 11,288-fold, implying that DIPs are not required for initiation of persistence. However, after 15 passages, DIPs constituted approximately 34% of the total LGTV population (coverage of 1,293-fold). Furthermore, at this point, one specific DIP population predominated in which nucleotides 1058 to 2881 had been deleted. This defective genome specified an intact polyprotein that coded for a truncated fusion protein containing 28 N-terminal residues of E and 134 C-terminal residues of NS1. Such a fusion protein has not previously been described, and a possible function in persistent infection is uncertain. DIPs are not required for the initiation of persistent LGTV infection but may play a role in the maintenance of viral persistence. PMID:26045539

  4. Early Development in the Peritoneal Cavity of CD49dhigh Th1 Memory Phenotype CD4+ T Cells with Enhanced B Cell Helper Activity.

    PubMed

    Moon, Hana; Park, Chanho; Lee, Jae-Ghi; Shin, Sang Hyuck; Lee, Joo Hee; Kho, Inseong; Kang, KyeongJin; Cha, Hoon-Suk; Kim, Tae Jin

    2015-07-15

    The Th cells that regulate peritoneal B-1 cell functions have not yet been well characterized. To address this question, we investigated peritoneal CD4(+) T cells, observed a high frequency of the conjugates of B-CD4(+) T cells in the peritoneal cavity, and identified a population of CD49d(high)CD4(+) T cells that constituted about half of all CD4(+) T cells in the peritoneal cavity, but were rarely found in other compartments. Peritoneal CD49d(high)CD4(+) T cells were CD44(high)CD62L(low); expressed integrin ?4?1 and CXCR3; and rapidly secreted IFN-?, TNF-?, and IL-2, showing features of proinflammatory Th1 cells. Peritoneal CD49d(high)CD4(+) T cells developed spontaneously, were detected at the age of 12 d, and showed stem cell-like properties. Their development was observed in mice deficient for signaling lymphocytic activation molecule-associated protein, but not in athymic nude mice and mice lacking in expression of MHC class II on thymic epithelial cells. Peritoneal CD49d(high)CD4(+) T cells were more resistant to irradiation and more sensitive to NAD-induced cell death than CD49d(low)CD4(+) T cells. Notably, peritoneal CD49d(high)CD4(+) T cells also showed some characteristics of follicular Th cells, such as the expression of programmed cell death 1, ICOS, IL-21, and CXCR5. Moreover, peritoneal CD49d(high)CD4(+) T cells enhanced the secretion of IgM Abs by B-1a cells and IgG Abs by splenic B cells. These data suggest that peritoneal CD49d(high)CD4(+) T cells may be innate-like CD4(+) T cells, which develop early and have a dual capacity to support both humoral and cellular immunity. PMID:26056253

  5. The Nuclear Effector of Wnt-Signaling, Tcf1, Functions as a T-Cell–Specific Tumor Suppressor for Development of Lymphomas

    PubMed Central

    Tiemessen, Machteld M.; Baert, Miranda R. M.; Schonewille, Tom; Brugman, Martijn H.; Famili, Farbod; Salvatori, Daniela C. F.; Meijerink, Jules P. P.; Ozbek, Ugur; Clevers, Hans; van Dongen, Jacques J. M.; Staal, Frank J. T.

    2012-01-01

    The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1?/? mice have previously been characterized and show developmental blocks at the CD4?CD8? double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1?/? mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1?/? mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell–specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus. PMID:23185135

  6. CD4+ T Cells and IFN-? Are Required for the Development of Pneumocystis-Associated Pulmonary Hypertension

    PubMed Central

    Swain, Steve D.; Siemsen, Dan W.; Pullen, Rebecca R.; Han, Soo

    2015-01-01

    Pulmonary hypertension (PH) is a disease of diverse etiology. Although primary PH can develop in the absence of prior disease, PH more commonly develops in conjunction with other pulmonary pathologies. We previously reported a mouse model in which PH occurs as a sequela of Pneumocystis infection in the context of transient CD4 depletion. Here, we report that instead of the expected Th2 pathways, the Th1 cytokine IFN-? is essential for the development of PH, as wild-type mice developed PH but IFN-? knockout mice did not. Because gene expression analysis showed few strain differences that were not immune-function related, we focused on those responses as potential pathologic mechanisms. In addition to dependence on IFN-?, we found that when CD4 cells were continuously depleted, but infection was limited by antibiotic treatment, PH did not occur, confirming that CD4 T cells are required for PH development. Also, although CD8 T-cells are implicated in the pathology of Pneumocystis pneumonia, they did not have a role in the onset of PH. Finally, we found differences in immune cell phenotypes that correlated with PH, including elevated CD204 expression in lung CD11c+ cells, but their role remains unclear. Overall, we demonstrate that a transient, localized, immune response requiring IFN-? and CD4-T cells can disrupt pulmonary vascular function and promote lingering PH. PMID:24361497

  7. Exclusive Development of T cell Neoplasms in Mice Transplanted with Bone Marrow Expressing Activated Notch Alleles

    Microsoft Academic Search

    Warren S. Pear; Jon C. Aster; Martin L. Scott; Robert E Hasserjian; Benny Softer; Jeffrey Sklar; David Baltimore

    1996-01-01

    Summary Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leu- kemias\\/lymphomas containing a t(7;9) chromosomal translocation; however, its role in onco- genesis has been unclear.

  8. The orphan nuclear receptor Ear-2 (Nr2f6) is a novel negative regulator of T cell development.

    PubMed

    Ichim, Christine V; Dervovi?, Džana D; Zúñiga-Pflücker, Juan Carlos; Wells, Richard A

    2014-01-01

    We describe a novel role for the orphan nuclear receptor Ear-2 in regulating T cell development. Retrovirus-mediated overexpression of Ear-2 (EAR-2++) in a bone marrow (BM) transplantation assay resulted in limited T cell development and a greater than tenfold decrease in thymus size and cellularity relative to controls. Ear-2-transduced murine BM hematopoietic stem cells (HSCs) in OP9-DL1 cultures showed a proliferation deficit during days 1-5 after induction of differentiation, which corresponded to increased expression of the cell cycle regulators p21 (cdkn1a) and p27 (cdkn1b), as well as increased expression of Hes1, Notch3, Egr1, and Scl (Tal1) and decreased expression of Gli1, Gfi-1, HoxA9, PU.1, Nrarp, and Tcf1. In addition, there was a block in differentiation at the DN4 to double-positive (DP) transition accompanied by an increase in apoptosis, similar to the deficit seen in the ROR?t null mouse. Gene expression profiling revealed that, like the ROR?t-deficient mouse, EAR-2++ DP cells had decreased expression of BclXL and increased expression of the proapoptosis gene Bad. In addition, EAR-2++ DP cells had decreased expression of Bcl11b, PU.1, and HoxA9, and increased expression of Id2. Based on these findings, we conclude that EAR-2++ cells were able to migrate to, but not fully repopulate, the thymus because of a cell-intrinsic defect in the proliferation of DN1 cells followed by a block in differentiation from the DN4 to DP stage of T cell development. We conclude that Ear-2 is a novel negative regulator of T-cell development and that downregulation of Ear-2 is indispensable for the proliferation of DN1 cells and the survival of DN4-DP cells. PMID:24096122

  9. Spontaneous Intestinal Tumorigenesis in Apc/Min+ Mice Requires Altered T Cell Development with IL-17A

    PubMed Central

    Chae, Wook-Jin; Bothwell, Alfred L. M.

    2015-01-01

    The control of inflammatory diseases requires functional regulatory T cells (Tregs) with significant Gata-3 expression. Here we address the inhibitory role of Tregs on intestinal tumorigenesis in the Apc/Min+ mouse model that resembles human familial adenomatous polyposis (FAP). Apc/Min+ mice had a markedly increased frequency of Foxp3+ Tregs and yet decreased Gata-3 expression in the lamina propria. To address the role of heterozygous Apc gene mutation in Tregs, we generated Foxp3-Cre, Apcflox/+ mice. Tregs from these mice effectively inhibited tumorigenesis comparable to wild type Tregs after adoptive transfer into Apc/Min+ mice, demonstrating that the heterozygous Apc gene mutation in Tregs does not induce the loss of control over tumor microenvironment. Adoptive transfer of in vitro generated Apc/Min+ iTregs (inducible Tregs) failed to inhibit intestinal tumorigenesis, suggesting that naïve CD4 T cells generated from Apc/Min+ mice thymus were impaired. We also showed that adoptively transferred IL-17A-deficient Apc/Min+ Tregs inhibited tumor growth, suggesting that IL-17A was critical to impair the tumor regression function of Apc/Min+ Tregs. Taken together, our results suggest that both T cell development in a functional thymus and IL-17A control the ability of Treg to inhibit intestinal tumorigenesis in Apc/Min+ mice. PMID:26146642

  10. Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.

    PubMed

    Ji, Hong; Rintelen, Felix; Waltzinger, Caroline; Bertschy Meier, Dominique; Bilancio, Antonio; Pearce, Wayne; Hirsch, Emilio; Wymann, Matthias P; Rückle, Thomas; Camps, Montserrat; Vanhaesebroeck, Bart; Okkenhaug, Klaus; Rommel, Christian

    2007-10-15

    Mice lacking both the p110gamma and p110delta isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110gamma-/-/p110delta(D910A/D910A) (p110gamma(KO)delta(D910A)) mice where the p110delta isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110gammadelta deficiency, which include profound T-cell lymphopenia, T-cell and eosinophil infiltration of mucosal organs, elevated IgE levels, and a skewing toward Th2 immune responses. Using small-molecule selective inhibitors, we demonstrated that in mature T cells, p110delta, but not p110gamma, controls Th1 and Th2 cytokine secretion. Thus, the pathology in the p110gammadelta-deficient mice is likely to be secondary to a developmental block in the thymus that leads to lymphopenia-associated inflammatory responses. PMID:17626838

  11. E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation.

    PubMed

    Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Guo, Hui; Shen, Huifeng; Li, Zhenping; Solway, Julian; Tao, Enxiang; Chiang, Y Jeffrey; Lipkowitz, Stanley; Penninger, Josef M; Langdon, Wallace Y; Zhang, Jian

    2014-02-27

    E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb(-/-) mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. PMID:24508458

  12. E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

    PubMed Central

    Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Guo, Hui; Shen, Huifeng; Li, Zhenping; Solway, Julian; Tao, Enxiang; Chiang, Y. Jeffrey; Lipkowitz, Stanley; Penninger, Josef M.; Langdon, Wallace Y.; Zhang, Jian

    2014-01-01

    SUMMARY E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/ CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb?/? mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. PMID:24508458

  13. Development of a luciferase based viral inhibition assay to evaluate vaccine induced CD8 T-cell responses

    PubMed Central

    Naarding, Marloes A.; Fernandez-Fernandez, Natalia; Kappes, John C.; Hayes, Peter; Ahmed, Tina; Icyuz, Mert; Edmonds, Tara G.; Bergin, Philip; Anzala, Omu; Hanke, Tomas; Clark, Lorna; Cox, Josephine H.; Cormier, Emmanuel; Ochsenbauer, Christina; Gilmour, Jill

    2014-01-01

    Emergence of SIV and HIV specific CD8 T cells has been shown to correlate with control of in vivo replication. Poor correlation between IFN-? ELISPOT responses and in vivo control of the virus has triggered the development of more relevant assays to assess functional HIV-1 specific CD8 T-cell responses for the evaluation and prioritization of new HIV-1 vaccine candidates. We previously established a viral inhibition assay (VIA) that measures the ability of vaccine-induced CD8 T-cell responses to inhibit viral replication in autologous CD4 T cells. In this assay, viral replication is determined by measuring p24 in the culture supernatant. Here we describe the development of a novel VIA, referred to as IMC LucR VIA that exploits replication-competent HIV-1 infectious molecular clones (IMCs) in which the complete proviral genome is strain-specific and which express the Renilla luciferase (LucR) gene to determine viral growth and inhibition. The introduction of the luciferase readout does provide significant improvement of the read out time. In addition to switching to the LucR read out, changes made to the overall protocol resulted in the miniaturization of the assay from a 48 to a 96-well plate format, which preserved sample and allowed for the introduction of replicates. The overall assay time was reduced from 13 to 8 days. The assay has a high degree of specificity, and the previously observed non-specific background inhibition in cells from HIV-1 negative volunteers has been reduced dramatically. Importantly, we observed an increase in positive responses, indicating an improvement in sensitivity compared to the original VIA. Currently, only a limited number of “whole-genome” IMC-LucR viruses are available and our efforts will focus on expanding the panel to better evaluate anti-viral breadth. Overall, we believe the IMC LucR VIA provides a platform to assess functional CD8 T-cell responses in large-scale clinical trial testing, which will enhance the ability to select the most promising HIV-1 vaccine candidates capable of controlling HIV-1 replication in vivo. PMID:24291126

  14. Differential regulation of the tumor suppressor molecules, retinoblastoma susceptibility gene product (Rb) and p53, during cell cycle progression of normal human T cells.

    PubMed

    Terada, N; Lucas, J J; Gelfand, E W

    1991-07-15

    We have activated resting human T lymphocytes to study the roles of the putative cell cycle control gene products, retinoblastoma susceptibility gene product (Rb) and p53, in regulating cell proliferation. After stimulation with phorbol, 12,13, dibutyrate and the calcium ionophore, ionomycin, which triggers a rapid entry of cells into G1 phase, we demonstrated Rb phosphorylation 24 h later, well before the onset of DNA synthesis. This finding, in contrast to reports using proliferating cell lines, implies that Rb phosphorylation is not a proximal event regulating the G1 to S transition. The production of p53 became detectable 3 to 6 h after addition of phorbol, 12,13,-dibutyrate and ionomycin, and peaked at 30 to 42 h. To further delineate the relationship of the synthesis and metabolism of the proteins to cell cycle progression, we used three agents to arrest progression of activated T cells at various points in the cell cycle. Aphidicolin arrested the cells at the G1/S boundary, whereas deferoxamine, an iron chelator, arrested the cells at an earlier stage of the cell cycle. Cyclosporin A blocked T cell activation at the earliest point in the cell cycle. In the presence of aphidicolin, Rb phosphorylation and p53 production proceeded normally whereas cyclosporin A inhibited both events. Although deferoxamine completely prevented Rb phosphorylation, p53 production was unaffected, suggesting a differential regulation of the two molecules. Our results place Rb phosphorylation and p53 production in the hierarchy of genetic events that are thought to regulate T lymphocyte progression through the cell cycle. PMID:1906503

  15. New developments in the treatment of peripheral T-cell lymphoma – role of Belinostat

    PubMed Central

    Reimer, Peter

    2015-01-01

    Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of rare malignancies that with the exception of anaplastic lymphoma kinase expressing anaplastic large cell lymphoma, share a poor outcome after standard (eg, anthracycline-based) chemotherapy. Most patients are either refractory to initial therapy or eventually relapse. Randomized studies for relapsed/refractory PTCL are not available, however, recently published data show that conventional chemotherapy has very limited efficacy in the salvage setting. Thus, novel drugs are urgently needed to improve the outcome in this setting. Belinostat, a pan-histone deacetylase inhibitor, has demonstrated meaningful efficacy and a favorable toxicity profile in two single-arm Phase II trials on 153 patients with relapsed/refractory PTCL. The conclusive results led to an accelerated approval by the US Food and Drug Administration. The present review summarizes the clinical data available for belinostat, its current role, and future perspectives.

  16. ERK1-Deficient Mice Show Normal T Cell Effector Function and Are Highly Susceptible to Experimental Autoimmune

    E-print Network

    oligodendrocyte glycoprotein peptide 35­55 and to the prototypic foreign Ag OVA are not impaired as compared- myelitis induced with myelin oligodendrocyte glycoprotein peptide 35­55. Finally, thymocyte development to the prototypic foreign Ag OVA and the self Ag myelin oligodendrocyte glycoprotein (MOG)3 35­55 in ERK1-de

  17. Characterization and Development of T-Cell Immune Responses in B-Cell-Deficient (Igh-6?/?) Mice with Salmonella enterica Serovar TyphimuriumInfection

    PubMed Central

    Ugrinovic, Sanja; Ménager, Nathalie; Goh, Natalie; Mastroeni, Pietro

    2003-01-01

    Infection of mice with Salmonella enterica serovar Typhimurium induces strong Th1 T-cell responses that are central to the control of the infection. In the present study, we examined the role of B cells in the development of Th1 T-cell responses to Salmonella by using gene-targeted B-cell-deficient mice (Igh-6?/? mice). The development of Th1 T-cell responses in Igh-6?/? mice was impaired in the early stage of a primary infection. This impairment persisted throughout the course of the disease. The ability of T cells to produce the Th1 cytokine gamma interferon and the frequency at which they did so were lower in Igh-6?/? mice than in control mice. We also observed a transient switch toward Th2 cytokine production in Igh-6?/? mice. Thus, B cells are important for the induction of protective Th1 T-cell responses in the early phase of a Salmonella infection. Activated B cells express high levels of major histocompatibility complex and costimulatory molecules and are nearly as effective as dendritic cells in their antigen-presenting cell (APC) activity. However, their importance as APCs in infection and their role in initiating and/or maintaining T-cell responses are unknown. Here, we show that B cells upregulate costimulatory molecules upon in vitro stimulation with S. enterica serovar Typhimurium and that they can present Salmonella antigens to Salmonella-specific CD4+ T cells. Our results show that B cells are important for the development of T-cell responses in the early stage of a Salmonella infection and that this property may be due to their ability to present antigens to T cells. PMID:14638767

  18. Gut microbiota and lipopolysaccharide content of the diet influence development of regulatory T cells: studies in germ-free mice

    PubMed Central

    Hrncir, Tomas; Stepankova, Renata; Kozakova, Hana; Hudcovic, Tomas; Tlaskalova-Hogenova, Helena

    2008-01-01

    Background Mammals are essentially born germ-free but the epithelial surfaces are promptly colonized by astounding numbers of bacteria soon after birth. The most extensive microbial community is harbored by the distal intestine. The gut microbiota outnumber ~10 times the total number of our somatic and germ cells. The host-microbiota relationship has evolved to become mutually beneficial. Studies in germ-free mice have shown that gut microbiota play a crucial role in the development of the immune system. The principal aim of the present study was to elucidate whether the presence of gut microbiota and the quality of a sterile diet containing various amounts of bacterial contaminants, measured by lipopolysaccharide (LPS) content, can influence maturation of the immune system in gnotobiotic mice. Results We have found that the presence of gut microbiota and to a lesser extent also the LPS-rich sterile diet drive the expansion of B and T cells in Peyer's patches and mesenteric lymph nodes. The most prominent was the expansion of CD4+ T cells including Foxp3-expressing T cells in mesenteric lymph nodes. Further, we have observed that both the presence of gut microbiota and the LPS-rich sterile diet influence in vitro cytokine profile of spleen cells. Both gut microbiota and LPS-rich diet increase the production of interleukin-12 and decrease the production of interleukin-4. In addition, the presence of gut microbiota increases the production of interleukin-10 and interferon-?. Conclusion Our data clearly show that not only live gut microbiota but also microbial components (LPS) contained in sterile diet stimulate the development, expansion and function of the immune system. Finally, we would like to emphasize that the composition of diet should be regularly tested especially in all gnotobiotic models as the LPS content and other microbial components present in the diet may significantly alter the outcome of experiments. PMID:18990206

  19. Bcl11b prevents the intrathymic development of innate CD8 T cells in a cell intrinsic manner.

    PubMed

    Hirose, Satoshi; Touma, Maki; Go, Rieka; Katsuragi, Yoshinori; Sakuraba, Yoshiyuki; Gondo, Yoichi; Abe, Manabu; Sakimura, Kenji; Mishima, Yukio; Kominami, Ryo

    2015-04-01

    If Bcl11b activity is compromised, CD4(+)CD8(+) double-positive (DP) thymocytes produce a greatly increased fraction of innate CD8(+) single-positive (SP) cells highly producing IFN-?, which are also increased in mice deficient of genes such as Itk, Id3 and NF-?B1 that affect TCR signaling. Of interest, the increase in the former two is due to the bystander effect of IL-4 that is secreted by promyelocytic leukemia zinc finger-expressing NKT and ??T cells whereas the increase in the latter is cell intrinsic. Bcl11b zinc-finger proteins play key roles in T cell development and T cell-mediated immune response likely through TCR signaling. We examined thymocytes at and after the DP stage in Bcl11b (F/S826G) CD4cre, Bcl11b (F/+) CD4cre and Bcl11b (+/S826G) mice, carrying the allele that substituted serine for glycine at the position of 826. Here we show that Bcl11b impairment leads to an increase in the population of TCR??(high)CD44(high)CD122(high) innate CD8SP thymocytes, together with two different developmental abnormalities: impaired positive and negative selection accompanying a reduction in the number of CD8SP cells, and developmental arrest of NKT cells at multiple steps. The innate CD8SP thymocytes express Eomes and secrete IFN-? after stimulation with PMA and ionomycin, and in this case their increase is not due to a bystander effect of IL-4 but cell intrinsic. Those results indicate that Bcl11b regulates development of different thymocyte subsets at multiple stages and prevents an excess of innate CD8SP thymocytes. PMID:25422283

  20. Expression of the Ian family of putative GTPases during T cell development and description of an Ian with three sets of GTP\\/GDP-binding motifs

    Microsoft Academic Search

    Carine Dion; Christine Carter; Lucy Hepburn; W. John Coadwell; Geoff Morgan; Margaret Graham; Nicholas Pugh; Graham Anderson; Geoffrey W. Butcher; J. Ross Miller

    2005-01-01

    Reports suggest that two members of the novel immune-associated nucleotide (Ian) GTPase family, Ian1 and Ian5, play roles in T cell development. We performed real-time PCR analysis of the expression of Ian genes of the rat during T cell maturation, in macrophages and in cell lines. We found that all of the genes were expressed at relatively low levels at

  1. The Role of B Cells in the Development of CD4 Effector T Cells during a Polarized Th2 Immune Response1

    PubMed Central

    Liu, Qian; Liu, Zhugong; Rozo, Cristina T.; Hamed, Hossein A.; Alem, Farhang; Urban, Joseph F.; Gause, William C.

    2008-01-01

    Previous studies have suggested that B cells promote Th2 cell development by inhibiting Th1 cell differentiation. To examine whether B cells are directly required for the development of IL-4-producing T cells in the lymph node during a highly polarized Th2 response, B cell-deficient and wild-type mice were inoculated with the nematode parasite, Nippostrongylus brasiliensis. On day 7, in the absence of increased IFN-?, IL-4 protein and gene expression from CD4 T cells in the draining lymph nodes were markedly reduced in B cell-deficient mice and could not be restored by multiple immunizations. Using a DO11.10 T cell adoptive transfer system, OVA-specific T cell IL-4 production and cell cycle progression, but not cell surface expression of early activation markers, were impaired in B cell-deficient recipient mice following immunization with N. brasiliensis plus OVA. Laser capture microdissection and immunofluorescent staining showed that pronounced IL-4 mRNA and protein secretion by donor DO11.10 T cells first occurred in the T cell:B cell zone of the lymph node shortly after inoculation of IL-4?/? recipients, suggesting that this microenvironment is critical for initial Th2 cell development. Reconstitution of B cell-deficient mice with wild-type naive B cells, or IL-4?/? B cells, substantially restored Ag-specific T cell IL-4 production. However, reconstitution with B7-1/B7-2-deficient B cells failed to rescue the IL-4-producing DO11.10 T cells. These results suggest that B cells, expressing B7 costimulatory molecules, are required in the absence of an underlying IFN-?-mediated response for the development of a polarized primary Ag-specific Th2 response in vivo. PMID:17785819

  2. Cytokines from activated T cells induce normal endothelial cells to acquire the phenotypic and functional features of AIDS-Kaposi's sarcoma spindle cells.

    PubMed Central

    Fiorelli, V; Gendelman, R; Samaniego, F; Markham, P D; Ensoli, B

    1995-01-01

    Kaposi's sarcoma (KS) is a proliferative disease of vascular origin particularly frequent in HIV-1-infected homosexual men (AIDS-KS) and characterized by proliferating spindle-shaped cells, angiogenesis, and inflammatory cell infiltration. Previous work has suggested that KS spindle cells are of endothelial cell origin and that chronic immune activation via the release of inflammatory cytokines may cooperate with basic fibroblast growth factor (bFGF) and the HIV-1 Tat protein in the induction and progression of AIDS-KS. Here we show that KS spindle cells have features of activated endothelial cells, and that conditioned media from activated T cells, rich in the same inflammatory cytokines increased in HIV-1-infected individuals, induce normal endothelial cells to acquire the phenotypic and functional features of KS cells. These include (a) acquisition of a similar pattern of cell surface antigen expression; (b) similar proliferative response to bFGF; (c) induction of the responsiveness to the mitogenic effect of extracellular HIV-1 Tat protein that is now able to promote the G1-S transition of endothelial cell cycle; and (d) induction in nude mice of vascular lesions closely resembling early KS as well as the lesions induced by inoculation of KS cells. These results suggest that chronic immune activation, via release of inflammatory cytokines, may play a role in the induction of KS. Images PMID:7535796

  3. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1.

    PubMed

    Touzot, Fabien; Moshous, Despina; Creidy, Rita; Neven, Bénédicte; Frange, Pierre; Cros, Guilhem; Caccavelli, Laure; Blondeau, Johanna; Magnani, Alessandra; Luby, Jean-Marc; Ternaux, Brigitte; Picard, Capucine; Blanche, Stéphane; Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana, Marina

    2015-06-01

    During the last decade, gene therapy via ex vivo gene transfer into autologous hematopoietic stem cells has emerged as a convincing therapy for severe combined immunodeficiency caused by ILR2G mutation (SCID-X1) despite the occurrence of genotoxicity caused by the integration of first-generation retroviral vectors. However, the place of gene therapy among the therapeutic armamentarium remains to be defined. We retrospectively analyze and compare clinical outcomes and immune reconstitution in 13 consecutive SCID-X1 patients having undergone haploidentical hematopoietic stem cell transplantation (HSCT) and 14 SCID-X1 patients treated with gene therapy over the same period at a single center level: the Necker Children's Hospital (Paris, France). Our results show a clear advantage in terms of T-cell development of gene therapy over HSCT with a mismatched donor. Patients treated with gene therapy display a faster T-cell reconstitution and a better long-term thymic output. Interestingly, this advantage of gene therapy vs haploidentical HSCT seems to be independent of the existence of clinical graft-versus-host disease in the latter condition. If data of safety are confirmed over the long term, gene therapy for SCID-X1 appears to be an equal, if not superior, alternative to haploidentical HSCT. PMID:25869287

  4. Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma

    PubMed Central

    Ganesan, Anusha-Preethi; Johansson, Magnus; Ruffell, Brian; Beltran, Adam; Lau, Jonathan; Jablons, David M.; Coussens, Lisa M.

    2013-01-01

    Immune cells comprise a substantial proportion of the tumor mass in human non-small cell lung cancers (NSCLC), but the precise composition and significance of this infiltration is unclear. Herein we examined immune complexity of human NSCLC as well as NSCLC developing in CC10-TAg transgenic mice, and revealed that CD4+ T lymphocytes represent the dominant population of CD45+ immune cells, and relative to normal lung tissue, CD4+FoxP3+ regulatory T cells (Tregs) were significantly increased as a proportion of total CD4+ cells. To assess the functional significance of increased Treg cells, we evaluated CD8+ T cell-deficient/CC10-TAg mice and revealed that CD8+ T cells significantly controlled tumor growth with anti-tumor activity that was partially repressed by Treg cells. However, while treatment with anti-CD25 depleting mAb as monotherapy preferentially depleted Tregs and improved CD8+ T cell-mediated control of tumor progression during early tumor development, similar monotherapy was ineffective at later stages. Since mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8+ T cells expressing elevated levels of granzyme A, granzyme B, perforin and interferon-?, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC. PMID:23851682

  5. Oxidative Stress, T Cell DNA Methylation, and Lupus

    PubMed Central

    Li, YePeng; Gorelik, Gabriela; Strickland, Faith M; Richardson, Bruce C

    2014-01-01

    Objective Lupus develops when genetically predisposed people encounter environmental agents, such as ultraviolet light, silica, infections, and cigarette smoke, that cause oxidative stress, but how oxidative damage modifies the immune system to cause lupus flares is unknown. We previously showed that inhibiting DNA methylation in CD4+ T cells by blocking ERK pathway signaling is sufficient to alter gene expression, and that the modified cells cause lupus-like autoimmunity in mice. We also reported that T cells from patients with active lupus have decreased ERK pathway signaling, have decreased DNA methylation, and overexpress genes normally suppressed by DNA methylation. This study was undertaken to test whether oxidizing agents decrease ERK pathway signaling in T cells, decrease DNA methyltransferase levels, and cause demethylation and overexpression of T cell genes similar to that found in T cells from patients with active lupus. Methods CD4+ T cells were treated with the oxidizers H2O2 or ONOO?. Effects on ERK pathway signaling were measured by immunoblotting, DNA methyltransferase 1 (DNMT-1) levels were measured by reverse transcriptase–polymerase chain reaction (RT-PCR), and the methylation and expression of T cell genes were measured using flow cytometry, RT-PCR, and bisulfite sequencing. Results H2O2 and ONOO? inhibited ERK pathway signaling in T cells by inhibiting the upstream regulator protein kinase C?, decreased DNMT-1 levels, and caused demethylation and overexpression of genes previously shown to be suppressed by DNA methylation in T cells from patients with active lupus. Conclusion Our findings indicate that oxidative stress may contribute to human lupus flares by inhibiting ERK pathway signaling in T cells to decrease DNMT-1 and cause DNA demethylation. PMID:24577881

  6. Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras

    PubMed Central

    Win, Chan M.; Parrott, Roberta E.; Cooney, Myriah; Moser, Barry K.; Roberts, Joseph L.; Sempowski, Gregory D.; Buckley, Rebecca H.

    2009-01-01

    Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen–identical or rigorously T cell–depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term. PMID:19433858

  7. Transformation of Human Umbilical Cord Blood T Cells by Human T-Cell Leukemia\\/Lymphoma Virus

    Microsoft Academic Search

    Mikulas Popovic; Gunhild Lange-Wantzin; Prem S. Sarin; Dean Mann; Robert C. Gallo

    1983-01-01

    Several isolates of human T-cell leukemia\\/lymphoma virus (HTLV) were transmitted to normal human T cells obtained from the umbilical cord blood of newborns. T cells from seven specimens were immortalized by infection with different HTLV isolates and their properties were compared with those of activated uninfected normal T cells grown in the presence of T-cell growth factor (TCGF) and with

  8. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic\\/suppressive state

    Microsoft Academic Search

    Takeshi Takahashi; Yuhshi Kuniyasu; Masaaki Toda; Noriko Sakaguchi; Misako Itoh; Makoto Iwata; Jun Shimizu; Shimon Sakaguchi

    1998-01-01

    Elimination of CD25 F T cells, which constitute 5-10% of peripheral CD4 F T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25 F CD4 F T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25 - CD4 F T cells and CD8 F T

  9. Vitamin D3 metabolite calcidiol primes human dendritic cells to promote the development of immunomodulatory IL-10-producing T cells.

    PubMed

    Bakdash, Ghaith; van Capel, Toni M M; Mason, Lauren M K; Kapsenberg, Martien L; de Jong, Esther C

    2014-10-29

    Vitamin D is recognized as a potent immunosuppressive drug. The suppressive effects of vitamin D are attributed to its physiologically active metabolite 1,25 dihydroxy vitamin D3 (calcitriol), which was shown, to prime dendritic cells (DCs) to promote the development of regulatory T (Treg) cells. Despite the potential benefit in treating autoimmune diseases, clinical application of calcitriol is hindered by deleterious side effects manifested by hypercalcemia and hypercalciuria. Conversely, the physiological precursors of calcitriol, vitamin D3 (cholecalciferol) and its first metabolite 25-hydroxy vitamin D3 (calcidiol) are widely applied in the clinic due to their low calcimic burden. However, the mechanisms by which cholecalciferol and calcidiol may modulate adaptive immunity remain elusive. This prompted us to unravel the immunosuppressive capacity of these precursors by assessing their influence on DC functions and the subsequent polarization of naïve CD4(+) T cells. In this study we show that, whereas cholecalciferol has insignificant effects on DC maturation and cytokine production, it only weakly primed DCs to induce suppressive T cells. However, like calcitriol, calcidiol not only exerted an inhibitory effect on DC maturation and cytokine production, and primed DCs to promote the development of suppressive IL-10-producing Treg cells. Strikingly, in contrast to the population of IL-10-producing Treg cells induced by calcitriol-primed DCs, the IL-10-producing Treg cells induced by calcidiol-primed DCs exhibited sustained IFN-? production in face of their suppressive capacity. Experiments with the steroid synthesis inhibitor ketoconazole indicated that the immunomodulatory features of the precursors are dependent on their conversion into calcitriol. Collectively, calcidiol is a potent immune modulator, which may be more adequate than calcitriol for the treatment of chronic inflammatory diseases, since it is less hypercalcimic. This may be of particular interest for the treatment of allergic disease, where concurrent suppression and sustained IFN-? production by Treg cells effectively counterbalance the Th2-dominated immune responses. PMID:25236584

  10. HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T cell proliferation and TH1/TH17 responses

    PubMed Central

    Michelsen, Kathrin S.; Wong, Michelle H.; Ko, Brian; Thomas, Lisa S.; Dhall, Deepti; Targan, Stephan R.

    2015-01-01

    Background Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double blind, placebo controlled, trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate UC. We aimed to determine if HMPL-004 could prevent the development of T cell dependent murine colitis and to define its in vivo mechanism(s) of action Methods CD4+CD45RBhigh T cells were transferred into Rag1?/? mice and gavaged daily with HMPL-004 or Methyl Cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression. Results Mice treated with MC developed colitis within 4–7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004 treated mice did not lose weight and displayed only very mild intestinal inflammation. TNF-?, IL-1?, IFN-?, and IL-22 expression were significantly decreased in HMPL-004 treated mice. We observed higher percentages of naïve CD4+ T cells in the lamina propria of HMPL-004 treated mice. At early time-points HMPL-004 treated mice have significantly reduced splenic cell counts, reduced CD4+, and IL-17+, and IFN-?+ T cells. Furthermore, HMPL-004 inhibited the proliferation of CD4+ T cells and differentiation into TH1/TH17 cells in vitro. Conclusions HMPL-004 inhibits the development of chronic colitis by affecting early T cell proliferation, differentiation, and TH1/TH17 responses in a T cell driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for IBD. PMID:23292349

  11. Fbw7 Targets GATA3 through Cyclin-Dependent Kinase 2-Dependent Proteolysis and Contributes to Regulation of T-Cell Development

    PubMed Central

    Kitagawa, Kyoko; Shibata, Kiyoshi; Matsumoto, Akinobu; Matsumoto, Masaki; Ohhata, Tatsuya; Nakayama, Keiichi I.; Niida, Hiroyuki

    2014-01-01

    Proper development of T cells depends on lineage-specific regulators controlled transcriptionally and posttranslationally to ensure precise levels at appropriate times. Conditional inactivation of F-box protein Fbw7 in mouse T-cell development resulted in reduced thymic CD4 single-positive (SP) and splenic CD4+ and CD8+ cell proportions. Fbw7 deficiency skewed CD8 SP lineage differentiation, which exhibited a higher incidence of apoptosis. Similar perturbations during development of CD8-positive cells were reported with transgenic mice, which enforced GATA3 (T-cell differentiation regulator) expression throughout T-cell development. We observed augmented GATA3 in CD4/CD8 double negative (DN) stage 4, CD4 SP, and CD8 SP lineages in Fbw7-deficient thymocytes. Using overexpressed proteins in cultured cells, we demonstrated that Fbw7 bound to, ubiquitylated, and destabilized GATA3. Two Cdc4 phosphodegron (CPD) candidate sequences, consensus Fbw7 recognition domains, were identified in GATA3, and phosphorylation of Thr-156 in CPD was required for Fbw7-mediated ubiquitylation and degradation. Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. These observations suggest that Fbw7-mediated GATA3 regulation with CDK2-mediated phosphorylation of CPD contributes to the precise differentiation of T-cell lineages. PMID:24820417

  12. Longitudinal analysis of the human T cell response during acute hantavirus infection.

    PubMed

    Lindgren, Therese; Ahlm, Clas; Mohamed, Nahla; Evander, Magnus; Ljunggren, Hans-Gustaf; Björkström, Niklas K

    2011-10-01

    Longitudinal studies of T cell immune responses during viral infections in humans are essential for our understanding of how effector T cell responses develop, clear infection, and provide long-lasting immunity. Here, following an outbreak of a Puumala hantavirus infection in the human population, we longitudinally analyzed the primary CD8 T cell response in infected individuals from the first onset of clinical symptoms until viral clearance. A vigorous CD8 T cell response was observed early following the onset of clinical symptoms, determined by the presence of high numbers of Ki67(+)CD38(+)HLA-DR(+) effector CD8 T cells. This response encompassed up to 50% of total blood CD8 T cells, and it subsequently contracted in parallel with a decrease in viral load. Expression levels of perforin and granzyme B were high throughout the initial T cell response and likewise normalized following viral clearance. When monitoring regulatory components, no induction of regulatory CD4 or CD8 T cells was observed in the patients during the infection. However, CD8 as well as CD4 T cells exhibited a distinct expression profile of inhibitory PD-1 and CTLA-4 molecules. The present results provide insight into the development of the T cell response in humans, from the very onset of clinical symptoms following a viral infection to resolution of the disease. PMID:21795350

  13. Development of an in vitro assay and demonstration of Plasmodium berghei liver-stage inhibition by TRAP-specific CD8+ T cells.

    PubMed

    Longley, Rhea J; Bauza, Karolis; Ewer, Katie J; Hill, Adrian V S; Spencer, Alexandra J

    2015-01-01

    The development of an efficacious vaccine against the Plasmodium parasite remains a top priority. Previous research has demonstrated the ability of a prime-boost virally vectored sub-unit vaccination regimen, delivering the liver-stage expressed malaria antigen TRAP, to produce high levels of antigen-specific T cells. The liver-stage of malaria is the main target of T cell-mediated immunity, yet a major challenge in assessing new T cell inducing vaccines has been the lack of a suitable pre-clinical assay. We have developed a flow-cytometry based in vitro T cell killing assay using a mouse hepatoma cell line, Hepa1-6, and Plasmodium berghei GFP expressing sporozoites. Using this assay, P. berghei TRAP-specific CD8+ T cell enriched splenocytes were shown to inhibit liver-stage parasites in an effector-to-target ratio dependent manner. Further development of this assay using human hepatocytes and P. falciparum would provide a new method to pre-clinically screen vaccine candidates and to elucidate mechanisms of protection in vitro. PMID:25822951

  14. Development of an In Vitro Assay and Demonstration of Plasmodium berghei Liver-Stage Inhibition by TRAP-Specific CD8+ T Cells

    PubMed Central

    Longley, Rhea J.; Bauza, Karolis; Ewer, Katie J.; Hill, Adrian V. S.; Spencer, Alexandra J.

    2015-01-01

    The development of an efficacious vaccine against the Plasmodium parasite remains a top priority. Previous research has demonstrated the ability of a prime-boost virally vectored sub-unit vaccination regimen, delivering the liver-stage expressed malaria antigen TRAP, to produce high levels of antigen-specific T cells. The liver-stage of malaria is the main target of T cell-mediated immunity, yet a major challenge in assessing new T cell inducing vaccines has been the lack of a suitable pre-clinical assay. We have developed a flow-cytometry based in vitro T cell killing assay using a mouse hepatoma cell line, Hepa1-6, and Plasmodium berghei GFP expressing sporozoites. Using this assay, P. berghei TRAP-specific CD8+ T cell enriched splenocytes were shown to inhibit liver-stage parasites in an effector-to-target ratio dependent manner. Further development of this assay using human hepatocytes and P. falciparum would provide a new method to pre-clinically screen vaccine candidates and to elucidate mechanisms of protection in vitro. PMID:25822951

  15. The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies

    PubMed Central

    Dosani, T; Carlsten, M; Maric, I; Landgren, O

    2015-01-01

    As vast strides are being made in the management and treatment of multiple myeloma (MM), recent interests are increasingly focusing on understanding the development of the disease. The knowledge that MM develops exclusively from a protracted phase of monoclonal gammopathy of undetermined significance provides an opportunity to study tumor evolution in this process. Although the immune system has been implicated in the development of MM, the scientific literature on the role and status of various immune components in this process is broad and sometimes contradictory. Accordingly, we present a review of cellular immune subsets in myelomagenesis. We summarize the current literature on the quantitative and functional profiles of natural killer cells and T-cells, including conventional T-cells, natural killer T-cells, ?? T-cells and regulatory T-cells, in myelomagenesis. Our goal is to provide an overview of the status and function of these immune cells in both the peripheral blood and the bone marrow during myelomagenesis. This provides a better understanding of the nature of the immune system in tumor evolution, the knowledge of which is especially significant considering that immunotherapies are increasingly being explored in the treatment of both MM and its precursor conditions. PMID:25885426

  16. CD8+ T cells eliminate liver-stage Plasmodium berghei parasites without detectable bystander effect.

    PubMed

    Cockburn, Ian A; Tse, Sze-Wah; Zavala, Fidel

    2014-04-01

    Immunization with attenuated Plasmodium sporozoites or viral vectored vaccines can induce protective CD8(+) T cells that can find and eliminate liver-stage malaria parasites. A key question is whether CD8(+) T cells must recognize and eliminate each parasite in the liver or whether bystander killing can occur. To test this, we transferred antigen-specific effector CD8(+) T cells to mice that were then coinfected with two Plasmodium berghei strains, only one of which could be recognized directly by the transferred T cells. We found that the noncognate parasites developed normally in these mice, demonstrating that bystander killing of parasites does not occur during the CD8(+) T cell response to malaria parasites. Rather, elimination of infected parasites is likely mediated by direct recognition of infected hepatocytes by antigen-specific CD8(+) T cells. PMID:24421043

  17. CD8+ T Cells Eliminate Liver-Stage Plasmodium berghei Parasites without Detectable Bystander Effect

    PubMed Central

    Tse, Sze-Wah; Zavala, Fidel

    2014-01-01

    Immunization with attenuated Plasmodium sporozoites or viral vectored vaccines can induce protective CD8+ T cells that can find and eliminate liver-stage malaria parasites. A key question is whether CD8+ T cells must recognize and eliminate each parasite in the liver or whether bystander killing can occur. To test this, we transferred antigen-specific effector CD8+ T cells to mice that were then coinfected with two Plasmodium berghei strains, only one of which could be recognized directly by the transferred T cells. We found that the noncognate parasites developed normally in these mice, demonstrating that bystander killing of parasites does not occur during the CD8+ T cell response to malaria parasites. Rather, elimination of infected parasites is likely mediated by direct recognition of infected hepatocytes by antigen-specific CD8+ T cells. PMID:24421043

  18. Cutaneous T Cell Lymphoma

    MedlinePLUS

    ... Tumours of Haematopoietic and Lymphoid Tissues (ed 4th) . Lyon, France: IARC Press; 2008. FS5 Cutaneous T-Cell ... Hematopoietic and Lymphoid Tissues. 4th ed. IARC Press Lyon, France; 2008. Wollina U. Cutaneous T-cell lymphoma: ...

  19. T-Cell Lineage Determination

    PubMed Central

    Yang, Qi; Bell, J. Jeremiah; Bhandoola, Avinash

    2010-01-01

    Summary T cells originate from hematopoietic stem cells (HSCs) in the bone marrow but complete their development in the thymus. HSCs give rise to a variety of non-renewing hematopoietic progenitors, among which a rare subset migrates to the thymus via the bloodstream. The earliest T-cell progenitors identified in the thymus are not T-lineage restricted but possess the ability to give rise to cells of many different lineages. Alternative lineage potentials are gradually lost as progenitors progress towards later developmental stages. Here, we review the early developmental events that might be involved in T-cell lineage fate determination, including the properties of possible thymus settling progenitors, their homing into the thymus, and their T-cell lineage specification and commitment. PMID:20969581

  20. Requirement for cyclin D3 in lymphocyte development and T cell leukemias

    Microsoft Academic Search

    Ewa Sicinska; Iannis Aifantis; Laurent Le Cam; Wojciech Swat; Christine Borowski; Qunyan Yu; Adolfo A Ferrando; Steven D Levin; Yan Geng; Harald von Boehmer; Piotr Sicinski

    2003-01-01

    The D-type cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. Cyclin D3 gene is rearranged and the protein is overexpressed in several human lymphoid malignancies. In order to determine the function of cyclin D3 in development and oncogenesis, we generated and analyzed cyclin D3-deficient mice. We found that cyclin D3?\\/? animals

  1. Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

    PubMed Central

    Shotwell, Elisabeth; Scott, John; Cruz, Stephanie; King, Lisa R.; Manischewitz, Jody; Diaz, Claudia G.; Jordan, Robert A.; Grosenbach, Douglas W.; Golding, Hana

    2013-01-01

    Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu?/nu?) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge. PMID:23468500

  2. Retinoic acid promotes the development of Th2-like human myelin basic protein-reactive T cells

    Microsoft Academic Search

    Amy E Lovett-Racke; Michael K Racke

    2002-01-01

    To determine if retinoids might be beneficial in the treatment of multiple sclerosis (MS), all-trans-retinoic acid (tRA) was tested for its effects on proliferation and cytokine expression in human autoreactive T cells. tRA decreased human lymphocyte proliferation in vitro in a dose-dependent manner. In addition, tRA induced IL-4 gene expression in myelin basic protein (MBP)-specific T cell lines which had

  3. Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy?

    PubMed Central

    2014-01-01

    Epidemiological evidence confirmed that raw cow’s milk consumption in the first year of life protects against the development of atopic diseases and increases the number of regulatory T-cells (Tregs). However, milk’s atopy-protective mode of action remains elusive. This review supported by translational research proposes that milk-derived microRNAs (miRs) may represent the missing candidates that promote long-term lineage commitment of Tregs downregulating IL-4/Th2-mediated atopic sensitization and effector immune responses. Milk transfers exosomal miRs including the ancient miR-155, which is important for the development of the immune system and controls pivotal target genes involved in the regulation of FoxP3 expression, IL-4 signaling, immunoglobulin class switching to IgE and Fc?RI expression. Boiling of milk abolishes milk’s exosomal miR-mediated bioactivity. Infant formula in comparison to human breast- or cow’s milk is deficient in bioactive exosomal miRs that may impair FoxP3 expression. The boost of milk-mediated miR may induce pivotal immunoregulatory and epigenetic modifications required for long-term thymic Treg lineage commitment explaining the atopy-protective effect of raw cow’s milk consumption. The presented concept offers a new option for the prevention of atopic diseases by the addition of physiological amounts of miR-155-enriched exosomes to infant formula for mothers incapable of breastfeeding. PMID:24521175

  4. Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection

    PubMed Central

    Boyd, Anders; Almeida, Jorge R.; Darrah, Patricia A.; Sauce, Delphine; Seder, Robert A.; Appay, Victor; Gorochov, Guy; Larsen, Martin

    2015-01-01

    Introduction Understanding the factors that delineate the efficacy of T cell responses towards pathogens is crucial for our ability to develop potent therapies against infectious diseases. Multidimensional evaluation of T cell functionality at the single-cell level enables exhaustive analysis of combinatorial functional properties, hence polyfunctionality. We have recently invented an algorithm that quantifies polyfunctionality, the Polyfunctionality Index (Larsen et al. PLoS One 2012). Here we demonstrate that quantitative assessment of T cell polyfunctionality correlates with T cell efficacy measured as the capacity to kill target cells in vitro and control infection in vivo. Methods We employed the polyfunctionality index on two datasets selected for their unique ability to evaluate the polyfunctional imprint on T cell efficacy. 1) HIV-specific CD8+ T cells and 2) Leishmania major-specific CD4+ T cells were analysed for their capacity to secrete multiple effector molecules, kill target cells and control infection. Briefly, employing the Polyfunctionality Index algorithm we determined the parameter estimates resulting in optimal correlation between T cell polyfunctionality and T cell efficacy. Results T cell polyfunctionality is correlated with T cell efficacy measured as 1) target killing (r=0.807, P<0.0001) and 2) lesion size upon challenge with Leishmania major (r=-0.50, P=0.004). Contrary to an approach relying on the Polyfunctionality Index algorithm, quantitative evaluation of T cell polyfunctionality traditionally ignores the gradual contribution of more or less polyfunctional T cells. Indeed, comparing both approaches we show that optimal description of T cell efficacy is obtained when gradually integrating all levels of polyfunctionality in accordance with the Polyfunctionality Index. Conclusions Our study presents a generalizable methodology to objectively evaluate the impact of polyfunctionality on T cell efficacy. We show that T cell polyfunctionality is a superior correlate of T cell efficacy both in vitro and in vivo as compared with response size. Therefore, future immunotherapies should aim to increase T cell polyfunctionality. PMID:26046523

  5. Hemimegalencephaly and normal intellectual development.

    PubMed Central

    Fusco, L; Ferracuti, S; Fariello, G; Manfredi, M; Vigevano, F

    1992-01-01

    Hemimegalencephaly is a rare congenital malformation characterised by overgrowth of one hemisphere. Although it is commonly thought to be associated with neurological deficits, developmental delay, and intractable epilepsy, the clinical expression of hemimegalencephaly, can vary widely. This patient was neurologically and neuropsychologically normal apart from rare partial seizures. Images PMID:1326602

  6. T cell metabolic fitness in antitumor immunity.

    PubMed

    Siska, Peter J; Rathmell, Jeffrey C

    2015-04-01

    T cell metabolism has a central role in supporting and shaping immune responses and may have a key role in antitumor immunity. T cell metabolism is normally held under tight regulation in an immune response of glycolysis to promote effector T cell expansion and function. However, tumors may deplete nutrients, generate toxic products, or stimulate conserved negative feedback mechanisms, such as through Programmed Cell Death 1 (PD-1), to impair effector T cell nutrient uptake and metabolic fitness. In addition, regulatory T cells are favored in low glucose conditions and may inhibit antitumor immune responses. Here, we review how the tumor microenvironment modifies metabolic and functional pathways in T cells and how these changes may uncover new targets and challenges for cancer immunotherapy and treatment. PMID:25773310

  7. Hepatitis B virus (HBV)-specific T-cell responses to recombinant HBV core protein in patients with normal liver function and co-infected with chronic HBV and human immunodeficiency virus 1 (HIV-1)

    PubMed Central

    2013-01-01

    Background Little is known about HBV-specific T-cell responses in chronic Hepatitis B patients (HBV) that are co-infected with Human immunodeficiency virus type 1 (HIV-1), especially those with normal alanine aminotransferase (ALT) levels. Methods Twenty-five patients with chronic HBV (11 hepatitis B e antigen [HBeAg]-positive, 14 HBeAg-negative) were enrolled in a cross-sectional study. A longitudinal study as also conducted in which follow-up was done at 3, 12, and 24 months, after acute HIV-1 infection, in 11 individuals who also had chronic HBV. Peripheral blood mononuclear cells were stimulated with recombinant HBV surface protein (S protein), core protein (C protein) or gag peptide. IFN-?-secreting T cells were identified by ELISPOT assay. Results In the cross-sectional study, co-infected chronic HBV patients had lower C protein-specific T-cell responses compared with mono-infected individuals, though the difference was not significant. In co-infected, chronic HBV patients, the magnitude of C protein-specific T-cell responses was significantly greater in HBeAg-positive subjects compared to HBeAg-negative subjects (p?=?0.011). C protein-specific T-cell responses were positively correlated with HBV viral load (rs = 0.40, p?=?0.046). However, gag-specific T-cell responses were negatively correlated with HIV viral load (rs?=??0.44, p?=?0.026) and positively correlated with CD4+ count (rs = 0.46, p?=?0.021). The results were different in mono-infected individuals. PBMCs from co-infected HBeAg-positive patients secreted more specific-IFN-? in cultured supernatants compared with PBMCs from co-infected HBeAg-negative patients (p?=?0.019). In the longitudinal study, S protein- and C protein-specific T-cell responses were decreased as the length of follow-up increased (p?=?0.034, for S protein; p?=?0.105, for C protein). Additionally, the S protein- and C protein-specific T-cell responses were significantly higher in HBeAg-positive patients than in HBeAg-negative patients at 3 and 12 months after HIV-1 infection (all p?T-cell responses and HBV viral load at 3 and 12 months after HIV-1 infection. Conclusions HBV-specific T-cell responses to recombinant HBV core protein were reduced in chronic HBV patients co-infected with HIV-1. The reduced C protein-specific T cell responses were positively correlated with HBV viral load in co-infected, chronic HBV patients. PMID:23849342

  8. The challenges and opportunities for the development of a T-cell epitope-based herpes simplex vaccine.

    PubMed

    Kuo, Tiffany; Wang, Christine; Badakhshan, Tina; Chilukuri, Sravya; BenMohamed, Lbachir

    2014-11-28

    Herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) infections have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a billion individuals worldwide. HSV-1 infections are predominant than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries, their development has been difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One "common denominator" among previously failed clinical herpes vaccine trials is that they either used a whole virus or a whole viral protein, which contain both "pathogenic symptomatic" and "protective asymptomatic" antigens and epitopes. In this report, we continue to advocate developing "asymptomatic" epitope-based sub-unit vaccine strategies that selectively incorporate "protective asymptomatic" epitopes which: (i) are exclusively recognized by effector memory CD4(+) and CD8(+) T cells (TEM cells) from "naturally" protected seropositive asymptomatic individuals; and (ii) protect human leukocyte antigen (HLA) transgenic animal models of ocular and genital herpes. We review the role of animal models in herpes vaccine development and discuss their current status, challenges, and prospects. PMID:25446827

  9. ?? T Cells and Their Potential for Immunotherapy

    PubMed Central

    Wu, Yan-Ling; Ding, Yan-Ping; Tanaka, Yoshimasa; Shen, Li-Wen; Wei, Chuan-He; Minato, Nagahiro; Zhang, Wen

    2014-01-01

    V?9V?2 (also termed V?2V?2) T cells, a major human peripheral blood ?? T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because ??T cells express both natural killer receptors such as NKG2D and ?? T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated ?? T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to ?? T cells. Utilizing these antimicrobial and anti-tumor properties of ?? T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of ?? T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of ?? T cell-based therapies so far performed. Based on the results of the reported trials, ?? T cells appear to be a promising tool for novel immunotherapies against certain types of diseases. PMID:24520210

  10. Cytotoxic T Lymphocytes to An Unmutated Tumor Rejection Antigen P1A: Normal Development but Restrained Effector Function In Vivo

    PubMed Central

    Sarma, Supria; Guo, Yong; Guilloux, Yannik; Lee, Cheng; Bai, Xue-Feng; Liu, Yang

    1999-01-01

    Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical issue is whether unmutated tumor antigens are expressed in normal cells, and if so, whether such expression imposes special restrictions on cytotoxic T lymphocyte (CTL) responses. In this study, we use a transgenic approach to study the development and effector function of T cells specific for P1A, a prototypical unmutated tumor antigen. We report here that although P1A is expressed at low levels in normal tissues, including lymphoid tissues, the P1A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopoietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cells must have escaped clonal deletion due to low expression of P1A in the thymus. Interestingly, despite the fact that an overwhelming majority of T cells in the T cell receptor for antigen (TCR)–transgenic mice are specific for P1A, these mice are no more resistant to a P1A-expressing plasmocytoma than nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1+ and B7-1? tumors, only B7-1+ tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunotherapy. PMID:10049945

  11. Spliced human endogenous retroviral HERV-H env transcripts in T-cell leukaemia cell lines and normal leukocytes: alternative splicing pattern of HERV-H transcripts

    Microsoft Academic Search

    Mats Lindeskog; Jonas Blomberg

    The majority of human endogenous retroviral HERV-H elements in the human genome have large deletions in pol and lack most of env, 5-10% are more or less complete with a potentially immuno- suppressive transmembrane protein-encoding env region. Spliced HERV-H env transcripts were detec- ted in T-cell leukaemia cell lines and lymphocytes from healthy blood donors by using RT-PCR. The transcripts

  12. Significant involvement of nuclear factor-?B-inducing kinase in proper differentiation of ?? and ?? T cells

    PubMed Central

    Eshima, Koji; Okabe, Motohito; Kajiura, Satoshi; Noma, Haruka; Shinohara, Nobukata; Iwabuchi, Kazuya

    2014-01-01

    Nuclear factor-?B-inducing kinase (NIK) is known to play a critical role in maintaining proper immune function. This is exemplified in the spontaneous mutant mouse lacking functional NIK, alymphoplasia (aly), which is simultaneously immune-compromised and autoimmune-prone. To investigate the role of NIK in ?? T-cell repertoire formation, we analysed T-cell development in aly/aly mice bearing a transgenic T-cell receptor (TCR). Although there were no apparent abnormalities in the mature ?? T cells of non-transgenic aly/aly mice, the maturation efficiency of idiotypehigh+ T cells in the TCR-transgenic mice was lower in aly/aly mice compared with those found in aly/+ mice, suggesting that the mature ?? T-cell repertoire could be altered by the absence of functional NIK. In one strain of TCR-transgenic aly/aly mice with a negatively selecting H-2 background, the proportion of CD8low+ idiotypehigh+ cells, which are thought to potentially represent the ?? lineage of T cells, was markedly decreased. When the ?? T cells in non-transgenic aly/aly mice were investigated, the proportion of ?? T cells in the peripheral organs of aly/aly mice was found to be one-half to one-fifth of those in aly/+ mice. Analyses of bone marrow chimera mice indicated that NIK in host cells, rather than in donor cells was important for generating a normal number of peripheral ?? T cells. Collectively, these results suggest that NIK could be involved in thymic positive selection of some ?? T cells and that NIK in non-haematopoietic cells is important for the optimal development and/or maintenance of ?? T cells. PMID:24117043

  13. T Cell-Dendritic Cell Interaction in Vivo: Random Encounters Favor Development of Long-Lasting Ties

    NSDL National Science Digital Library

    Oreste Acuto (Institut Pasteur; Molecular Immunology Unit, Department of Immunology REV)

    2003-07-22

    Understanding the complexity of the functional communication between cells composing the immune system is central to improving our capacity to manipulate it and conceive better strategies to combat microbial pathogens. So far, these studies have been based on immunohistochemistry of fixed tissues and in vitro attempts to reproduce functional connections between cells. The application of two-photon laser microscopy to the observation of viable immune cells in their natural environment where foreign antigens are carried to trigger an immune response opens a new era for these studies. They reveal exceptional properties of the locomotion of T cells that facilitate encounters with dendritic cells and the receipt of information that promotes T cell survival, death, or initiation of immune responses. These studies also complement in vitro observations addressing the importance of time of stimulation in determining T cell fates.

  14. Co-activation of naive CD4+ T cells and bone marrow-derived mast cells results in the development of Th2 cells.

    PubMed

    Huels, C; Germann, T; Goedert, S; Hoehn, P; Koelsch, S; Hültner, L; Palm, N; Rüde, E; Schmitt, E

    1995-04-01

    Activation of naive dense CD4+ T cells by plate-bound anti-CD3 antibodies favors the development of Th1 cells which, upon re-stimulation, produce significant amounts of IFN-gamma but no IL-4. However, co-activation of such naive T cells in the presence of IgE [anti-dinitrophenyl (DNP)]-loaded bone marrow-derived mast cells (BMMC) on plates coated with anti-CD3 antibodies and DNP-BSA led to the development of IL-4-producing Th2 cells. The same result could be observed if irradiated (800 rad) BMMC were applied as co-stimulators. Moreover, BMMC could be replaced by the supernatant of IgE-activated BMMC suggesting that a soluble mediator, presumably IL-4, was responsible for this effect. This assumption was substantiated using neutralizing anti-IL-4 antibodies which abolished the BMMC-mediated Th2 development in all cases. Addition of IL-12, a cytokine that was shown to antagonize the Th2-promoting effect of IL-4 in vivo, could not inhibit the development of IL-4-producing T cells, but gave rise to a T cell population which produced relatively high amounts of IL-4 and IFN-gamma. Since BMMC represent the in vitro equivalent of mucosal mast cells these data suggest that IgE-activated mucosal mast cells can bias an emerging T cell dependent immune response towards a Th2 dominated reaction by the initial production of IL-4. PMID:7547678

  15. Intradermal application of vitamin D3 increases migration of CD14+ dermal dendritic cells and promotes the development of Foxp3+ regulatory T cells.

    PubMed

    Bakdash, Ghaith; Schneider, Laura P; van Capel, Toni M M; Kapsenberg, Martien L; Teunissen, Marcel B M; de Jong, Esther C

    2013-02-01

    The active form of vitamin D3 (VitD) is a potent immunosuppressive drug. Its effects are mediated in part through dendritic cells (DCs) that promote the development of regulatory T cells (Tregs). However, it remains elusive how VitD would influence the different human skin DC subsets, e.g., CD1a(+)/langerin(+) Langerhans cells, CD14(+) DDCs and CD1a(+) DDCs upon administration through the skin route in their natural environment. We addressed this issue by intradermal (ID) administration of VitD in a human skin explant system that closely resembles physiological conditions. ID injection of VitD selectively enhanced the migration of CD14(+) DDCs, a subset known for the induction of tolerance. Moreover, ID injection of VitD repressed the LPS-induced T cell stimulatory capacity of migrating DCs. These migrating DCs collectively induced T cells with suppressive activity and abolished IFN-? productivity. Those induced T cells were characterized by the expression of Foxp3. Thus, we report the novel finding that ID injection of VitD not only modifies skin DC migration, but also programs these DCs in their natural milieu to promote the development of Foxp3(+) Tregs. PMID:23291929

  16. Intradermal application of vitamin D3 increases migration of CD14+ dermal dendritic cells and promotes the development of Foxp3+ regulatory T cells

    PubMed Central

    Bakdash, Ghaith; Schneider, Laura P.; van Capel, Toni M. M.; Kapsenberg, Martien L.; Teunissen, Marcel B. M.; de Jong, Esther C.

    2013-01-01

    The active form of vitamin D3 (VitD) is a potent immunosuppressive drug. Its effects are mediated in part through dendritic cells (DCs) that promote the development of regulatory T cells (Tregs). However, it remains elusive how VitD would influence the different human skin DC subsets, e.g., CD1a+/langerin+ Langerhans cells, CD14+ DDCs and CD1a+ DDCs upon administration through the skin route in their natural environment. We addressed this issue by intradermal (ID) administration of VitD in a human skin explant system that closely resembles physiological conditions. ID injection of VitD selectively enhanced the migration of CD14+ DDCs, a subset known for the induction of tolerance. Moreover, ID injection of VitD repressed the LPS-induced T cell stimulatory capacity of migrating DCs. These migrating DCs collectively induced T cells with suppressive activity and abolished IFN-? productivity. Those induced T cells were characterized by the expression of Foxp3. Thus, we report the novel finding that ID injection of VitD not only modifies skin DC migration, but also programs these DCs in their natural milieu to promote the development of Foxp3+ Tregs. PMID:23291929

  17. Non-Fas(CD95/APO1)-mediated apoptosis of activated T cells inhibits the development of atherosclerosis

    PubMed Central

    Esparza, Leticia; De Haro, Joaquin; Bleda, Silvia; Acin, Francisco

    2012-01-01

    Atherosclerosis is a chronic systemic inflammatory disease. The innate and adaptive immune response might be involved in atherogenesis. Methotrexate (MTX) induces apoptosis of activated T cells by a CD95-independent pathway. The aim of this study was to analyse the effect of immunomodulation by MTX in the development of early atherosclerotic vascular lesions in an animal model. Four-week old male C57BL6 LDL-receptor-deficient mice were fed a diet rich in saturated fat (82%) and cholesterol (2.8%). Thirty animals were given a weekly intramuscular injection of MTX, establishing three subgroups: 10, 30 and 50 mg/kg. Ten further mice were used as an immunocompetent control group. Aortic thickening was significantly inhibited in all MTX-treated groups compared with the control group at 30 days (0.46 ± 0.003 mm2 in the control group vs 0.31 ± 0.002, 0.14 ± 0.009 and 0.16 ± 0.006 mm2 in the low-, intermediate- and high-dose group, respectively; P = 0.01) and at 60 days. The aortic lumen/total area ratio was also increased in the MTX-treated groups (0.82 ± 0.06 in the control group vs 0.88 ± 0.07, 0.86 ± 0.05 and 0.88 ± 0.04, respectively; P = 0.02). Immunosuppression by MTX inhibits the development of atherosclerotic lesions in arterial vessels in mice, which highlights the crucial role of the immune system in atherogenesis. PMID:22617501

  18. Non-Fas(CD95/APO1)-mediated apoptosis of activated T cells inhibits the development of atherosclerosis.

    PubMed

    Esparza, Leticia; De Haro, Joaquin; Bleda, Silvia; Acin, Francisco

    2012-09-01

    Atherosclerosis is a chronic systemic inflammatory disease. The innate and adaptive immune response might be involved in atherogenesis. Methotrexate (MTX) induces apoptosis of activated T cells by a CD95-independent pathway. The aim of this study was to analyse the effect of immunomodulation by MTX in the development of early atherosclerotic vascular lesions in an animal model. Four-week old male C57BL6 LDL-receptor-deficient mice were fed a diet rich in saturated fat (82%) and cholesterol (2.8%). Thirty animals were given a weekly intramuscular injection of MTX, establishing three subgroups: 10, 30 and 50 mg/kg. Ten further mice were used as an immunocompetent control group. Aortic thickening was significantly inhibited in all MTX-treated groups compared with the control group at 30 days (0.46 ± 0.003 mm(2) in the control group vs 0.31 ± 0.002, 0.14 ± 0.009 and 0.16 ± 0.006 mm(2) in the low-, intermediate- and high-dose group, respectively; P = 0.01) and at 60 days. The aortic lumen/total area ratio was also increased in the MTX-treated groups (0.82 ± 0.06 in the control group vs 0.88 ± 0.07, 0.86 ± 0.05 and 0.88 ± 0.04, respectively; P = 0.02). Immunosuppression by MTX inhibits the development of atherosclerotic lesions in arterial vessels in mice, which highlights the crucial role of the immune system in atherogenesis. PMID:22617501

  19. The BMP Pathway Participates in Human Naive CD4+ T Cell Activation and Homeostasis

    PubMed Central

    Martínez, Víctor G.; Sacedón, Rosa; Hidalgo, Laura; Valencia, Jaris; Fernández-Sevilla, Lidia M.; Hernández-López, Carmen

    2015-01-01

    Bone Morphogenetic Proteins (BMPs) form a group of secreted factors that belongs to the TGF-? superfamily. Among different roles in a number of immune cell types, BMPs are known to regulate T cell development within the thymus, although the role of BMP signaling in human mature T cells remains elusive. In this study, we demonstrate that canonical BMP signaling is necessary during two critical events that regulate the size and function of human naive CD4+ T cell population: activation and homeostasis. Upon stimulation via TCR, naive CD4+ T cells upregulate the expression of BMP ligands triggering canonical BMP signaling in CD25+ cells. Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling. Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis. Moreover, upregulation of two critical receptors for T cell homeostasis, CXCR4 and CCR9, triggered by IL-7 is also abrogated in the absence of BMP signaling. Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application. PMID:26110906

  20. T Cell Immune Reconstitution Following Lymphodepletion

    PubMed Central

    Williams, Kirsten; Hakim, Frances T.; Gress, Ronald E.

    2007-01-01

    T cell reconstitution following lymphopenia from chemotherapy or stem cell transplant is often slow and incompetent, contributing to the development of infectious diseases, relapse, and graft-versus-host disease. This is due to the fact that de novo T cell production is impaired following cytoreductive regimens. T cells can be generated from two pathways: 1) thymus derived through active thymopoiesis and 2) peripherally expanded clones through homeostatic proliferation. In the development of lymphopenia, the thymic pathway is commonly compromised in adults and T cells rely upon peripheral expansion to recover T cell numbers. This homeostatic proliferation exploits the high cytokine levels following lymphopenia to rapidly generate T cells in the periphery. Moreover, this early peripheral expansion of T cells can also be driven by exogenous antigen. This results in loss of T cell repertoire diversity and may predispose to auto- or alloimmunity. Alternatively, the high homeostatic proliferation following lymphopenia may facilitate expansion of anti-tumor immunity. Murine and human studies have provided insight into the cytokine and cellular regulators of these two pathways of T cell generation and the disparate portraits of T cell immunity created through robust thymopoiesis or peripheral expansion following lymphopenia. This insight has permitted the manipulation of the immune system to maximize anti-tumor immunity through lymphopenia and led to an appreciation of mechanisms that underlie graft vs. host disease. PMID:18023361

  1. Engineering T cells for cancer therapy

    Microsoft Academic Search

    W Mansoor; D E Gilham; F C Thistlethwaite; R E Hawkins

    2005-01-01

    It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing

  2. Splenic suppressor of cytokine signaling 3 transgene expression affects T cell responses and prevents development of collagen-induced arthritis

    Microsoft Academic Search

    Sharon Veenbergen; Miranda B. Bennink; Alfons S. K. de Hooge; Onno J. Arntz; Ruben L. Smeets; Wim B. van den Berg

    2008-01-01

    OBJECTIVE: Members of the suppressor of cytokine signaling (SOCS) family are key negative intracellular regulators of cytokine and growth factor responses, including those that regulate immune responses in autoimmune disorders, such as rheumatoid arthritis (RA). The aim of this study was to investigate modulation of T cell immunity for the treatment of experimental arthritis, via enhanced expression of SOCS-3 in

  3. Normal Development of Brain Circuits

    Microsoft Academic Search

    Gregory Z Tau; Bradley S Peterson

    2010-01-01

    Spanning functions from the simplest reflex arc to complex cognitive processes, neural circuits have diverse functional roles. In the cerebral cortex, functional domains such as visual processing, attention, memory, and cognitive control rely on the development of distinct yet interconnected sets of anatomically distributed cortical and subcortical regions. The developmental organization of these circuits is a remarkably complex process that

  4. Ex vivo T cell–based HIV suppression assay to evaluate HIV-specific CD8+ T-cell responses

    Microsoft Academic Search

    So Youn Shin; Pierre Versmisse; Françoise Barré-Sinoussi; Gianfranco Pancino; Asier Sáez-Cirión

    2010-01-01

    To advance T cell–based HIV vaccine development, it is necessary to evaluate the immune correlates of a protective CD8+ T-cell response. We have developed an assay that assesses the capacity ex vivo of HIV-specific CD8+ T cells to suppress HIV-1 infection of autologous CD4+ T cells. This assay directly reflects the ultimate effector function of CD8+ T cells, the elimination

  5. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity.

    PubMed

    Focke, M; Swoboda, I; Marth, K; Valenta, R

    2010-03-01

    Allergen-specific immunotherapy (SIT) is the only specific and disease-modifying approach for the treatment of allergy but several disadvantages have limited its broad applicability. We argue that the majority of the possible disadvantages of SIT such as unwanted effects, poor efficacy and specificity as well as inconvenient application are related to the poor quality of natural allergen extracts, which are the active ingredients of all currently available allergy vaccines. Because of the progress made in the field of molecular allergen characterization, new allergy vaccines based on recombinant allergens, recombinant hypoallergenic allergen derivatives and allergen-derived T cell peptides have entered clinical testing and hold promise to reduce the side-effects and to increase the specificity as well as the efficacy of SIT. Here, we present a refined immunotherapy concept, which is based on the use of peptides derived from allergen surfaces that exhibit reduced, allergen-specific IgE as well as T cell reactivity. These peptides when fused to non-allergenic carriers give rise to allergen-specific protective IgG responses with T cell help from a non-allergenic carrier molecule. We summarize the experimental data demonstrating that such peptide vaccines can bypass allergen-specific IgE as well as T cell activation and may be administered at high doses without IgE- and T cell-mediated side-effects. Should these peptide vaccines prove efficacious and safe in clinical trials, it may become possible to develop convenient, safe and broadly applicable forms of SIT as true alternatives to symptomatic, drug-based allergy treatment. PMID:20210812

  6. E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination.

    PubMed

    Zhao, Yixia; Guo, Hui; Qiao, Guilin; Zucker, Mark; Langdon, Wallace Y; Zhang, Jian

    2015-02-15

    CD28 costimulation is essential for the development of thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28(-/-) mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28(-/-) T cells, the defective development of tTregs in Cd28(-/-) mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28(-/-) mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development. PMID:25560411

  7. Protein phosphatase-1 is involved in the maintenance of normal homeostasis and in UVA irradiation-induced pathological alterations in HaCaT cells and in mouse skin.

    PubMed

    Dedinszki, Dóra; Sipos, Adrienn; Kiss, Andrea; Bátori, Róbert; Kónya, Zoltán; Virág, László; Erd?di, Ferenc; Lontay, Beáta

    2015-01-01

    The number of ultraviolet (UV) radiation-induced skin diseases such as melanomas is on the rise. The altered behavior of keratinocytes is often coupled with signaling events in which Ser/Thr specific protein kinases and phosphatases regulate various cellular functions. In the present study the role of protein phosphatase-1 (PP1) was investigated in the response of human keratinocyte (HaCaT) cells and mouse skin to UV radiation. PP1 catalytic subunit (PP1c) isoforms, PP1c?/? and PP1c?, are all localized to the cytoskeleton and cytosol of keratinocytes, but PP1c? was found to be dominant over PP1?/? in the nucleus. PP1c-silencing in HaCaT cells decreased the phosphatase activity and suppressed the viability of the cells. Exposure to a 10 J/cm(2) UVA dose induced HaCaT cell death and resulted in a 30% decrease of phosphatase activity. PP1c-silencing and UVA irradiation altered the gene expression profile of HaCaT cells and suggested that the expression of 19 genes was regulated by the combined treatments with many of these genes being involved in malignant transformation. Microarray analysis detected altered expression levels of genes coding for melanoma-associated proteins such as keratin 1/10, calcium binding protein S100A8 and histone 1b. Treatment of Balb/c mice with the PP1-specific inhibitor tautomycin (TM) exhibited increased levels of keratin 1/10 and S100A8, and a decreased level of histone 1b proteins following UVA irradiation. Moreover, TM treatment increased pigmentation of the skin which was even more apparent when TM was followed by UVA irradiation. Our data identify PP1 as a regulator of the normal homeostasis of keratinocytes and the UV-response. PMID:25446992

  8. T Cell Renewal Rates, Telomerase, and Telomere Length Shortening1

    E-print Network

    Utrecht, Universiteit

    T Cell Renewal Rates, Telomerase, and Telomere Length Shortening1 Rob J. De Boer2 and Andre´ J division rates of naive and memory T cells during clonal expansion and normal renewal. The results show and memory T cells may largely reflect the difference in renewal rates between these subpopulations rather

  9. The T Cell Leukemia Oncoprotein SCL\\/tal-1 Is Essential for Development of All Hematopoietic Lineages

    Microsoft Academic Search

    Catherine Porcher; Wojciech Swat; Karen Rockwell; Yuko Fujiwara; Frederick W Alt; Stuart H Orkin

    1996-01-01

    The T cell leukemia oncoprotein SCL\\/tal-1, a basic–helix-loop-helix transcription factor, is required for production of embryonic red blood cells in the mouse yolk sac. To define roles in other lineages, we studied the hematopoietic potential of homozygous mutant SCL\\/tal-1 ?\\/? embryonic stem cells upon in vitro differentiation and in vivo in chimeric mice. Here we show that in the absence

  10. IL4 Rapidly Produced by V?4 V?8 CD4 + T Cells Instructs Th2 Development and Susceptibility to Leishmania major in BALB\\/c Mice

    Microsoft Academic Search

    Pascal Launois; Ivan Maillard; Sabine Pingel; Kristin G. Swihart; Ioannis Xénarios; Hans Acha-Orbea; Heidi Diggelmann; Richard M. Locksley; H. Robson MacDonald; Jacques A. Louis

    1997-01-01

    BALB\\/c mice develop aberrant T helper 2 (Th2) responses and suffer progressive disease after infection with Leishmania major. These outcomes depend on the production of interleukin-4 (IL-4) early after infection. Here we demonstrate that the burst of IL-4 mRNA, peaking in draining lymph nodes of BALB\\/c mice 16 hr after infection, occurs within CD4+ T cells that express V?4 V?8

  11. Infection of BALB/c mice with the filarial nematode Litomosoides sigmodontis: role of CD4+ T cells in controlling larval development.

    PubMed Central

    Al-Qaoud, K M; Taubert, A; Zahner, H; Fleischer, B; Hoerauf, A

    1997-01-01

    Litomosoides sigmodontis is the only filaria which develops from infective larvae into adults in immunocompetent laboratory mice. Depletion of CD4+ T cells from infected BALB/c mice resulted in worm and microfilarial burdens significantly higher than those of infected controls. Th2 cytokines, eosinophilia, and immunoglobulin E, which were strongly induced in infected controls, were diminished in CD4-depleted mice. PMID:9169791

  12. Development of a whole blood intracellular cytokine staining assay for mapping CD4 + and CD8 + T-cell responses across the HIV1 genome

    Microsoft Academic Search

    Stephen Meddows-Taylor; Sharon Shalekoff; Louise Kuhn; Glenda E. Gray; Caroline T. Tiemessen

    2007-01-01

    A whole blood peptide mapping intracellular cytokine staining (ICS) assay was developed that allows the direct comparison, at the individual peptide level, of CD4+ and CD8+ T-cell responses that span every encoded protein, in patients infected with HIV-1. Whole blood samples from HIV-1 infected patients were stimulated with overlapping synthetic peptides spanning nine subtype C HIV-1 gene regions (Gag, Pol,

  13. Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase.

    PubMed

    Webb, Louise M C; Vigorito, Elena; Wymann, Matthias P; Hirsch, Emilio; Turner, Martin

    2005-09-01

    The role of PI3K activity in T lymphocyte development is obscure because mice deficient in single PI3K catalytic subunits either die before birth (p110alpha-/- and p110beta-/-) or lack a significant T cell developmental phenotype (p110gamma-/- and p110delta-/-). We have generated mice deficient in both p110gamma and p110delta and show that p110gamma/delta-/- mice have a profound block in T cell development that occurs at the beta-selection checkpoint. We show that pre-TCR-induced signaling is significantly reduced in p110gamma/delta-/- thymocytes and that this results in a concomitant lack of proliferative expansion and increased apoptosis. The survival defect in p110gamma/delta-/- thymocytes is associated with increased levels of the pro-apoptotic molecule Bcl2 interacting mediator of cell death. This work demonstrates that PI3K activity is critical for T cell development and depends on the combined function of p110gamma and p110delta. PMID:16116162

  14. Epithelial Defence by ?? T Cells

    Microsoft Academic Search

    Dieter Kabelitz; Lothar Marischen; Hans-Heinrich Oberg; Wolfgang Holtmeier; Daniela Wesch

    2005-01-01

    ?? T cells constitute a separate lineage of T lymphocytes which differ from conventional ?? T cells with regard to T cell receptor (TCR) repertoire and tissue localization. In murine skin, ?? T cells expressing a canonical V?5 TCR are abundant and contribute as so-called dendritic epidermal T cells to local immune surveillance. In humans, major subsets of ?? T

  15. Homeostasis and effector function of lymphopenia-induced ‘memory-like’ T cells in constitutively T cell-depleted mice.1

    PubMed Central

    Voehringer, David; Liang, Hong-Erh; Locksley, Richard M.

    2009-01-01

    Summary Naive T lymphocytes acquire a phenotype similar to antigen-experienced memory T cells as a result of proliferation under lymphopenic conditions. Such ‘memory-like’ T cells (TML) constitute a large fraction of the peripheral T cell pool in patients recovering from T cell ablative therapies, HIV patients under highly active antiretroviral therapy and in the elderly population. To generate a model which allows characterization of TML cells without adoptive transfer, irradiation or thymectomy, we developed genetically modified mice which express diphtheria toxin A under control of a loxP flanked stop cassette (R-DTA mice). Crossing these mice to CD4Cre mice resulted in efficient ablation of CD4 single positive thymocytes whereas double positive and CD8 single positive thymocytes were only partially affected. In the periphery the pool of naïve (CD44lo CD62Lhi) T cells was depleted. However, some T cells were resistant to Cre-activity, escaped deletion in the thymus and underwent lymphopenia-induced proliferation resulting in a pool of TML cells that was similar in size and turnover to the pool of CD44hiCD62Llo memory-phenotype T cells in control mice. CD4Cre/R-DTA mice remained lymphopenic despite the large available immunological ‘space’ and normal antigen-induced T cell proliferation. CD4Cre/R-DTA mice showed a biased T cell receptor repertoire indicating oligoclonal T cell expansion. Infection with the helminth Nippostrongylus brasiliensis resulted in diminished effector cell recruitment and impaired worm expulsion demonstrating that TML cells are not sufficient to mediate an effective immune response. PMID:18354198

  16. T cell receptor restriction of diabetogenic autoimmune NOD T cells.

    PubMed

    Simone, E; Daniel, D; Schloot, N; Gottlieb, P; Babu, S; Kawasaki, E; Wegmann, D; Eisenbarth, G S

    1997-03-18

    Restricted use of T cell receptor (TCR) gene segments is characteristic of several induced autoimmune disease models. TCR sequences have previously been unavailable for pathogenic T cells which react with a defined autoantigen in a spontaneous autoimmune disease. The majority of T cell clones, derived from islets of NOD mice which spontaneously develop type I diabetes, react with insulin peptide B-(9-23). We have sequenced the alpha and beta chains of TCRs from these B-(9-23)-reactive T cell clones. No TCR beta chain restriction was found. In contrast, the clones (10 of 13) used V alpha13 coupled with one of two homologous J alpha segments (J alpha45 or J alpha34 in 8 of 13 clones). Furthermore, 9 of 10 of the V alpha13 segments are a novel NOD sequence that we have tentatively termed V alpha13.3. This dramatic alpha chain restriction, similar to the beta chain restriction of other autoimmune models, provides a target for diagnostics and immunomodulatory therapy. PMID:9122227

  17. T cells in atherosclerosis

    PubMed Central

    2013-01-01

    Atherosclerosis is a chronic inflammatory disease of the artery wall. Atherosclerotic lesions contain monocytes, macrophages, smooth muscle cells and T lymphocytes. Here, we review the role of T-lymphocyte subsets in atherosclerosis. Among CD4+ T cells, Th1 cells are pro-atherogenic, Treg cells are athero-protective and the role of Th2 and Th17 cells remains unclear. The role of follicular helper T cells in atherosclerosis remains unknown, as is the role of CD8+ T cells. NKT cells bind glycolipid antigens and exert a pro-atherogenic role. The antigen specificity of T-cell responses in atherosclerosis is poorly understood. In order to enable antigen-specific prevention or therapy, a better understanding of these mechanisms is needed. PMID:24154816

  18. Development of angioimmunoblastic T-cell lymphoma after treatment of diffuse large B-cell lymphoma: a case report and review of literature

    PubMed Central

    Wang, Yaya; Xie, Bailu; Chen, Yu; Huang, Zhenqian; Tan, Huo

    2014-01-01

    Cases of diffuse large B-cell lymphoma (DLBCL) arising after the initial diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and DLBCL synchronous with AITL have been reported. To date, there is no report on the subsequent development of AITL in patients with DLBCL. Here we presented a rare case of AITL developing six months after the initial diagnosis of DLBCL. In order to investigate the clinical and molecular features of patients with AITL and DLBCL, we also reviewed the literature on AITL patients developing DLBCL, and patients with composite AITL and DLBCL. PMID:25031772

  19. Impaired T-Cell Function in B-Cell Lymphoma: A Direct Consequence of Events at the Immunological Synapse?

    PubMed Central

    Nassef Kadry Naguib Roufaiel, Marian; Wells, James W.; Steptoe, Raymond J.

    2015-01-01

    Tumors can escape immune destruction through the development of antigen loss variants and loss of antigen processing/presentation pathways, thereby rendering them invisible to T cells. Alternatively, mechanisms of peripheral T-cell tolerance that would normally be important for protection from the development of autoimmunity may also be co-opted to (i) generate an immuno-inhibitory tumor environment, (ii) promote development of regulatory cell populations, or (iii) cell-intrinsically inactivate tumor-specific T cells. Emerging evidence suggests that T-cell function is impaired in hematological malignancies, which may manifest from cognate interactions between T cells and the tumor. The immunological synapse forms the cognate T-cell and antigen-presenting cell interaction and is the site where key signalling events, including those delivered by co-inhibitory receptors, that determine the fate of T cells occur. Here, we review evidence that events at the immune synapse between T cells and malignant B cells and alterations in immune synapse function may contribute to loss of T-cell function in B-cell malignancies.

  20. Immunoregulatory T Cell Function in Multiple Myeloma

    PubMed Central

    Ozer, H.; Han, T.; Henderson, E. S.; Nussbaum, A.; Sheedy, D.

    1981-01-01

    Multiple myeloma is a malignancy characterized by uncontrolled monoclonal B cell differentiation and immunoglobulin production. In most instances, there is concomitant reduction in polyclonal differentiation and immunoglobulin synthesis both in vivo and in vitro. In in vitro pokeweed mitogen-induced B cell differentiation assays, proliferation and polyclonal immunoglobulin secretion optimally requires T cell help and can be inhibited both by monocytes and suppressor T cells. Helper function and monocyte-mediated suppression are relatively radio-resistant whereas T suppressor function is sensitive to 2,000 rad x-irradiation. We have examined myeloma T cell subset function in this assay using recombinations of isolated patient and normal B cells, T cells, and T cell subsets. Monocytes were removed by a carbonyl iron ingestion technique, normal and myeloma T cells were fractionated on the basis of Fc receptors for immunoglobulin (Ig) G (T?) or IgM (T? or T non-?), and proliferation and IgG secretion after co-culture determined by [3H]thymidine incorporation and radio-immunoassay, respectively. Myeloma B cells demonstrate quantitatively and qualitatively normal blastogenic responses and are appropriately regulated by either autologous or allogeneic T helper and suppressor subsets. Despite normal proliferation, however, myeloma B cells remain deficient in subsequent differentiation and immunoglobulin secretion even when co-cultured in the absence of monocytes or suppressor T cells and the presence of normal helper cells. Myeloma T cell populations, in contrast, are entirely normal in helper capacity over a range of T:B ratios but are markedly deficient in radiosensitive and concanavalin A-induced suppressor activity. T suppressor cell dysfunction in multiple myeloma is apparently due to a deficit in the T non-? suppressor subset, whereas T? cells, although proportionately reduced, are functionally normal. This unique T suppressor deficit reflects the heterogeneity of suppressor mechanisms in this disease and may represent a compensatory response to the monoclonal proliferation or the involvement of regulatory T cells in the pathogenesis of the malignancy. PMID:6451635

  1. Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell progenitors.

    PubMed

    Rolink, A G; Nutt, S L; Melchers, F; Busslinger, M

    1999-10-01

    The mechanisms controlling the commitment of haematopoietic progenitors to the B-lymphoid lineage are poorly understood. The observations that mice deficient in E2A and EBF lack B-lineage cells have implicated these two transcription factors in the commitment process. Moreover, the expression of genes encoding components of the rearrangement machinery (RAG1, RAG2, TdT) or pre-B-cell receptor (lambda5, VpreB, Igalpha, Igbeta) has been considered to indicate B-lineage commitment. All these genes including E2A and EBF are expressed in pro-B cells lacking the transcription factor Pax5. Here we show that cloned Pax5-deficient pro-B cells transferred into RAG2-deficient mice provide long-term reconstitution of the thymus and give rise to mature T cells expressing alpha/beta-T-cell receptors. The bone marrow of these mice contains a population of cells of Pax5-/- origin with the same phenotype as the donor pro-B cells. When transferred into secondary recipients, these pro-B cells again home to the bone marrow and reconstitute the thymus. Hence, B-lineage commitment is determined neither by immunoglobulin DJ rearrangement nor by the expression of E2A, EBF, lambda5, VpreB, Igalpha and Igbeta. Instead, our data implicate Pax5 in the control of B-lineage commitment. PMID:10524629

  2. T cell activation.

    PubMed

    Smith-Garvin, Jennifer E; Koretzky, Gary A; Jordan, Martha S

    2009-01-01

    This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.Acronyms and DefinitionsAdapter protein: cellular protein that functions to bridge molecular interactions via characteristic domains able to mediate protein/protein or protein/lipid interactions Costimulation: signals delivered to T cells by cell surface receptors other than the TCR itself that potentiate T cell activation cSMAC: central supramolecular activation cluster Immunoreceptor tyrosine-based activation motif (ITAM): a short peptide sequence in the cytoplasmic tails of key surface receptors on hematopoietic cells that is characterized by tyrosine residues that are phosphorylated by Src family PTKs, enabling the ITAM to recruit activated Syk family kinases Inside-out signaling: signals initiated by engagement of immunoreceptors that lead to conformational changes and clustering of integrins, thereby increasing the affinity and avidity of the integrins for their ligands NFAT: nuclear factor of activated T cells PI3K: phosphoinositide 3-kinase PKC: protein kinase C PLC: phospholipase C pMHC: peptide major histocompatibility complex (MHC) complex pSMAC: peripheral supramolecular activation cluster PTK: protein tyrosine kinase Signal transduction: biochemical events linking surface receptor engagement to cellular responses TCR: T cell antigen receptor PMID:19132916

  3. Visualizing T Cell Migration in situ.

    PubMed

    Benechet, Alexandre P; Menon, Manisha; Khanna, Kamal M

    2014-01-01

    Mounting a protective immune response is critically dependent on the orchestrated movement of cells within lymphoid tissues. The structure of secondary lymphoid organs regulates immune responses by promoting optimal cell-cell and cell-extracellular matrix interactions. Naïve T cells are initially activated by antigen presenting cells in secondary lymphoid organs. Following priming, effector T cells migrate to the site of infection to exert their functions. Majority of the effector cells die while a small population of antigen-specific T cells persists as memory cells in distinct anatomical locations. The persistence and location of memory cells in lymphoid and non-lymphoid tissues is critical to protect the host from re-infection. The localization of memory T cells is carefully regulated by several factors including the highly organized secondary lymphoid structure, the cellular expression of chemokine receptors and compartmentalized secretion of their cognate ligands. This balance between the anatomy and the ordered expression of cell surface and soluble proteins regulates the subtle choreography of T cell migration. In recent years, our understanding of cellular dynamics of T cells has been advanced by the development of new imaging techniques allowing in situ visualization of T cell responses. Here, we review the past and more recent studies that have utilized sophisticated imaging technologies to investigate the migration dynamics of naïve, effector, and memory T cells. PMID:25120547

  4. T Cell Apoptosis in Human Heart Allografts

    PubMed Central

    Van Hoffen, Els; Van Wichen, Dick F.; Leemans, Jaklien C.; Broekhuizen, Richard A.J.F.; Bruggink, Annette H.; De Boer, Mark; De Jonge, Nicolaas; Kirkels, Hans; Slootweg, Piet J.; Gmelig-Meyling, Frits H.J.; De Weger, Roel A.

    1998-01-01

    It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation. PMID:9846972

  5. A leaky mutation in CD3D differentially affects ?? and ?? T cells and leads to a T??–T??+B+NK+ human SCID

    PubMed Central

    Gil, Juana; Busto, Elena M.; Garcillán, Beatriz; Chean, Carmen; García-Rodríguez, Maria Cruz; Díaz-Alderete, Andrea; Navarro, Joaquín; Reiné, Jesús; Mencía, Angeles; Gurbindo, Dolores; Beléndez, Cristina; Gordillo, Isabel; Duchniewicz, Marlena; Höhne, Kerstin; García-Sánchez, Félix; Fernández-Cruz, Eduardo; López-Granados, Eduardo; Schamel, Wolfgang W.A.; Moreno-Pelayo, Miguel A.; Recio, María J.; Regueiro, José R.

    2011-01-01

    T cells recognize antigens via their cell surface TCR and are classified as either ?? or ?? depending on the variable chains in their TCR, ? and ? or ? and ?, respectively. Both ?? and ?? TCRs also contain several invariant chains, including CD3?, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3?-deficient patients described to date showed a complete block in T cell development. However, CD3?-KO mice have an ?? T cell–specific defect. Here, we report 2 unrelated cases of SCID with a selective block in ?? but not in ?? T cell development, associated with a new splicing mutation in the CD3D gene. The patients’ T cells showed reduced CD3D transcripts, CD3? proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant ?? T cells were oligoclonal. T cell–dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of ?? T cells, surface TCR expression was more reduced in ?? than in ?? T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3? requirements for ?? versus ?? T cell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected. PMID:21926461

  6. Double Negative (DN) ?? T Cells: misperception and overdue recognition

    PubMed Central

    Martina, Maria N; Noel, Sanjeev; Saxena, Ankit; Rabb, Hamid; Hamad, Abdel Rahim A

    2015-01-01

    CD4?CD8? double negative (DN) ?? T cells are legitimate components of the normal immune system. However, they are poorly understood and largely ignored by immunologists because of their historical association with the lymphoproliferation that occurs in mice (lpr and gld) and humans (ALPS patients) with impaired Fas-mediated apoptosis where they are considered abnormal T cells. We believe that the traditional view that DN T cells that cause lymphoproliferation (hereafter referred to as lpr DN T cells) are CD4 and CD8 T cells that lost their coreceptor, conceived more than two decades ago, is flawed and that conflating lpr DN T cells with DN T cells found in normal immune system (hereafter referred to as nDN T cells) is unnecessarily dampening interest of this potentially important cell type. To begin rectifying these misperceptions, we will revisit the traditional view of lpr DN T cells and show that it does not hold true in light of recent immunological advances. In lieu of it, we offer a new model proposing that Fas-mediated apoptosis actively removes normally existing DN T cells from the periphery and that impaired Fas-mediated apoptosis leads to accumulation of these cells rather than de novo generation of DN T cells from activated CD4 or CD8 T cells. By doing so, we hope to provoke a new discussion that may lead to a consensus about the origin of lpr DN T cells and regulation of their homeostasis by the Fas pathway and reignite wider interest in nDN T cells. PMID:25420721

  7. Breaking the co-operation between bystander T-cells and natural killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice.

    PubMed

    Wirsdörfer, Florian; Bangen, Jörg M; Pastille, Eva; Hansen, Wiebke; Flohé, Stefanie B

    2015-06-01

    Nosocomial infections represent serious complications after traumatic or surgical injuries in intensive care units. The pathogenesis of the underlying immunosuppression is only incompletely understood. In the present study, we investigated whether injury interferes with the function of the adaptive immune system in particular with the differentiation of antigen-specific T helper (Th)-cell responses in vivo. We used a mouse model for traumatic gastrocnemius muscle injury. Ovalbumin (OVA), which served as a foreign model antigen, was injected into the hind footpads for determination of the differentiation of OVA-specific Th-cells in the draining popliteal lymph node (pLN). The release of interferon (IFN)-? from OVA-specific Th-cells was impaired within 24 h after injury and this impairment persisted for at least 7 days. In contrast, the proliferation of OVA-specific Th-cells remained unaffected. Injury did not modulate the function of antigen-presenting cells (APCs) in the pLN. Adoptive transfer of total T-cells from pLNs of injured mice inhibited IFN-? production by OVA-specific Th-cells in naive mice. Suppressed Th1 priming did not occur in lymphocyte-deficient mice after injury but was restored by administration of T-cells before injury. Moreover, the suppression of Th1 differentiation required the presence of natural killer (NK) cells that were recruited to the pLN after injury; this recruitment was dependent on lymphocytes, toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). In summary, upon traumatic skeletal muscle injury T-cells and NK cells together prevent the development of protective Th1 immunity. Breaking this co-operation might be a novel approach to reduce the risk of infectious complications after injury. PMID:25609031

  8. Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes.

    PubMed

    Paul, Sinu; Lindestam Arlehamn, Cecilia S; Scriba, Thomas J; Dillon, Myles B C; Oseroff, Carla; Hinz, Denise; McKinney, Denise M; Carrasco Pro, Sebastian; Sidney, John; Peters, Bjoern; Sette, Alessandro

    2015-07-01

    Computational prediction of HLA class II restricted T cell epitopes has great significance in many immunological studies including vaccine discovery. In recent years, prediction of HLA class II binding has improved significantly but a strategy to globally predict the most dominant epitopes has not been rigorously defined. Using human immunogenicity data associated with sets of 15-mer peptides overlapping by 10 residues spanning over 30 different allergens and bacterial antigens, and HLA class II binding prediction tools from the Immune Epitope Database and Analysis Resource (IEDB), we optimized a strategy to predict the top epitopes recognized by human populations. The most effective strategy was to select peptides based on predicted median binding percentiles for a set of seven DRB1 and DRB3/4/5 alleles. These results were validated with predictions on a blind set of 15 new allergens and bacterial antigens. We found that the top 21% predicted peptides (based on the predicted binding to seven DRB1 and DRB3/4/5 alleles) were required to capture 50% of the immune response. This corresponded to an IEDB consensus percentile rank of 20.0, which could be used as a universal prediction threshold. Utilizing actual binding data (as opposed to predicted binding data) did not appreciably change the efficacy of global predictions, suggesting that the imperfect predictive capacity is not due to poor algorithm performance, but intrinsic limitations of HLA class II epitope prediction schema based on HLA binding in genetically diverse human populations. PMID:25862607

  9. Transnuclear Mice with Pre-defined T Cell Receptor Specificities Against Toxoplasma gondii Obtained via SCNT

    E-print Network

    Suh, Heikyung

    Mice that are transgenic for rearranged antigen-specific T cell receptors (TCRs) are essential tools to study T cell development and function. Such TCRs are usually isolated from the relevant T cells after long-term culture, ...

  10. High Epitope Expression Levels Increase Competition between T Cells

    E-print Network

    Bonhoeffer, Sebastian

    High Epitope Expression Levels Increase Competition between T Cells Almut Scherer, Marcel Salathe epitope ligand. We have developed an individual- based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell

  11. The role of the T cell in autoimmune inflammation

    Microsoft Academic Search

    Alla Skapenko; Jan Leipe; Peter E Lipsky; Hendrik Schulze-Koops

    2005-01-01

    T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as

  12. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship.

    PubMed

    Strasser, A; Harris, A W; Cory, S

    1991-11-29

    Early death is the fate of most developing T lymphocytes. Because bcl-2 can promote cell survival, we tested its impact in mice expressing an E mu-bcl-2 transgene within the T lymphoid compartment. The T cells showed remarkably sustained viability and some spontaneous differentiation in vitro. They also resisted killing by lymphotoxic agents. Although total T cell numbers and the rate of thymic involution were unaltered, the response to immunization was enhanced, consistent with reduced death of activated T cells. No T cells reactive with self-superantigens appeared in the lymph nodes, but an excess was found in the thymus. These observations, together with previous findings on B cells, suggest that modulated bcl-2 expression is a determinant of life and death in normal lymphocytes. PMID:1959134

  13. Obesity Impairs ?? T Cell Homeostasis and Antiviral Function in Humans

    PubMed Central

    Dutt, Shelley; Han, Peggy P.; Fujioka, Ken; Jameson, Julie M.

    2015-01-01

    Obese patients are susceptible to increased morbidity and mortality associated with infectious diseases such as influenza A virus. ?? T cells and memory ?? T cells play key roles in reducing viral load by rapidly producing IFN-? and lysing infected cells. In this article we analyze the impact of obesity on T lymphocyte antiviral immunity. Obese donors exhibit a reduction in ?? T cells in the peripheral blood. The severity of obesity negatively correlates with the number of ?? T cells. The remaining ?? T cells have a skewed maturation similar to that observed in aged populations. This skewed ?? T cell population exhibits a blunted antiviral IFN-? response. Full ?? T cell function can be restored by potent stimulation with 1-Hydroxy-2-methyl-buten-4yl 4-diphosphate (HDMAPP), suggesting that ?? T cells retain the ability to produce IFN-?. Additionally, ?? T cells from obese donors have reduced levels of IL-2R?. IL-2 is able to restore ?? T cell antiviral cytokine production, which suggests that ?? T cells lack key T cell specific growth factor signals. These studies make the novel finding that the ?? T cell antiviral immune response to influenza is compromised by obesity. This has important implications for the development of therapeutic strategies to improve vaccination and antiviral responses in obese patients. PMID:25785862

  14. CD8 T Cell Tolerance to a Tumor-Associated Self-Antigen Is Reversed by CD4 T Cells Engineered To Express the Same T Cell Receptor

    PubMed Central

    Ghorashian, Sara; Veliça, Pedro; Chua, Ignatius; McNicol, Anne-Marie; Carpenter, Ben; Holler, Angelika; Nicholson, Emma; Ahmadi, Maryam; Zech, Mathias; Xue, Shao-An; Uckert, Wolfgang; Morris, Emma; Chakraverty, Ronjon

    2015-01-01

    Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR–engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8+ T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR–engineered CD4+ T cells provided help and restored cytotoxic function of CD8+ T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4+ T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I–restricted TCR responsible for Ag recognition and tolerance induction in CD8+ T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I–restricted CD4+ T cells may enhance the efficacy of therapeutic TCR-engineered CD8+ T cells and can be readily generated with the same TCR. PMID:25539815

  15. Hepatosplenic alphabeta T cell lymphoma.

    PubMed

    Nagai, Yuya; Ikegame, Kazuhiro; Mori, Minako; Inoue, Daichi; Kimura, Takaharu; Shimoji, Sonoko; Togami, Katsuhiro; Tabata, Sumie; Kurata, Masayuki; Imai, Yukihiro; Matsushita, Akiko; Nagai, Kenichi; Ogawa, Hiroyasu; Takahashi, Takayuki

    2010-04-01

    A 32-year-old male with chronic hepatitis B was admitted to a hospital with cellulitis in the right leg in September 2006. Pancytopenia, hepatosplenomegaly, and systemic superficial lymph node swelling were noted, and he was referred to our hospital. He developed fever and liver dysfunction in June 2007 and underwent a splenectomy. His pancytopenia subsequently improved. A pathologic diagnosis of hepatosplenic alphabeta T cell lymphoma was made by examining spleen tissue and biopsy specimens of the liver and mesenteric lymph node. He had stage IVB disease because neoplastic T cells were noted in the bone marrow. The response of the lymphoma to conventional chemotherapy including the CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) and DeVIC (dexamethasone, etoposide, ifoshamide, carboplatin) regimens was poor and transient. A partial remission was obtained with an ESHAP (etoposide, cisplatin, cytarabine, methylprednisolone) regimen. Therefore, we planned a bone marrow transplantation (BMT) from an HLA-haploidentical sibling donor. He was moved to the Department of Hematology, Hyogo Medical College, to receive this BMT as part of a clinical trial. During the conditioning procedure for the transplantation, however, he died of septicemia. Since hepatosplenic alphabeta T cell lymphoma is very rare with only 23 reported cases to date, herein we report this case and discuss the therapeutic strategy. PMID:20217452

  16. A Comparative Study of N-glycolylneuraminic Acid (Neu5Gc) and Cytotoxic T Cell (CT) Carbohydrate Expression in Normal and Dystrophin-Deficient Dog and Human Skeletal Muscle

    PubMed Central

    Martin, Paul T.; Golden, Bethannie; Okerblom, Jonathan; Camboni, Marybeth; Chandrasekharan, Kumaran; Xu, Rui; Varki, Ajit; Flanigan, Kevin M.; Kornegay, Joe N.

    2014-01-01

    The expression of N-glycolylneuraminic acid (Neu5Gc) and the cytotoxic T cell (CT) carbohydrate can impact the severity of muscular dystrophy arising from the loss of dystrophin in mdx mice. Here, we describe the expression of these two glycans in skeletal muscles of dogs and humans with or without dystrophin-deficiency. Neu5Gc expression was highly reduced (>95%) in muscle from normal golden retriever crosses (GR, n?=?3) and from golden retriever with muscular dystrophy (GRMD, n?=?5) dogs at multiple ages (3, 6 and 13 months) when compared to mouse muscle, however, overall sialic acid expression in GR and GRMD muscles remained high at all ages. Neu5Gc was expressed on only a minority of GRMD satellite cells, CD8+ T lymphocytes and macrophages. Human muscle from normal (no evident disease, n?=?3), Becker (BMD, n?=?3) and Duchenne (DMD, n?=?3) muscular dystrophy individuals had absent to very low Neu5Gc staining, but some punctate intracellular muscle staining was present in BMD and DMD muscles. The CT carbohydrate was localized to the neuromuscular junction in GR muscle, while GRMD muscles had increased expression on a subset of myofibers and macrophages. In humans, the CT carbohydrate was ectopically expressed on the sarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. These data are consistent with the notion that altered Neu5Gc and CT carbohydrate expression may modify disease severity resulting from dystrophin deficiency in dogs and humans. PMID:24505439

  17. Tumor Evasion from T Cell Surveillance

    PubMed Central

    Töpfer, Katrin; Kempe, Stefanie; Müller, Nadja; Schmitz, Marc; Bachmann, Michael; Cartellieri, Marc; Schackert, Gabriele; Temme, Achim

    2011-01-01

    An intact immune system is essential to prevent the development and progression of neoplastic cells in a process termed immune surveillance. During this process the innate and the adaptive immune systems closely cooperate and especially T cells play an important role to detect and eliminate tumor cells. Due to the mechanism of central tolerance the frequency of T cells displaying appropriate arranged tumor-peptide-specific-T-cell receptors is very low and their activation by professional antigen-presenting cells, such as dendritic cells, is frequently hampered by insufficient costimulation resulting in peripheral tolerance. In addition, inhibitory immune circuits can impair an efficient antitumoral response of reactive T cells. It also has been demonstrated that large tumor burden can promote a state of immunosuppression that in turn can facilitate neoplastic progression. Moreover, tumor cells, which mostly are genetically instable, can gain rescue mechanisms which further impair immune surveillance by T cells. Herein, we summarize the data on how tumor cells evade T-cell immune surveillance with the focus on solid tumors and describe approaches to improve anticancer capacity of T cells. PMID:22190859

  18. Heterogeneity of gangliosides among T cell subsets.

    PubMed

    Inokuchi, Jin-ichi; Nagafuku, Masakazu; Ohno, Isao; Suzuki, Akemi

    2013-09-01

    Gangliosides are major components of highly organized membrane microdomains or rafts, yet little is known about the role of gangliosides in raft organization. This is also the case of gangliosides in TCR-mediated activation. Comprehensive structural analysis of gangliosides in the primary thymocytes and CD4(+) T and CD8(+) T cells was not achieved due to technical difficulties. We have found that CD8(+) T cells express very high levels of o-series gangliosides, but on the other hand, CD4(+) T cells preferably express a-series gangliosides. In the TCR-dependent activation, CD4(+) T cells selectively require a-series gangliosides, but CD8(+) T cells do require only o-series gangliosides but not a-series gangliosides. Ganglioside GM3 synthase-deficient mice lacking a-series gangliosides neither exhibited the TCR-dependent activation of CD4(+) T nor developed ovalbumin-induced allergic airway inflammation. These findings imply that the distinct expression pattern of ganglioside species in CD4(+) and CD8(+) T cells define the immune function of each T cell subset. PMID:23233133

  19. Increased Interleukin-4 production by CD8 and gammadelta T cells in health-care workers is associated with the subsequent development of active tuberculosis.

    PubMed

    Ordway, Diane J; Costa, Leonor; Martins, Marta; Silveira, Henrique; Amaral, Leonard; Arroz, Maria J; Ventura, Fernando A; Dockrell, Hazel M

    2004-08-15

    We evaluated immune responses to Mycobacterium tuberculosis in 10 health-care workers (HCWs) and 10 non-HCWs and correlated their immune status with the development of active tuberculosis (TB). Twenty individuals were randomly recruited, tested, and monitored longitudinally for TB presentation. Peripheral blood mononuclear cells (PBMCs) from donors were stimulated with M. tuberculosis and tested for cell proliferation and the production of interferon (IFN)- gamma, interleukin (IL)-5, and IL-4, by use of enzyme-linked immunosorbent or flow-cytometric assays. HCWs had higher levels of cell proliferation (24,258 cpm) and IFN- gamma (6373 pg/mL) to M. tuberculosis than did non-HCWs (cell proliferation, 11,462 cpm; IFN- gamma, 3228 pg/mL). Six of 10 HCWs showed increased median percentages of CD8+IL-4+ (4.7%) and gammadelta +IL-4+ (2.3%) T cells and progressed to active TB. HCWs who remained healthy showed increased median percentages of CD8+IFN- gamma+ (25.0%) and gammadelta +IFN- gamma+ (8.0%) and lower percentages of CD8+IL-4+ (0.05%) and gammadelta +IL-4+ (0.03%) T cells. PMID:15272404

  20. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells.

    PubMed

    Yang, Baoli; Gay, Denise L; MacLeod, Megan K L; Cao, Xiao; Hala, Tamara; Sweezer, Eileen M; Kappler, John; Marrack, Philippa; Oliver, Paula M

    2008-12-01

    Nedd4 and Itch are E3 ubiquitin ligases that ubiquitinate similar targets in vitro and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 polarization. To test whether loss of Nedd4 affects T cells in the same way, we generated Nedd4(+/+) and Nedd4(-/-) fetal liver chimeras. Nedd4(-/-) T cells developed normally but proliferated less, produced less interleukin 2 and provided inadequate help to B cells. Nedd4(-/-) T cells contained more of the E3 ubiquitin ligase Cbl-b, and Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation. Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells. We propose that Nedd4 and Itch ubiquitinate distinct target proteins in vivo. PMID:18931680

  1. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells

    PubMed Central

    Yang, Baoli; Gay, Denise L.; MacLeod, Megan K.L.; Cao, Xiao; Hala, Tamara; Sweezer, Eileen M.; Kappler, John; Marrack, Philippa; Oliver, Paula M.

    2010-01-01

    Nedd4 and Itch are E3 ubiquitin ligases that, in vitro, ubiquitinate similar targets and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 (TH2) polarization. To test whether the loss of Nedd4 affects T cells in the same way, we generated Nedd4+/+ and Nedd4?/?fetal liver chimeras. Nedd4?/?T cells developed normally but proliferated less, produced less interleukin 2, and provided inadequate help to B cells. Nedd4?/?T cells contain increased amounts of Cbl-b protein, and Nedd4 was required for Cbl-b poly-ubquitination induced by CD28 co-stimulation. These data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells. We propose that Nedd4 and Itch ubiquitinate distinct target proteins in vivo. PMID:18931680

  2. Lipopolysaccharide enhances in vivo interleukin-2 production and proliferation by naive antigen-specific CD4 T cells via a Toll-like receptor 4-dependent mechanism

    PubMed Central

    Costalonga, Massimo; Zell, Traci

    2007-01-01

    Microbial adjuvants are essential for the development of T-cell-dependent antibody production, recall T-cell proliferation and interferon-? production following immunization with protein antigens. Using an adoptive transfer approach, we showed that the adjuvant lipopolysaccharide enhanced the frequency of cells producing interleukin-2, enhanced clonal expansion by antigen-specific CD4 T cells and increased CD86 and interleukin-1? production by antigen-presenting cells. All of these effects were dependent on Toll-like receptor-4 (TLR4) expression by cells other than the antigen-specific CD4 T cells. The ability of lipopolysaccharides to increase the number of antigen-specific CD4 T cells that survive after immunization probably explains the previous finding that antigen-specific proliferation by T cells from normal mice depends on previous exposure to antigen and adjuvant. PMID:17484770

  3. Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy

    PubMed Central

    Blyth, Benjamin J.; Kakinuma, Shizuko; Sunaoshi, Masaaki; Amasaki, Yoshiko; Hirano-Sakairi, Shinobu; Ogawa, Kanae; Shirakami, Ayana; Shang, Yi; Tsuruoka, Chizuru; Nishimura, Mayumi; Shimada, Yoshiya

    2015-01-01

    Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction in normal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, male and female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam at the Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumour volume (average linear energy transfer = 13 keV.?m-1) during patient radiotherapy protocols. The mice were monitored for the remainder of their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following an equivalent dose of 137Cs gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved in radiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared the genetic profile of the carbon ion- and gamma ray-induced tumours. The canonical set of genes previously associated with radiation-induced T cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhat different between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most striking finding was the observation of large interstitial deletions at various sites across the genome in carbon ion-induced tumours, which were only seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristic lesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed in radiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing second cancer risk in carbon ion radiotherapy patients. PMID:26125582

  4. Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy.

    PubMed

    Blyth, Benjamin J; Kakinuma, Shizuko; Sunaoshi, Masaaki; Amasaki, Yoshiko; Hirano-Sakairi, Shinobu; Ogawa, Kanae; Shirakami, Ayana; Shang, Yi; Tsuruoka, Chizuru; Nishimura, Mayumi; Shimada, Yoshiya

    2015-01-01

    Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction in normal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, male and female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam at the Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumour volume (average linear energy transfer = 13 keV.?m-1) during patient radiotherapy protocols. The mice were monitored for the remainder of their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following an equivalent dose of 137Cs gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved in radiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared the genetic profile of the carbon ion- and gamma ray-induced tumours. The canonical set of genes previously associated with radiation-induced T cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhat different between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most striking finding was the observation of large interstitial deletions at various sites across the genome in carbon ion-induced tumours, which were only seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristic lesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed in radiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing second cancer risk in carbon ion radiotherapy patients. PMID:26125582

  5. Non-Core RAG1 Regions Promote V? Rearrangements and ?? T Cell Development by Overcoming Inherent Inefficiency of V? Recombination Signal Sequences

    PubMed Central

    Horowitz, Julie E.; Bassing, Craig H.

    2014-01-01

    The RAG proteins are comprised of core endonuclease domains and non-core regions that modulate endonuclease activity. Mutation or deletion of non-core RAG regions in humans causes immunodeficiency and altered TCR repertoire, and mice expressing core but not full-length Rag1 (Rag1C/C) or Rag2 (Rag2C/C) exhibit lymphopenia, reflecting impaired V(D)J recombination and lymphocyte development. Rag1C/C mice display reduced D-to-J and V-to-DJ rearrangements of TCR? and IgH loci, while Rag2C/C mice show decreased V-to-DJ rearrangements and altered V?/VH repertoire. Since V?s/VHs only recombine to DJ complexes, the Rag1C/C phenotype could reflect roles for non-core RAG1 regions in promoting recombination during only the D-to-J step or during both steps. Here, we demonstrate that a pre-assembled TCR? gene, but not a pre-assembled D?J? complex or the pro-survival BCL2 protein, completely rescues ?? T cell development in Rag1C/C mice. We find that Rag1C/C mice exhibit altered V? utilization in V?-to-DJ? rearrangements, increased usage of 3’J? gene segments in V?-to-J? rearrangements, and abnormal changes in V? repertoire during ?? TCR selection. Inefficient V?/VH recombination signal sequences (RSSs) have been hypothesized to cause impaired V-to-DJ recombination on the background of a defective recombinase as in core-Rag mice. We show that replacement of the V?14 RSS with a more efficient RSS increases V?14 recombination and rescues ?? T cell development in Rag1C/C mice. Our data indicate that non-core RAG1 regions establish a diverse TCR repertoire by overcoming V? RSS inefficiency to promote V? recombination and ?? T cell development, and by modulating TCR? and TCR? gene segment utilization. PMID:24415779

  6. I spy alloreactive T cells.

    PubMed

    Alegre, Maria-Luisa

    2015-01-28

    High-throughput sequencing of the T cell receptor V? CDR3 region allowed longitudinal tracking of alloreactive T cells in kidney transplant patients, revealing clonal deletion as a mechanism of transplantation tolerance (Morris et al., this issue). PMID:25632032

  7. Southern Blot Patterns, Frequencies, and Junctional Diversity of T-cell Receptor4 Gene Rearrangements in Acute Lymphoblastic Leukemia

    Microsoft Academic Search

    Timo M. Breit; Ingrid L. M. Wolvers-Tettero; Auke Beishuizen; Marie-Anne J. Verhoeven; Elisabeth R. van Wering; Jacques J. M. van Dongen

    1993-01-01

    Southern blot analysis of T-cell receptor (TCR)-6 gene rear- rangements is useful for diagnostic studies on the clonality of lymphoproliferative diseases. We have developed 18 new TCR-8 gene probes by use of the polymerase chain reaction (PCR) techniques. Application of these probes for detailed analysis of the TCR-6 genes in normal control sam- ples, 138 T-cell acute lymphoblastic leukemias (T-ALL),

  8. Biological and biochemical characterization of a factor produced spontaneously by adherent cells of human immunodeficiency virus-infected patients inhibiting interleukin-2 receptor alpha chain (Tac) expression on normal T cells.

    PubMed Central

    Ammar, A; Cibert, C; Bertoli, A M; Tsilivakos, V; Jasmin, C; Georgoulias, V

    1991-01-01

    Adherent cells from human immunodeficiency virus (HIV)-infected subjects but not from normal blood donors, patients with Gram-positive or -negative bacteremia, active tuberculosis, toxoplasmosis, pulmonary aspergillosis, and cytomegalovirus infection produce spontaneously an activity which inhibits alpha chain of interleukin-2 (Tac) expression and interleukin 2 (IL-2) production by normal activated T cells and IL-2 production by these cells. A similar biologic activity was detected in culture supernatants of in vitro HIV-I-infected normal adherent and leukemic U937 cells. Tac-inhibitory activity is not cytotoxic and it could be detected in serum-free conditioned media. Recombinant granulocyte/macrophage colony-stimulating factor and phorbol myristate acetate stimulation of patients' and normal adherent cells did not enhance specifically the production of the Tac inhibitor. Biologically active conditioned media did not contain infectious virus as well as secreted p24, gp120 viral proteins; the biologic activity could not be abolished by anti-p24, anti-gp120, and anti-nef monoclonal antibodies or human purified polyclonal anti-HIV IgG. Gel filtration of conditioned media followed by anion exchange chromatography resulted in a 1,200-fold degree of purification and revealed that the biologically active molecule was cationic. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of this fraction and gel elution of the proteins showed that the biologic activity was associated with a 29-kD protein which was distinct from alpha- or gamma-interferon, tumor necrosis factor-alpha, and prostaglandin E2. The above findings demonstrate the production of inhibitory factor(s) during HIV infection, which might be involved in the pathogenesis of the patients' immune defect. Images PMID:1904071

  9. Memory CD8+ T cell differentiation

    PubMed Central

    Obar, Joshua J.; Lefrançois, Leo

    2010-01-01

    In response to infection or effective vaccination, naive antigen-specific CD8+ T cells undergo a dramatic highly orchestrated activation process. Initial encounter with an appropriately activated antigen-presenting cell leads to blastogenesis and an exponential increase in antigen-specific CD8+ T cell numbers. Simultaneously, a dynamic differentiation process occurs, resulting in formation of both primary effector and long-lived memory cells. Current findings have emphasized the heterogeneity of effector and memory cell populations with the description of multiple cellular subsets based on phenotype, function, and anatomic location. Yet, only recently have we begun to dissect the underlying factors mediating the temporal control of the development of distinct effector and memory CD8+ T cell sublineages. In this review we will focus on the requirements for mounting an effective CD8+ T cell response and highlight the elements regulating the differentiation of effector and memory subsets. PMID:20146720

  10. Distinct NF-kB activation pathways engaged by T-cell receptor and co-receptor CD28 on T-cells

    E-print Network

    Thaker, Youg Raj; Rudd, Christopher E

    2015-03-02

    biochemical signals which are amplified and converted into effector functions in a series of well-defined signaling pathways [7-10]. One of the earliest events of antigen ligation is the activation of src and syk family kinases such as Lck and ZAP-70... T Cell. Science 1998;281:413-416. 14. Clements JL, Yang B, Ross-Barta SE, Eliason SL, Hrstka RF, Williamson RA, et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 1998;281:416-419.\\ 15...

  11. An Exhaustion-Like Phenotype Constrains the Activity of CD4+ T Cells Specific for a Self and Melanoma Antigen

    PubMed Central

    Rausch, Matthew P.; Hastings, Karen Taraszka

    2015-01-01

    While the immune system has the capacity to recognize and destroy melanoma, tolerance mechanisms often hinder the development of effective anti-tumor immune responses. Since many melanoma antigens are self proteins expressed in normal melanocytes, self antigen exposure before tumor development can negatively impact the function of T cells specific for these self/tumor antigens. However, the contribution of self tolerance to anti-melanoma T cell dysfunction remains largely unexplored. We have previously described a TCR transgenic (Tg) mouse model in which T cells specific for the self/melanoma antigen, tyrosinase-related protein 1 (TRP1), develop in the presence of endogenous TRP1 expression (Ag+) and diminished antigen presentation due to the absence of gamma-interferon-inducible lysosomal thiol reductase (GILT-/-). We show that TRP1-specific T cells from these Ag+GILT-/-Tg mice do not protect from melanoma tumor growth, fail to induce autoimmune vitiligo, and undergo diminished proliferation compared to T cells from Ag-GILT+/+Tg mice. Despite an increased frequency of TRP1-specific Treg cells in Ag+GILT-/-Tg mice compared to Ag-GILT+/+Tg animals, Treg cell depletion only partially rescues the proliferative capacity of T cells from TRP1-expressing mice, suggesting the involvement of additional suppressive mechanisms. An increased percentage of melanoma-specific T cells from Ag+GILT-/-Tg animals express PD-1, an inhibitory receptor associated with the maintenance of T cell exhaustion. Antibody blockade of PD-1 partially improves the ability of TRP1-specific T cells from Ag+GILT-/-Tg mice to produce IL-2. These findings demonstrate that melanoma-specific T cells exposed to a self/melanoma antigen in healthy tissue develop an exhaustion-like phenotype characterized by PD-1-mediated immunosuppression prior to encounter with tumor. PMID:25875653

  12. Eos Is Redundant for Regulatory T Cell Function but Plays an Important Role in IL-2 and Th17 Production by CD4+ Conventional T Cells.

    PubMed

    Rieder, Sadiye Amcaoglu; Metidji, Amina; Glass, Deborah Dacek; Thornton, Angela M; Ikeda, Tohru; Morgan, Bruce A; Shevach, Ethan M

    2015-07-15

    Eos belongs to the Ikaros family of transcription factors. It was reported to be a regulatory T cell (Treg) signature gene, to play a critical role in Treg suppressor functions, and to maintain Treg stability. We used mice with a global deficiency in Eos to re-examine the role of Eos expression in both Tregs and conventional T cells (Tconvs). Tregs from Eos-deficient (Eos(-/-)) mice developed normally, displayed a normal Treg phenotype, and exhibited normal suppressor function in vitro. Eos(-/-) Tregs were as effective as Tregs from wild-type (WT) mice in suppressing inflammation in a model of inflammatory bowel disease. Bone marrow (BM) from Eos(-/-) mice was as effective as that from WT mice in controlling T cell activation when used to reconstitute immunodeficient mice in the presence of scurfy fetal liver cells. Surprisingly, Eos was expressed in activated Tconvs and was required for IL-2 production, CD25 expression, and proliferation in vitro by CD4(+) Tconvs. Eos(-/-) mice developed more severe experimental autoimmune encephalomyelitis than WT mice, displayed increased numbers of effector T cells in the periphery and CNS, and amplified IL-17 production. In conclusion, our studies are not consistent with a role for Eos in Treg development and function but demonstrate that Eos plays an important role in the activation and differentiation of Tconvs. PMID:26062998

  13. Cutting edge: CTLA-4 on effector T cells inhibits in trans.

    PubMed

    Corse, Emily; Allison, James P

    2012-08-01

    CTLA-4 is thought to inhibit effector T cells both intrinsically, by competing with CD28 for B7 ligands, and extrinsically, through the action of regulatory T cells (Tregs). We studied in vivo responses of normal and CTLA-4-deficient Ag-specific murine effector CD4(+) T cells. We directly demonstrate that effector T cell-restricted CTLA-4 inhibits T cell responses in a cell-extrinsic manner. Cotransfer experiments show that CTLA-4 on normal effector CD4(+) T cells completely abrogates the dramatically increased expansion normally experienced by their CTLA-4-deficient counterparts. Neither the wild-type nor the CTLA-4-deficient T cells express the Treg transcription factor Foxp3 when transferred alone or together. Thus, cell-extrinsic inhibition of T cell responses by CTLA-4 is not limited to Tregs but is also a function of effector T cells. PMID:22753941

  14. Apoptosis and T-cell depletion during feline infectious peritonitis.

    PubMed Central

    Haagmans, B L; Egberink, H F; Horzinek, M C

    1996-01-01

    Cats that have succumbed to feline infectious peritonitis, an immune-mediated disease caused by variants of feline coronaviruses, show apoptosis and T-cell depletion in their lymphoid organs. The ascitic fluid that develops in the course of the condition causes apoptosis in vitro but only in activated T cells. Since feline infectious peritonitis virus does not infect T cells, and viral proteins did not inhibit T-cell proliferation, we postulate that soluble mediators released during the infection cause apoptosis and T-cell depletion. PMID:8971027

  15. T Cell Receptor Signaling Kinetics Takes the Stage

    NSDL National Science Digital Library

    Yuri Sykulev (Thomas Jefferson University; Department of Microbiology and Immunology and Kimmel Cancer Center REV)

    2010-12-21

    It has been long surmised that the strength of stimulation of the T cell receptor (TCR) determines the robustness of TCR-mediated signaling and the magnitude of a T cell response. However, it is becoming evident that the signal from the TCR develops over time to approach its steady-state, affinity-determined maximal extent and that variations in this time have a substantial effect on the responsiveness of T cells. Here, I discuss data that show that the kinetics of signal propagation in various segments of the TCR signaling network can influence the spatiotemporal regulation of the effector functions of T cells and the quality of the T cell response.

  16. CD31 is required on CD4+ T cells to promote T cell survival during Salmonella infection

    PubMed Central

    Ross, Ewan A; Coughlan, Ruth E; Flores-Langarica, Adriana; Bobat, Saeeda; Marshall, Jennifer L; Hussain, Khiyam; Charlesworth, James; Abhyankar, Nikita; Hitchcock, Jessica; Gil, Cristina; López-Macías, Constantino; Henderson, Ian R; Khan, Mahmood; Watson, Steve P; MacLennan, Ian C M; Buckley, Christopher D; Cunningham, Adam F

    2011-01-01

    Haematopoietic cells constitutively express CD31/PECAM1 a signalling, adhesion receptor associated with controlling responses to inflammatory stimuli. Although expressed on CD4+ T cells, its function on these cells is unclear. To address this we have used a model of systemic Salmonella infection that induces high levels of T cell activation and depends upon CD4+ T cells for resolution. Infection of CD31-deficient (CD31KO) mice demonstrates that these mice fail to control infection effectively. During infection, CD31KO mice have diminished numbers of total CD4+ T cells and IFN-?-secreting Th1 cells. This is despite a higher proportion of CD31KO CD4+ T cells exhibiting an activated phenotype, and an undiminished capacity to prime normally and polarize to Th1. Reduced numbers of T cells reflected the increased propensity of naive and activated CD31KO T cells to undergo apoptosis after infection compared to wild-type (WT) T cells. Using adoptive transfer experiments we show that loss of CD31 on CD4+ T cells alone is sufficient to account for the defective CD31KO T cell accumulation. These data are consistent with CD31 helping to control T cell activation as in its absence T cells have a greater propensity to become activated, resulting in increased susceptibility to become apoptotic. The impact of CD31 loss on T cell homeostasis becomes most pronounced during severe, inflammatory and immunological stresses such as those caused by systemic Salmonella infection. This identifies a novel role for CD31 in regulating CD4 T cell homeostasis. PMID:21734076

  17. PTPN2 attenuates T-cell lymphopenia-induced proliferation

    NASA Astrophysics Data System (ADS)

    Wiede, Florian; La Gruta, Nicole L.; Tiganis, Tony

    2014-01-01

    When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8+ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigen-experienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptor-dependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

  18. Memory T Cells in Transplantation.

    PubMed

    Su, Charles A; Fairchild, Robert L

    2014-09-01

    Following infections and environmental exposures, memory T cells are generated that provide long-term protective immunity. Compared to their naïve T cell counterparts, memory T cells possess unique characteristics that endow them with the ability to quickly and robustly respond to foreign antigens. While such memory T cells are beneficial in protecting their hosts from recurrent infection, memory cells reactive to donor antigens pose a major barrier to successful transplantation and tolerance induction. Significant progress has been made over the past several decades contributing to our understanding of memory T cell generation, their distinct biology, and their detrimental impact in clinical and animal models of transplantation. This review focuses on the unique features which make memory T cells relevant to the transplant community and discusses potential therapies targeting memory T cells which may ameliorate allograft rejection. PMID:25435071

  19. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice

    Microsoft Academic Search

    Sharon L. Erickson; Frederic J. de Sauvage; Kristine Kikly; Karen Carver-Moore; Sharon Pitts-Meek; Nancy Gillett; Kathleen C. F. Sheehan; Robert D. Schreiber; David V. Goeddel; Mark W. Moore

    1994-01-01

    TUMOUR necrosis factor (TNF) elicits multiple biological effects through two distinct cell surface receptors, TNF-R1 (p55) and TNF-R2 (p75). Most TNF-mediated biological responses, such as cell death, gene induction, antiviral activity and cytokine production, have been attributed to TNF-R1 (refs 1-5). Gene targeting of this receptor confirms its role in the lethality attributable to low doses of lipopolysaccharide after sensitization

  20. Self-recognition specificity expressed by T cells from nude mice. Absence of detectable Ia-restricted T cells in nude mice that do exhibit self-K/D-restricted T cell responses

    SciTech Connect

    Kruisbeek, A.M.; Davis, M.L.; Matis, L.A.; Longo, D.L.

    1984-09-01

    The presence in athymic nude mice of precursor T cells with self-recognition specificity for either H-2 K/D or H-2 I region determinants was investigated. Chimeras were constructed of lethally irradiated parental mice receiving a mixture of F1 nude mouse (6-8 wk old) spleen and bone marrow cells. The donor inoculum was deliberately not subjected to any T cell depletion procedure, so that any potential major histocompatibility complex-committed precursor T cells were allowed to differentiate and expand in the normal parental recipients. 3 mo after reconstitution, the chimeras were immunized with several protein antigens in complete Freund's adjuvant in the footpads and their purified draining lymph node T cells tested 10 d later for ability to recognize antigen on antigen-presenting cells of either parental haplotype. Also, their spleen and lymph node cells were tested for ability to generate a cytotoxic T lymphocyte (CTL) response to trinitrophenyl (TNP)-modified stimulator cells of either parental haplotype. It was demonstrated that T cell proliferative responses of these F1(nude)----parent chimeras were restricted solely to recognizing parental host I region determinants as self and expressed the Ir gene phenotype of the host. In contrast, CTL responses could be generated (in the presence of interleukin 2) to TNP-modified stimulator cells of either parental haplotype. Thus these results indicate that nude mice which do have CTL with self-specificity for K/D region determinants lack proliferating T cells with self-specificity for I region determinants. These results provide evidence for the concepts that development of the I region-restricted T cell repertoire is strictly an intrathymically determined event and that young nude mice lack the unique thymic elements responsible for edu

  1. Identification and characterization of the transcription factors involved in T-cell development, t-bet, stat6 and foxp3, within the zebrafish, Danio rerio.

    PubMed

    Mitra, Suman; Alnabulsi, Ayham; Secombes, Chris J; Bird, Steve

    2010-01-01

    The discovery of cytokines expressed by T-helper 1 (Th1), Th2, Th17 and T-regulatory (T(reg)) cells has prompted speculation that these types of responses may exist in fish, arising early in vertebrate evolution. In this investigation, we cloned three zebrafish transcription factors, T-box expressed in T cells (t-bet), signal transducer and activator of transcription 6 (stat6) and fork-head box p3 (foxp3), in which two transcripts are present, that are important in the development of a number of these cell types. They were found within the zebrafish genome, using a synteny approach in the case of t-bet and foxp3. Multiple alignments of zebrafish t-bet, stat6 and foxp3 amino acids with known vertebrate homologues revealed regions of high conservation, subsequently identified to be protein domains important in the functioning of these transcription factors. The gene organizations of zebrafish t-bet and foxp3 were identical to those of the human genes, with the second foxp3 transcript lacking exons 5, 6, 7 and 8. Zebrafish stat6 (21 exons and 20 introns) was slightly different from the human gene, which contained 22 exons and 21 introns. Immunostimulation of zebrafish head kidney and spleen cells with phytohaemagglutinin, lipopolysaccharide or Poly I:C, showed a correlation between the expression of t-bet, stat6 and foxp3 with other genes involved in Th and T(reg) responses using quantitative PCR. These transcription factors, together with many of the cytokines that are expressed by different T-cell subtypes, will aid future investigations into the Th and T(reg) cell types that exist in teleosts. PMID:19961539

  2. Optimized Peptide Vaccines Eliciting Extensive CD8 T Cell Responses with Therapeutic Anti-Tumor Effects

    PubMed Central

    Cho, Hyun-Il; Celis, Esteban

    2009-01-01

    A major challenge for developing effective therapeutic vaccines against cancer is overcoming immunological tolerance to tumor-associated antigens that are expressed on both malignant cells and normal tissues. Herein, we describe a novel vaccination approach, TriVax that utilizes synthetic peptides representing CD8 T cell epitopes, Toll-like receptor (TLR) agonists that function as a potent immunological adjuvants and costimulatory anti-CD40 antibodies to generate large numbers of high avidity antigen-reactive T cells capable of recognizing and killing tumor cells. Our results show that TriVax induced huge numbers of long-lasting antigen specific CD8 T cells that displayed significant anti-tumor effects in vivo. The administration of a TriVax formulation containing a CD8 T cell epitope derived from a melanosomal antigen (Trp2180-188) elicited antigen-specific CD8 T cells that induced systemic autoimmunity (vitiligo). More important, TriVax immunization was effective in eliciting potent protective anti-tumor immunity as well as remarkable therapeutic effects against established B16 melanoma. This therapeutic effect was mediated by CD8 T cells via perforin-mediated lysis and required the participation of type I-IFN but not IFN?. These results suggest that similar strategies would be applicable for the design of effective vaccination for conducting clinical studies in cancer patients. PMID:19903852

  3. MEETING ABSTRACT Open Access HTLV-1 propels thymic human T cell

    E-print Network

    Paris-Sud XI, Université de

    MEETING ABSTRACT Open Access HTLV-1 propels thymic human T cell development in "human immune system have previously shown that HTLV-1 (Human T cell Leukemia Virus type 1) is able not only to infect for early T cell development. To further clarify the role of the natural HTLV-1 infection on human T-cell

  4. [Psychomotor development and its disorders: between normal and pathological development].

    PubMed

    Vericat, Agustina; Bibiana Orden, Alicia

    2013-10-01

    This article discusses some aspects of psychomotor development and its disorders, with special emphasis on psychomotor retardation. Diagnostic classifications of psychomotor problems, such as DSM-IV and CIE-10, are referred to and their advantages and disadvantages are analyzed. The concept of normality as a synonym for the statistical mean in the context of psychomotor disorders is also analyzed in order to consider its dynamic and variability, thereby avoiding the normality/pathology opposition, while some issues, such as the social and cultural aspects, are highlighted, making it possible to rethink the universality and relativity of psychomotor development. PMID:24061024

  5. Deficiency in NOD antigen-presenting cell function may be responsible for suboptimal CD4+CD25+ T-cell-mediated regulation and type 1 diabetes development in NOD mice.

    PubMed

    Alard, Pascale; Manirarora, Jean N; Parnell, Sarah A; Hudkins, Jason L; Clark, Sherry L; Kosiewicz, Michele M

    2006-07-01

    Various defects in antigen-presenting cells (APCs) and T-cells, including regulatory cells, have been associated with type 1 diabetes development in NOD mice. CD4(+)CD25(+) regulatory cells play a crucial role in controlling various autoimmune diseases, and a deficiency in their number or function could be involved in disease development. The current study shows that NOD mice had fewer CD4(+)CD25(+) regulatory cells, which expressed normal levels of glucocorticoid-induced tumor necrosis factor receptor and cytotoxic T-lymphocyte-associated antigen-4. We have also found that NOD CD4(+)CD25(+) cells regulate poorly in vitro after stimulation with anti-CD3 and NOD APCs in comparison with B6 CD4(+)CD25(+) cells stimulated with B6 APCs. Surprisingly, stimulation of NOD CD4(+)CD25(+) cells with B6 APCs restored regulation, whereas with the reciprocal combination, NOD APCs failed to activate B6 CD4(+)CD25(+) cells properly. Interestingly, APCs from disease-free (>30 weeks of age), but not diabetic, NOD mice were able to activate CD4(+)CD25(+) regulatory function in vitro and apparently in vivo because only spleens of disease-free NOD mice contained potent CD4(+)CD25(+) regulatory cells that prevented disease development when transferred into young NOD recipients. These data suggest that the failure of NOD APCs to activate CD4(+)CD25(+) regulatory cells may play an important role in controlling type 1 diabetes development in NOD mice. PMID:16804081

  6. The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4? and CD8? T-cell immunity.

    PubMed

    Twohig, Jason P; Marsden, Morgan; Cuff, Simone M; Ferdinand, John R; Gallimore, Awen M; Perks, William V; Al-Shamkhani, Aymen; Humphreys, Ian R; Wang, Eddie C Y

    2012-08-01

    Death receptor 3 (DR3, TNFRSF25), the closest family relative to tumor necrosis factor receptor 1, promotes CD4(+) T-cell-driven inflammatory disease. We investigated the in vivo role of DR3 and its ligand TL1A in viral infection, by challenging DR3-deficient (DR3(KO)) mice and their DR3(WT) littermates with the ?-herpesvirus murine cytomegalovirus or the poxvirus vaccinia virus. The phenotype and function of splenic T-cells were analyzed using flow cytometry and molecular biological techniques. We report surface expression of DR3 by naive CD8(+) T cells, with TCR activation increasing its levels 4-fold and altering the ratio of DR3 splice variants. T-cell responses were reduced up to 90% in DR3(KO) mice during acute infection. Adoptive transfer experiments indicated this was dependent on T-cell-restricted expression of DR3. DR3-dependent CD8(+) T-cell expansion was NK and CD4 independent and due to proliferation, not decreased cell death. Notably, impaired immunity in DR3(KO) hosts on a C57BL/6 background was associated with 4- to 7-fold increases in viral loads during the acute phase of infection, and in mice with suboptimal NK responses was essential for survival (37.5%). This is the first description of DR3 regulating virus-specific T-cell function in vivo and uncovers a critical role for DR3 in mediating antiviral immunity. PMID:22593543

  7. The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+ and CD8+ T-cell immunity

    PubMed Central

    Twohig, Jason P.; Marsden, Morgan; Cuff, Simone M.; Ferdinand, John R.; Gallimore, Awen M.; Perks, William V.; Al-Shamkhani, Aymen; Humphreys, Ian R.; Wang, Eddie C. Y.

    2012-01-01

    Death receptor 3 (DR3, TNFRSF25), the closest family relative to tumor necrosis factor receptor 1, promotes CD4+ T-cell-driven inflammatory disease. We investigated the in vivo role of DR3 and its ligand TL1A in viral infection, by challenging DR3-deficient (DR3KO) mice and their DR3WT littermates with the ?-herpesvirus murine cytomegalovirus or the poxvirus vaccinia virus. The phenotype and function of splenic T-cells were analyzed using flow cytometry and molecular biological techniques. We report surface expression of DR3 by naive CD8+ T cells, with TCR activation increasing its levels 4-fold and altering the ratio of DR3 splice variants. T-cell responses were reduced up to 90% in DR3KO mice during acute infection. Adoptive transfer experiments indicated this was dependent on T-cell-restricted expression of DR3. DR3-dependent CD8+ T-cell expansion was NK and CD4 independent and due to proliferation, not decreased cell death. Notably, impaired immunity in DR3KO hosts on a C57BL/6 background was associated with 4- to 7-fold increases in viral loads during the acute phase of infection, and in mice with suboptimal NK responses was essential for survival (37.5%). This is the first description of DR3 regulating virus-specific T-cell function in vivo and uncovers a critical role for DR3 in mediating antiviral immunity. PMID:22593543

  8. CD8 T cell memory recall is enhanced by novel direct interactions with CD4 T cells enabled by MHC class II transferred from APCs.

    PubMed

    Romagnoli, Pablo A; Premenko-Lanier, Mary F; Loria, Gilbert D; Altman, John D

    2013-01-01

    Protection against many intracellular pathogens is provided by CD8 T cells, which are thought to need CD4 T cell help to develop into effective memory CD8 T cells. Because murine CD8 T cells do not transcribe MHC class II (MHC-II) genes, several models have proposed antigen presenting cells (APCs) as intermediaries required for CD4 T cells to deliver their help to CD8 T cells. Here, we demonstrate the presence of MHC-II molecules on activated murine CD8 T cells in vitro as well as in vivo. These MHC-II molecules are acquired via trogocytosis by CD8 T cells from their activating APCs, particularly CD11c positive dendritic cells (DCs). Transferred MHC-II molecules on activated murine CD8 T cells were functionally competent in stimulating specific indicator CD4 T cells. CD8 T cells that were "helped" in vitro and subsequently allowed to rest in vivo showed enhanced recall responses upon challenge compared to "helpless" CD8 T cells; in contrast, no differences were seen upon immediate challenge. These data indicate that direct CD8:CD4 T cell interactions may significantly contribute to help for CD8 T cells. Furthermore, this mechanism may enable CD8 T cells to communicate with different subsets of interacting CD4 T cells that could modulate immune responses. PMID:23441229

  9. Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

    PubMed Central

    Shin, Jinwook; Wang, Shang; Deng, Wenhai; Wu, Jinhong; Gao, Jimin; Zhong, Xiao-Ping

    2014-01-01

    The mechanisms that control invariant natural killer T (iNKT)-cell development and function are still poorly understood. The mechanistic or mammalian target of rapamycin (mTOR) integrates various environmental signals/cues to regulate cell growth, proliferation, metabolism, and survival. We report here that ablation of mTOR complex 1 (mTORC1) signaling by conditionally deleting Raptor causes severe defects in iNKT-cell development at early stages, leading to drastic reductions in iNKT-cell numbers in the thymus and periphery. In addition, loss of Raptor impairs iNKT-cell proliferation and production of cytokines upon ?-galactosylceramide stimulation in vitro and in vivo, and inhibits liver inflammation in an iNKT cell-mediated hepatitis model. Furthermore, Raptor deficiency and rapamycin treatment lead to aberrant intracellular localization and functional impairment of promyelocytic leukemia zinc-finger, a transcription factor critical for iNKT-cell development and effector programs. Our findings define an essential role of mTORC1 to direct iNKT-cell lineage development and effector function. PMID:24516149

  10. T cells in murine lupus: propagation and regulation of disease

    Microsoft Academic Search

    Stanford L. Peng; Joe Craft

    1996-01-01

    MRL\\/Mp-lpr\\/lpr mice develop a spontaneous lupus syndrome, including hypergammaglobulinemia, autoantibodies, glomerulonephritis, and lymphadenopathy. To investigate the role of lymphocyte subsets in the pathogenesis of disease, lupus-prone MRL mice deficient in aß T cells, ?d T cells, or both were generated. Mice deficient in aß T cells developed a partially penetrant lupus syndrome, characterized by lymphadenopathy, elevated levels of class-switched immunoglobulins,

  11. Regulation of the development of asthmatic inflammation by in situ CD4(+)Foxp3 (+) T cells in a mouse model of late allergic asthma.

    PubMed

    Nakashima, Tomomi; Hayashi, Toshiharu; Mizuno, Takuya

    2014-10-01

    CD4(+)Foxp3(+)T cells (Tregs) mediate homeostatic peripheral tolerance by suppressing helper T2 cells in allergy. However, the regulation of asthmatic inflammation by local (in situ) Tregs in asthma remains unclear. BALB/c mice sensitized and challenged with ovalbumin (OVA) (asthma group) developed asthmatic inflammation with eosinophils and lymphocytes, but not mast cells. The number of Tregs in the circulation, pulmonary lymph nodes (pLNs), and thymi significantly decreased in the asthma group compared to the control group without OVA sensitization and challenge in the effector phase. The development of asthmatic inflammation is inversely related to decreased Tregs with reduced mRNA expression such as interleukin (IL)-4, transforming growth factor-?1, and IL-10, but not interferon-?, in pLNs. Moreover, M2 macrophages increased in the local site. The present study suggests that Tregs, at least in part, may regulate the development of asthmatic inflammation by cell-cell contact and regional cytokine productions. PMID:24854160

  12. Deficiency of antigen-specific B cells results in decreased Trypanosoma cruzi systemic but not mucosal immunity due to CD8 T cell exhaustion.

    PubMed

    Sullivan, Nicole L; Eickhoff, Christopher S; Sagartz, John; Hoft, Daniel F

    2015-02-15

    Vaccines against mucosally invasive, intracellular pathogens must induce a myriad of immune responses to provide optimal mucosal and systemic protection, including CD4(+) T cells, CD8(+) T cells, and Ab-producing B cells. In general, CD4(+) T cells are known to provide important helper functions for both CD8(+) T cell and B cell responses. However, the relative importance of CD4(+) T cells, CD8(+) T cells, and B cells for mucosal protection is less clearly defined. We have studied these questions in detail using the murine model of Trypanosoma cruzi infection. Despite our initial hypothesis that mucosal Abs would be important, we show that B cells are critical for systemic, but not mucosal, T. cruzi protective immunity. B cell-deficient mice developed normal levels of CD8(+) effector T cell responses early after mucosal T. cruzi infection and T. cruzi trans-sialidase vaccination. However, after highly virulent systemic challenge, T. cruzi immune mice lacking T. cruzi-specific B cells failed to control parasitemia or prevent death. Mechanistically, T. cruzi-specific CD8(+) T cells generated in the absence of B cells expressed increased PD-1 and Lag-3 and became functionally exhausted after high-level T. cruzi systemic challenge. T. cruzi immune serum prevented CD8(+) T cell functional exhaustion and reduced mortality in mice lacking B cells. Overall, these results demonstrate that T. cruzi-specific B cells are necessary during systemic, but not mucosal, parasite challenge. PMID:25595788

  13. Unbalanced Neonatal CD4+ T-Cell Immunity

    PubMed Central

    Debock, Isabelle; Flamand, Véronique

    2014-01-01

    In comparison to adults, newborns display a heightened susceptibility to pathogens and a propensity to develop allergic diseases. Particular properties of the neonatal immune system can account for this sensitivity. Indeed, a defect in developing protective Th1-type responses and a skewing toward Th2 immunity characterize today the neonatal T-cell immunity. Recently, new findings concerning Th17, regulatory helper T-cell, and follicular helper T-cell subsets in newborns have emerged. In some circumstances, development of effector inflammatory Th17-type responses can be induced in neonates, while differentiation in regulatory T-cells appears to be a default program of neonatal CD4+ T-cells. Poor antibody production, affinity maturation, and germinal center reaction in vaccinated neonates are correlated with a limiting expansion of TFH lymphocytes. We review herein the factors accounting for and the implications of the unbalanced neonatal helper T-cell immunity. PMID:25221551

  14. The fragile environments of inexpensive CD4+ T-cell enumeration in the least developed countries: strategies for accessible support.

    PubMed

    Larsen, Christoph H

    2008-01-01

    With the advent of affordable antiretroviral treatment (ART), flow cytometry has ventured out of the exclusive realms of First World research to the resource-strapped clinical environment of developing countries (DCs). Flow cytometric instrumentation for ART has become more cost-efficient, thanks to simplified, yet accurate protocols and smart technologies. These positive developments have, however, not taken shape without problems, as health care in DCs remains weak due to chronic underfunding of their primary health systems. In addition, the multiplicity of donors has created parallel infrastructures that are difficult to manage and may undermine the responsibilities of public services. Hence, there is a prevailing lack of attention to maintenance, support, and human resource development. Not uncommonly, the procurement of high-value equipment is guided by nontechnical interests with mixed results. As conventional service contracts are unpopular, the sustainability of equipment is under serious threat after warranty periods, with environmental factors such as dust and unreliable power supplies being well-known culprits. Reagent supplies and servicing constitute further challenges, where a combination of short reagent shelf life, cold-box shipping, huge distances across poor infrastructures, rigid accounting procedures, and erratic customs requirements cause significant delays and extra costs. Although excellent, highly trained or trainable local staff is available, it is frequently diverted by brain drain from the government sector to privately funded hospitals, research facilities, and overseas postings. Despite these challenges, corporate service management has commonly remained loyal to its roots in the developed world.A number of propositions address the current situation: "Reagent-rental" agreements represent an attractive alternative to service contracts, while smart instrument design has started to make inroads into more robust device concepts. To avoid logistical bottlenecks, reagents call for lyophilization and increased heat stability. Newly designed remote diagnostic tools are expected to save costs on service visits. Furthermore, web-based customer-relationship management and enterprise resource planning software is expected to ease the existing complex communication- and logistics issues. In addition, a public-private partnership is proposed that involves government, manufacturers, and local distributors with field application specialists. The latter operate crossbrand as independent subcontractors to manufacturers under a nationally endorsed cost-capping and quality assurance agreement to service all cytometric devices common in the region. These locally run networks may serve as "templates" for improved laboratory services in general, in collaboration with CD4 counting, haematology and infectious disease diagnostics. PMID:18228565

  15. Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation.

    PubMed

    Phee, Hyewon; Au-Yeung, Byron B; Pryshchep, Olga; O'Hagan, Kyle Leonard; Fairbairn, Stephanie Grace; Radu, Maria; Kosoff, Rachelle; Mollenauer, Marianne; Cheng, Debra; Chernoff, Jonathan; Weiss, Arthur

    2014-01-01

    The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR ?-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLC?1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation.DOI: http://dx.doi.org/10.7554/eLife.02270.001. PMID:24843022

  16. Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation

    PubMed Central

    Phee, Hyewon; Au-Yeung, Byron B; Pryshchep, Olga; O'Hagan, Kyle Leonard; Fairbairn, Stephanie Grace; Radu, Maria; Kosoff, Rachelle; Mollenauer, Marianne; Cheng, Debra; Chernoff, Jonathan; Weiss, Arthur

    2014-01-01

    The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR ?-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLC?1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation. DOI: http://dx.doi.org/10.7554/eLife.02270.001 PMID:24843022

  17. Development of genetically engineered CD4 + and CD8 + T cells expressing TCRs specific for a M. tuberculosis 38-kDa antigen

    Microsoft Academic Search

    Wei Luo; Xiao-Bing Zhang; Yong-Ta Huang; Pei-Pei Hao; Zhen-Min Jiang; Qian Wen; Ming-Qian Zhou; Qi Jin; Li Ma

    Cell-mediated immunity is critical to the clearance of Mycobacterium tuberculosis due to the primarily intracellular niche of this pathogen. Adoptive transfer of M. tuberculosis-specific effector T cells has been shown to confer immunity to M. tuberculosis-infected recipients resulting in M. tuberculosis clearance. However, it is difficult to generate sufficient numbers of M. tuberculosis antigen-specific T cells in a short time.

  18. Immunophenotypic and antigen receptor gene rearrangement analysis in T cell neoplasia.

    PubMed Central

    Knowles, D. M.

    1989-01-01

    The author reviews the immunophenotypic profiles displayed by the major clinicopathologic categories of T cell neoplasia, the immunophenotypic criteria useful in the immunodiagnosis of T cell neoplasia, and the contributions made by antigen receptor gene rearrangement analysis to the understanding of T cell neoplasia. Neoplasms belonging to distinct clinicopathologic categories of T cell neoplasia often exhibit characteristic immunophenotypic profiles. Approximately 80% of lymphoblastic lymphomas and 20% of acute lymphoblastic leukemias express phenotypes consistent with prethymic and intrathymic stages of T cell differentiation, including intranuclear terminal deoxynucleotidyl transferase. Cutaneous T cell lymphomas of mycosis fungoides type usually express pan-T cell antigens CD2, CD5, and CD3, often lack the pan-T cell antigen CD7, and usually express the mature, peripheral helper subset phenotype, CD4+ CD8-. Cutaneous T cell lymphomas of nonmycosis fungoides type and peripheral T cell lymphomas often lack one or more pan-T cell antigens and, in addition, occasionally express the anomalous CD4+ CD8+ or CD4- CD8- phenotypes. T gamma-lymphoproliferative disease is divisable into two broad categories: those cases that are CD3 antigen positive and exhibit clonal T cell receptor beta chain (TCR-beta) gene rearrangements and those cases that are CD3 antigen negative and exhibit the TCR-beta gene germline configuration. Human T cell lymphotropic virus-I (HTLV-I) associated Japanese, Carribean, and sporadic adult T cell leukemia/lymphomas usually express pan-T cell antigens, the CD4+ CD8- phenotype, and various T cell-associated activation antigens, including the interleukin-2 receptor (CD25). Immunophenotypic criteria useful in the immunodiagnosis of T cell neoplasia include, in increasing order of utility, T cell predominance, T cell subset antigen restriction, anomalous T cell subset antigen expression, and deletion of one or more pan-T cell antigens. Only in exceptional circumstances do normal, non-neoplastic T cell populations express the CD4- CD8- or the CD4+ CD8+ phenotype and/or lack one or more pan-T cell antigens. T cell receptor beta chain gene rearrangement analysis represents an accurate, objective, and sensitive molecular genetic marker of T cell lineage and clonality that allows discrimination among non-T cell, polyclonal T cell and monoclonal T cell populations. Non-T cells exhibit the TCR-beta gene germline configuration.(ABSTRACT TRUNCATED AT 400 WORDS) Images Figure 3 Figure 6 Figure 7 PMID:2495724

  19. Established Thymic Epithelial Progenitor/Stem Cell-Like Cell Lines Differentiate into Mature Thymic Epithelial Cells and Support T Cell Development

    PubMed Central

    Zhan, Yu; Su, Juanjuan; Du, Yarui; Xu, Guoliang; Shi, Yufang; Siebenlist, Ulrich; Zhang, Xiaoren

    2013-01-01

    Common thymic epithelial progenitor/stem cells (TEPCs) differentiate into cortical and medullary thymic epithelial cells (TECs), which are required for the development and selection of thymocytes. Mature TEC lines have been widely established. However, the establishment of TEPC lines is rarely reported. Here we describe the establishment of thymic epithelial stomal cell lines, named TSCs, from fetal thymus. TSCs express some of the markers present on tissue progenitor/stem cells such as Sca-1. Gene expression profiling verifies the thymic identity of TSCs. RANK stimulation of these cells induces expression of autoimmune regulator (Aire) and Aire-dependent tissue-restricted antigens (TRAs) in TSCs in vitro. TSCs could be differentiated into medullary thymic epithelial cell-like cells with exogenously expressed NF-?B subunits RelB and p52. Importantly, upon transplantation under the kidney capsules of nude mice, TSCs are able to differentiate into mature TEC-like cells that can support some limited development of T cells in vivo. These findings suggest that the TSC lines we established bear some characteristics of TEPC cells and are able to differentiate into functional TEC-like cells in vitro and in vivo. The cloned TEPC-like cell lines may provide useful tools to study the differentiation of mature TEC cells from precursors. PMID:24086471

  20. HELIGMOSOMOIDES BAKERI INDUCES TOLEROGENIC DENDRITIC CELLS THAT BLOCK COLITIS AND PREVENT ANTIGEN-SPECIFIC GUT T CELL RESPONSES

    PubMed Central

    Blum, Arthur M.; Hang, Long; Setiawan, Tommy; Urban, Joseph P.; Stoyanoff, Korynn M.; Leung, John; Weinstock, Joel V.

    2012-01-01

    Immunological diseases like IBD are infrequent in less developed countries possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri (Hpb) prevents colitis. It was determined if Hpb mediated IBD protection by altering DC function. We used a Rag IBD model where animals were reconstituted with IL10-/- T cells making them susceptible to IBD and with OVA antigen-responsive OT2 T cells allowing study of a gut antigenic response. Intestinal DC from Hpb-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFNg/IL17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from Hpb-infected mice into Rag mice reconstituted with IL10-/- T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered antigen-nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be Treg independent. Thus, Hpb modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which Hpb suppresses colitis. IFNg and IL17 are colitogenic. The capacity of these DC to block a gut antigen-specific IFNg/IL17 T cell response also is significant. PMID:22844110

  1. SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells

    PubMed Central

    Chatterjee, Madhumouli; Kis-Toth, Katalin; Thai, To-Ha; Terhorst, Cox; Tsokos, George C.

    2015-01-01

    The CD28 co-stimulatory pathway is well established for T cell activation. However, there is evidence suggesting the existence of additional co-stimulatory pathways. Here we report that a member of the SLAM superfamily, SLAMF6, or CD352 plays an important role in T cell co-stimulation. Cross-linking of SLAMF6 with anti-CD3 primes human T cell to secrete Th1 cytokines. Among the T cell subsets, CD8+ and CD3+CD4?CD8? cells display the highest Th1 production responses. Engagement of SLAMF6 mobilizes the modulation of the same set of NF-?B-associated genes. Although the expression of SLAMF6 on the surface of T cells from patients with systemic lupus erythematosus (SLE) T cells is comparable to that on the normal T cells, engagement of SLAMF6 results in severely reduced Th1 and IL-2 cytokine production. Our results suggest the existence of an additional co-stimulatory pathway in human T cells, which is defective in SLE T cells. PMID:21231893

  2. Developmental Regulation of Lck Targeting to the CD8 Coreceptor Controls Signaling in Naive and Memory T Cells

    Microsoft Academic Search

    Martin F. Bachmann; Awen Gallimore; Susanne Linkert; Vincenzo Cerundolo; Antonio Lanzavecchia; Manfred Kopf; Antonella Viola

    Summary The question of whether enhanced memory T cell responses are simply due to an increased frequency of specific cells or also to an improved response at the single cell level is widely de- bated. In this study, we analyzed T cell receptor (TCR) transgenic memory T cells and bona fide memory T cells isolated from virally infected normal mice

  3. Regulatory T Cells as Immunotherapy

    PubMed Central

    Singer, Benjamin D.; King, Landon S.; D’Alessio, Franco R.

    2014-01-01

    Regulatory T cells (Tregs) suppress exuberant immune system activation and promote immunologic tolerance. Because Tregs modulate both innate and adaptive immunity, the biomedical community has developed an intense interest in using Tregs for immunotherapy. Conditions that require clinical tolerance to improve outcomes – autoimmune disease, solid organ transplantation, and hematopoietic stem cell transplantation – may benefit from Treg immunotherapy. Investigators have designed ex vivo strategies to isolate, preserve, expand, and infuse Tregs. Protocols to manipulate Treg populations in vivo have also been considered. Barriers to clinically feasible Treg immunotherapy include Treg stability, off-cell effects, and demonstration of cell preparation purity and potency. Clinical trials involving Treg adoptive transfer to treat graft versus host disease preliminarily demonstrated the safety and efficacy of Treg immunotherapy in humans. Future work will need to confirm the safety of Treg immunotherapy and establish the efficacy of specific Treg subsets for the treatment of immune-mediated disease. PMID:24575095

  4. Activity of host-derived T cells which differentiate in nude mice grafted with co-isogenic or allogeneic thymuses.

    PubMed

    Kindred, B; Loor, F

    1974-05-01

    If nude mice are grafted with a neonatal thymus, host type precursor cells develop within the graft thymus and after about 6 wk the T-cell population of the thymus, spleen, and lymph nodes is of host type. However, immunological responsiveness produced in nude mice in this manner is incomplete: (a) the ability to react to T-cell mitogens in vitro is greater than in untreated nudes but lower than in normal mice; (b) the response to T-cell dependent antigens is less than normal; and (c) the rejection of skin grafts is slower than in normal animals. Whether host precursor cells which differentiate in an allogeneic thymus are able to reject skin grafts from thymus donor strain appears to depend on the strain combination used. PMID:4596513

  5. Depressed immune surveillance against cancer: role of deficient T cell: extracellular matrix interactions.

    PubMed

    Górski, A; Castronovo, V; Stepie?-Sopniewska, B; Grieb, P; Ryba, M; Mrowiec, T; Korczak-Kowalska, G; Wierzbicki, P; Matysiak, W; Dybowska, B

    1994-07-01

    Although T cells infiltrate malignant tumors, the local immune response is usually inefficient and tumors escape destruction. While extracellular matrix proteins strongly costimulate T cell responses in normal individuals, our studies indicate that peripheral blood T cells from cancer patients and tumor infiltrating cells respond poorly or are resistant to stimulative signals mediated by collagen I and IV and fibronectin. Moreover, the adhesive properties of cancer T cells are markedly depressed. Those functional deficiencies are paralleled by variable deficits in integrin and non-integrin T cell receptors for extracellular matrix. Immunotherapy with BCG causes a dramatic but transient increase in T cell: ECM interactions. PMID:7827959

  6. T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity

    PubMed Central

    Burger, Megan L; Leung, Kenneth K; Bennett, Margaux J; Winoto, Astar

    2014-01-01

    T cell self-tolerance is thought to involve peripheral tolerance and negative selection, involving apoptosis of autoreactive thymocytes. However, evidence supporting an essential role for negative selection is limited. Loss of Bim, a Bcl-2 BH3-only protein essential for thymocyte apoptosis, rarely results in autoimmunity on the C57BL/6 background. Mice with T cell-specific over-expression of Bcl-2, that blocks multiple BH3-only proteins, are also largely normal. The nuclear receptor Nur77, also implicated in negative selection, might function redundantly to promote apoptosis by associating with Bcl-2 and exposing its potentially pro-apoptotic BH3 domain. Here, we report that T cell-specific expression of a Bcl2 BH3 mutant transgene results in enhanced rescue of thymocytes from negative selection. Concomitantly, Treg development is increased. However, aged BH3 mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance. DOI: http://dx.doi.org/10.7554/eLife.03468.001 PMID:25182415

  7. The receptor Ly108 functions as a SAP adaptor dependent on-off switch for T cell help to B cells and NKT cell development

    PubMed Central

    Kageyama, Robin; Cannons, Jennifer L.; Zhao, Fang; Yusuf, Isharat; Lao, Christopher; Locci, Michela; Schwartzberg, Pamela L.; Crotty, Shane

    2012-01-01

    Humans and mice deficient in the adaptor protein SAP (Sh2d1a) have a major defect in humoral immunity, due to lack of T cell help for B cells. The role of SAP in this process is incompletely understood. We found that deletion of receptor Ly108 (Slamf6) in CD4+ T cells reversed the Sh2d1a?/? phenotype, eliminating the SAP requirement for germinal centers. This potent negative signaling by Ly108 required immunotyrosine switch motifs (ITSMs) and SHP-1 recruitment, resulting in high amounts of SHP-1 at the T:B synapse, limiting T:B adhesion. Ly108 negative signaling was not only important in CD4+ T cells, as we found that NKT cell differentiation was substantially restored in Slamf6?/?Sh2d1a?/? mice. The ability of SAP to regulate both positive and negative signals in T cells can explain the severity of SAP-deficiency and highlights the importance of SAP and SHP-1 competition for Ly108 ITSM binding as a rheostat for the magnitude of T cell help to B cells. PMID:22683125

  8. Analysis of ?? T Cell Functions in the Mouse

    PubMed Central

    Born, Willi K.; Yin, Zhinan; Hahn, Youn-Soo; Sun, Deming; O’Brien, Rebecca L.

    2015-01-01

    Mouse models of disease and injury have been invaluable in investigations of the functional role of ?? T cells. They show that ?? T cells engage in immune responses both early and late, that they can function both polyclonally and as peripherally selected clones, and that they can be effector cells and immune regulators. They also suggest that functional development of ?? T cells occurs step-wise in thymus and periphery, and that it is governed by ?? TCR-signaling and other signals. Finally, they indicate that ?? T cell functions often segregate with TCR-defined subsets, in contrast to conventional T cells. From the functional studies in mice and other animal models, ?? T cells emerge as a distinct lymphocyte population with a unique and broad functional repertoire, and with important roles in Ab responses, inflammation and tissue repair. They also are revealed as a potentially useful target for immune intervention. PMID:20368285

  9. Induction of GVHD-Like Skin Disease by Passively Transferred CD8+ T-Cell Receptor Transgenic T Cells into Keratin 14Ovalbumin Transgenic Mice

    Microsoft Academic Search

    Akihiko Shibaki; Atsushi Sato; Jonathan C. Vogel; Fumi Miyagawa; Stephen I. Katz

    2004-01-01

    To understand the mechanisms involved in immunological tolerance to skin-associated antigens, we have developed transgenic (Tg) mice that express a model self-antigen, membrane-bound chicken ovalbumin (OVA), under the control of a keratin 14 (K14) promoter. K14-mOVA Tg mice express OVA mRNA in the epidermis, and appear normal. K14-mOVA Tg mice failed to mount T cell and delayed type hypersensitivity reactions

  10. Changes of cytoskeleton affect T cell biological behaviors.

    PubMed

    Yang, Hui; Tang, Ruihua; Li, Jing; Li, Ji; Liu, Yaxiong; Ye, Linjie; Shao, Dongyan; Jin, Mingliang; Huang, Qingsheng; Shi, Junling

    2015-01-01

    T lymphocyte (T cell) is a crucial member in adaptive immunity that protects the organism against foreign pathogens and cancer by producing cytokines and cytotoxic molecules. In T cell, the cytoskeleton is in a stable and dynamic renewed condition and maintains shape and mechanical resistance to deformation. The cytoskeleton changes lead to morphological differences of T cell, and then affect local mechanical properties and cellular behavior, including development, differentiation, polarization, migration or adhesion. In this review, we will discuss the effect of cytoskeleton changes on T cell biological behaviors and its mechanism. PMID:25553482

  11. Intestinal ?? T-cell lymphomas are most frequently of type II enteropathy-associated T-cell type.

    PubMed

    Wilson, Amanda L; Swerdlow, Steven H; Przybylski, Grzegorz K; Surti, Urvashi; Choi, John K; Campo, Elias; Trucco, Massimo M; Van Oss, S Branden; Felgar, Raymond E

    2013-06-01

    Enteropathy-associated T-cell lymphoma includes type I cases and distinctive type II cases that, according to 2008 and 2010 World Health Organization descriptions, are T-cell receptor ?+. Although T-cell receptor ?? enteropathy-associated T-cell lymphomas are reported, it is unknown if they have distinctive features and if they should be categorized as enteropathy-associated T-cell lymphoma or as a mucocutaneous ?? T-cell lymphoma. To address these questions, the clinicopathologic, immunophenotypic, molecular, and cytogenetic features of 5 ??-enteropathy-associated T-cell lymphomas were investigated. Only 1 patient had celiac disease and had type I enteropathy-associated T-cell lymphoma, and the others fulfilled the histopathologic criteria for type II enteropathy-associated T-cell lymphoma. All lacked cutaneous involvement. A celiac disease-associated HLA type was found in the patient with CD and one of four others. All were T-cell receptor ?+, T-cell receptor ?+, ?F1-, CD3+, CD7+, CD5-, CD4-, and TIA-1+ with variable staining for CD2 (3/5), CD8 (2/5), Granzyme B (1/5), and CD56 (4/5). Fluorescence in situ hybridization demonstrated 9q34 gains in 4 cases, with 9q33-34 gains by single nucleotide polymorphism in 3 of these. Single nucleotide polymorphism analysis also demonstrated gains in 5q34-q35.1/5q35.1 (4/5), 8q24 (3/5), and in 32 other regions in 3 of 5 cases. V?1 rearrangements were identified in 4 of 4 cases with documented clonality showing the same clone in normal-appearing distant mucosa (3/3 tested cases). Thus, ??-enteropathy-associated T-cell lymphomas share many features with other enteropathy-associated T-cell lymphoma and are mostly of type II. Their usual nonactivated cytotoxic phenotype and V?1 usage are features unlike many other mucocutaneous ?? T-cell lymphomas but shared with hepatosplenic T-cell lymphoma. These findings support the conclusion that a ?? T-cell origin at extracutaneous sites does not define a specific entity. PMID:23332928

  12. T cell vaccination against autoimmune diabetes in nonobese diabetic mice.

    PubMed

    Formby, B; Shao, T

    1993-01-01

    The diabetogenic autoimmune process was accelerated in 23 days nonirradiated postnatal nonobese diabetic (NOD) female mice by adoptive transfer of pathogenic, polyclonal CD4+ 8- T cells isolated from diabetic spleens. Recipient mice developed hyperglycemia 15 days after transfer of pathogenic immune cells with typical histological signs of pancreatic infiltration. The CD4+V beta 8+ T cells isolated from diabetic spleens and activated by surface-immobilized anti-TCRV beta 8 monoclonal antibody (mAb, clone F23.1) induced suppression of a diabetogenic disease process accelerated earlier by adoptively transferred polyclonal CD4+8- T cells. When CD4+V beta 8+ T cells isolated from diabetic spleens were activated by cross-linking TCRV beta 8 and systemically injected into young female NOD mice, an endogenous immunosuppressive circuit was stimulated that completely prevented development of insulitis and disease. A suppressor mechanism involving CD8+ T cells might be involved since in vitro these cells strongly proliferated in response to irradiated CD4+ V beta 8+ T cells that in blocking experiments with specific mAb was found to be class I major histocompatibility complex (MHC)-restricted. Hence, T cells expressing the CD8 phenotype specifically respond to idiotypic or ergotypic determinants on the inducing activated CD4+V beta 8+ T cells and effectively suppress a diabetogenic disease process by a mechanism that may involve T-T cell interactions. PMID:8096128

  13. T Cells in Vascular Inflammatory Diseases

    PubMed Central

    Lintermans, Lucas L.; Stegeman, Coen A.; Heeringa, Peter; Abdulahad, Wayel H.

    2014-01-01

    Inflammation of the human vasculature is a manifestation of many different diseases ranging from systemic autoimmune diseases to chronic inflammatory diseases, in which multiple types of immune cells are involved. For both autoimmune diseases and chronic inflammatory diseases several observations support a key role for T lymphocytes in these disease pathologies, but the underlying mechanisms are poorly understood. Previous studies in several autoimmune diseases have demonstrated a significant role for a specific subset of CD4+ T cells termed effector memory T (TEM) cells. This expanded population of TEM cells may contribute to tissue injury and disease progression. These cells exert multiple pro-inflammatory functions through the release of effector cytokines. Many of these cytokines have been detected in the inflammatory lesions and participate in the vasculitic reaction, contributing to recruitment of macrophages, neutrophils, dendritic cells, natural killer cells, B cells, and T cells. In addition, functional impairment of regulatory T cells paralyzes anti-inflammatory effects in vasculitic disorders. Interestingly, activation of TEM cells is uniquely dependent on the voltage-gated potassium Kv1.3 channel providing an anchor for specific drug targeting. In this review, we focus on the CD4+ T cells in the context of vascular inflammation and describe the evidence supporting the role of different T cell subsets in vascular inflammation. Selective targeting of pathogenic TEM cells might enable a more tailored therapeutic approach that avoids unwanted adverse side effects of generalized immunosuppression by modulating the effector functions of T cell responses to inhibit the development of vascular inflammation. PMID:25352848

  14. Recombinant salmonella-based 4-1BBL vaccine enhances T cell immunity and inhibits the development of colorectal cancer in rats: in vivo effects of vaccine containing 4-1BBL

    PubMed Central

    2013-01-01

    Background Immunotherapy with vaccines is attractive for the treatment of cancer. This study is aimed at determining the effect of recombinant Salmonella (SL3261)-based 4-1BB ligand (4-1BBL) vaccine on the development of colorectal cancers and the potential immune mechanisms in rats. Results In comparison with that in the PBS group, similar levels of 4-1BBL expression, the frequency of T cells, IFN-? responses, and comparable numbers of tumors were detected in the SL3261 and SL3261C groups of rats. In contrast, significantly fewer numbers of tumors, increased levels of 4-1BBL expression in the spleens and colorectal tissues, higher frequency of peripheral blood and splenic CD3+CD25+ T cells, and stronger splenic T cell IFN-? responses were detected in the SL3261R group of rats. Conclusion Our results indicated that vaccination with recombinant attenuated Salmonella harboring the 4-1BBL gene efficiently enhanced T cell immunity and inhibited the development of carcinogen-induced colorectal cancers in rats. PMID:23413971

  15. Effective gene suppression using small interfering RNA in hard-to-transfect human T cells.

    PubMed

    Yin, Jiyi; Ma, Zhengyu; Selliah, Nithianandan; Shivers, Debra K; Cron, Randy Q; Finkel, Terri H

    2006-05-30

    RNA interference (RNAi) is an evolutionarily conserved cellular defense mechanism that protects cells from hostile genes and regulates the function of normal genes during growth and development. In this study, we established proof of principle of small interfering RNA (siRNA) silencing in hard-to-transfect human T cell lines and primary human CD4 T cells. We used public and in-house programs to design four siRNAs each for GFP, for our novel cellular gene HALP, and for their corresponding scrambled siRNA controls. We generated siRNA expression cassettes (SECs) by PCR and directly transfected the PCR products into T cells using amaxa Nucleofector technology. The most effective SECs were selected and cloned into a TA cloning vector and titered with their respective controls to increase transfection efficiency. Flow cytometry and fluorescence microscopy analyses were performed for GFP siRNAs, and Northern blot analysis was done to assess the HALP silencing effect. These experiments demonstrate that SECs are an excellent screening tool to identify siRNA sequences effective in silencing expression of genes of interest. The vector expressing the most effective siRNA robustly inhibited GFP expression (up to 92%) in the context of co-transfection in human T cell lines and primary CD4 T cells. The optimized siRNA for our endogenous cellular gene HALP also silenced its target RNA expression by more than 90%. These studies demonstrate that the combination of SEC, siRNA expression vectors and Nucleofector technology can be successfully applied to hard-to-transfect human T cell lines and primary T cells to effectively silence genes. PMID:16603179

  16. Up-Regulation of Th17 Cells May Underlie Inhibition of Treg Development Caused by Immunization with Activated Syngeneic T Cells

    PubMed Central

    Wang, Li; Lin, Jinpiao; Zhou, Zhou; Huo, Rongfen; Shen, Baihua; Sun, Yue; Li, Ningli

    2011-01-01

    Background Our previous work showed that mice immunized with attenuated activated syngeneic T cells (aTCV) led to damping Treg function which resulted in enhancing anti-tumor immunity. It is well known that DC plays a very important role in controlling Th cell differentiation; whether DC involves Treg attenuation in immunized mice remained unknown. In this study, we provided evidence that increased mature DC (mDC) after immunization with aTCV skewed Th17 differentiation, which resulted in inhibition of Treg differentiation through IL-6 signaling pathway. Principal Findings In the present study, we found that the frequency of mDCs increased dramatically in the immunized mice accompanied by lower Treg cells compared to the controls. Moreover, both DCs and serum derived from the immunized mice suppressed Treg differentiation in vitro, respectively. mDCs generated from bone marrow precursor cells in vitro strongly inhibited Treg development and simultaneously drove Th17 differentiation with elevated IL-6 production. However, PD-L1, a potent Treg inducer did not show effect on Treg down-regulation. Assay with transwell systems showed that cell-cell contact was necessary for IL-6 production to a threshold to activate Th17 transcriptional factor ROR?t and to inhibit Treg counterpart Foxp3. Conclusions Our results implicate up-regulated Th17 development might be one of mechanisms of enhancing anti-tumor immunity induced by immunization with aTCV, which provide a novel insight in numerous mechanisms responsible for anti-tumor immunity. PMID:22087281

  17. The tumor suppressor CYLD controls the function of murine regulatory T cells.

    PubMed

    Reissig, Sonja; Hövelmeyer, Nadine; Weigmann, Benno; Nikolaev, Alexei; Kalt, Bettina; Wunderlich, Thomas F; Hahn, Matthias; Neurath, Marcus F; Waisman, Ari

    2012-11-15

    CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple benign neoplasms of the skin known as cylindromas. The CYLD protein is a deubiquitinating enzyme that acts as a negative regulator of NF-?B and JNK signaling through its interaction with NEMO and TNFR-associated factor 2. We have previously described a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8)). In this study, we demonstrate that CYLD plays a critical role in Treg development and function. T cells of CYLD(ex7/8) mice had a hyperactive phenotype manifested by increased production of inflammatory cytokines and constitutive activation of the NF-?B pathway. Furthermore, the amount of Foxp3(+) regulatory T cells in these mice was markedly enhanced in thymus and peripheral organs. Importantly, these regulatory T cells displayed decreased expression levels of CD25 and CTLA-4 associated with impaired suppressive capacity. Hence, our data emphasize an essential role of CYLD in maintaining T cell homeostasis as well as normal T regulatory cell function, thereby controlling abnormal T cell responses. PMID:23066153

  18. Mapping the life histories of T cells

    Microsoft Academic Search

    Carmen Gerlach; Jeroen W. J. van Heijst; Ton N. M. Schumacher

    2010-01-01

    The behaviour of T cells is not fixed in the germ line, but is highly adaptable depending on experiences encountered during a T cell's life. To understand how different T cell subsets arise and how prior signalling input regulates subsequent T cell behaviour, approaches are required that couple a given T cell state to signals received by the cell, or

  19. Normal muscle structure, growth, development, and regeneration.

    PubMed

    de Rezende Pinto, Wladimir Bocca Vieira; de Souza, Paulo Victor Sgobbi; Oliveira, Acary Souza Bulle

    2015-06-01

    Knowledge about biochemical, structural and physiological aspects, and properties regarding the skeletal muscle has been widely obtained in the last decades. Muscle disorders, mainly represented in neuromuscular clinical practice by acquired and hereditary myopathies, are well-recognized and frequently diagnosed in practice. Most clinical complaints and biochemical characterizations of each myopathy depends on the appropriate knowledge and interpretation of pathological findings and their comparison with normal muscle findings. Great improvement has been obtained in the last decades mainly involving the mechanisms of normal muscle architecture and physiological function in the healthy individuals. Genetic mechanisms have also been widely studied. We provide an extensive literature review involving current knowledge regarding muscle cell structure and function and embryological and regenerative processes linked to muscle lesion. An updated comprehensive description involving the main nuclear genomic regulatory mechanisms of muscle regeneration and embryogenesis is provided in this review. PMID:25860794

  20. T-cell exhaustion in allograft rejection and tolerance

    PubMed Central

    Thorp, Edward B.; Stehlik, Christian; Ansari, M. Javeed

    2015-01-01

    Purpose of review The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. Recent findings Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. Summary Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance. PMID:25563990

  1. CD1 and mycobacterial lipids activate human T cells.

    PubMed

    Van Rhijn, Ildiko; Moody, D Branch

    2015-03-01

    For decades, proteins were thought to be the sole or at least the dominant source of antigens for T cells. Studies in the 1990s demonstrated that CD1 proteins and mycobacterial lipids form specific targets of human ?? T cells. The molecular basis by which T-cell receptors (TCRs) recognize CD1-lipid complexes is now well understood. Many types of mycobacterial lipids function as antigens in the CD1 system, and new studies done with CD1 tetramers identify T-cell populations in the blood of tuberculosis patients. In human populations, a fundamental difference between the CD1 and major histocompatibility complex systems is that all humans express nearly identical CD1 proteins. Correspondingly, human CD1 responsive T cells show evidence of conserved TCRs. In addition to natural killer T cells and mucosal-associated invariant T (MAIT cells), conserved TCRs define other subsets of human T cells, including germline-encoded mycolyl-reactive (GEM) T cells. The simple immunogenetics of the CD1 system and new investigative tools to measure T-cell responses in humans now creates a situation in which known lipid antigens can be developed as immunodiagnostic and immunotherapeutic reagents for tuberculosis disease. PMID:25703557

  2. The production of alpha/beta and gamma/delta double negative (DN) T-cells and their role in the maintenance of pregnancy.

    PubMed

    Chapman, John C; Chapman, Fae M; Michael, Sandra D

    2015-01-01

    The ability of the thymus gland to convert bone marrow-derived progenitor cells into single positive (SP) T-cells is well known. In this review we present evidence that the thymus, in addition to producing SP T-cells, also has a pathway for the production of double negative (DN) T-cells. The existence of this pathway was noted during our examination of relevant literature to determine the cause of sex steroid-induced thymocyte loss. In conducting this search our objective was to answer the question of whether thymocyte loss is the end product of a typical interaction between the reproductive and immune systems, or evidence that the two systems are incompatible. We can now report that "thymocyte loss" is a normal process that occurs during the production of DN T-cells. The DN T-cell pathway is unique in that it is mediated by thymic mast cells, and becomes functional following puberty. Sex steroids initiate the development of the pathway by binding to an estrogen receptor alpha located in the outer membrane of the mast cells, causing their activation. This results in their uptake of extracellular calcium, and the production and subsequent release of histamine and serotonin. Lymphatic vessels, located in the subcapsular region of the thymus, respond to the two vasodilators by undergoing a substantial and preferential uptake of gamma/delta and alpha/beta DN T- cells. These T- cells exit the thymus via efferent lymphatic vessels and enter the lymphatic system.The DN pathway is responsible for the production of three subsets of gamma/delta DN T-cells and one subset of alpha/beta DN T-cells. In postpubertal animals approximately 35 % of total thymocytes exit the thymus as DN T-cells, regardless of sex. In pregnant females, their levels undergo a dramatic increase. Gamma/delta DN T-cells produce cytokines that are essential for the maintenance of pregnancy. PMID:26164866

  3. Peripheral engraftment of fetal intestine into athymic mice sponsors T cell development: direct evidence for thymopoietic function of murine small intestine

    Microsoft Academic Search

    R. Lee Mosley; John R. Klein

    1992-01-01

    Summary Adult athymic, lethally irradiated, F l - parent bone marrow-reconstituted (AT x BM) mice were engrafted bilaterally with day 16-18 fetal intestine or fetal thymus into the kidney capsule and were studied for evidence of peripheral T cell repopulation of 1-12 wk postengraftment . Throughout that time period, both types of grafts were macroscopically and histologically characteristic of differentiated

  4. Natural killer T cells and the regulation of asthma

    Microsoft Academic Search

    P Matangkasombut; M Pichavant; R H DeKruyff; D T Umetsu

    2009-01-01

    A crucial role has been suggested for invariant natural killer T cells (iNKT) in regulating the development of asthma, a complex and heterogeneous disease characterized by airway inflammation and airway hyperreactivity (AHR). iNKT cells constitute a unique subset of T cells responding to endogenous and exogenous lipid antigens, rapidly secreting a large amount of cytokines, which amplify both innate and

  5. ZFAT plays critical roles in peripheral T cell homeostasis and its T cell receptor-mediated response

    SciTech Connect

    Doi, Keiko [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute of Life Sciences for the Next Generation of Women Scientists, Fukuoka University, Fukuoka (Japan); Fujimoto, Takahiro [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Okamura, Tadashi [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan)] [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan); Ogawa, Masahiro [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)] [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Tanaka, Yoko [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan)] [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Mototani, Yasumasa; Goto, Motohito [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan)] [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan); Ota, Takeharu; Matsuzaki, Hiroshi [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan)] [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Kuroki, Masahide [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)] [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Tsunoda, Toshiyuki [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Sasazuki, Takehiko [Institute for Advanced Study, Kyushu University, Fukuoka (Japan)] [Institute for Advanced Study, Kyushu University, Fukuoka (Japan); Shirasawa, Senji, E-mail: sshirasa@fukuoka-u.ac.jp [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer We generated Cd4-Cre-mediated T cell-specific Zfat-deficient mice. Black-Right-Pointing-Pointer Zfat-deficiency leads to reduction in the number of the peripheral T cells. Black-Right-Pointing-Pointer Impaired T cell receptor-mediated response in Zfat-deficient peripheral T cells. Black-Right-Pointing-Pointer Decreased expression of IL-7R{alpha}, IL-2R{alpha} and IL-2 in Zfat-deficient peripheral T cells. Black-Right-Pointing-Pointer Zfat plays critical roles in peripheral T cell homeostasis. -- Abstract: ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in apoptosis, development and primitive hematopoiesis. Zfat is highly expressed in T- and B-cells in the lymphoid tissues, however, its physiological function in the immune system remains totally unknown. Here, we generated the T cell-specific Zfat-deficient mice and demonstrated that Zfat-deficiency leads to a remarkable reduction in the number of the peripheral T cells. Intriguingly, a reduced expression of IL-7R{alpha} and the impaired responsiveness to IL-7 for the survival were observed in the Zfat-deficient T cells. Furthermore, a severe defect in proliferation and increased apoptosis in the Zfat-deficient T cells following T cell receptor (TCR) stimulation was observed with a reduced IL-2R{alpha} expression as well as a reduced IL-2 production. Thus, our findings reveal that Zfat is a critical regulator in peripheral T cell homeostasis and its TCR-mediated response.

  6. Humoral response to Porphyromonas (Bacteroides) gingivalis in rats: time course and T-cell dependence.

    PubMed Central

    Katz, J; Leary, R M; Ward, D C; Harmon, C C; Michalek, S M

    1992-01-01

    In this study, we describe the time course and T-cell dependence of the serum antibody response to the periodontopathogen Porphyromonas (Bacteroides) gingivalis in an experimental rat model. Normal Fischer rats were challenged by a local injection of P. gingivalis (2 x 10(8) bacteria) into gingival tissue or by the administration of a similar number of bacteria by the intravenous (i.v.) route on days 0, 2, and 4. Serum antibody activity was detected within 1 week and peaked at 8 weeks after gingival challenge. A similar but lower response was seen for rats challenged by the i.v. route. The response in both groups of rats was mainly of the immunoglobulin G (IgG) isotype; some IgM but no IgA antibody activity was detected. Analysis of the IgG subclass revealed mainly IgG2c in animals challenged locally in the gingiva with P. gingivalis, whereas IgG2b predominated in rats challenged by the i.v. route. The importance of T cells in the response was established by demonstrating the absence of serum IgG antibodies in nude rats after a local challenge of gingival tissue with P. gingivalis. Nude rats given purified splenic T cells from normal rats immunized systemically with P. gingivalis prior to a local gingival challenge showed a rapid appearance of serum antibody activity that peaked between 4 and 6 weeks. This initial peak occurred 2 to 4 weeks earlier than that seen in normal animals. Fluorescence-activated cell sorter analysis of splenic lymphoid cells from these nude rats revealed a helper T-cell population. The levels of serum IgG antibodies in nude rats given nonimmune T cells rose slowly, and the antibodies were mainly of the IgG2a and IgG2b subclasses. Nude rats given immune T cells showed a rapid increase primarily in IgG2b antibody levels following a local gingival challenge. These findings suggest that the immune helper T-cells contributed to the rapid development of the response to P. gingivalis. Furthermore, it is likely that the IgG subclass response to P. gingivalis in these nude rats was related to the splenic origin of the T cells used for adoptive transfer. PMID:1323534

  7. Fli-1 regulates the DN2 to DN3 thymocyte transition and promotes ?? T-cell commitment by enhancing TCR signal strength.

    PubMed

    Smeets, Monique F M A; Wiest, David L; Izon, David J

    2014-09-01

    Friend leukemia integration 1 (Fli-1) is a member of the Ets transcription factor family and is expressed during T-cell development; however, the role Fli-1 plays in early T-cell differentiation has not been elucidated. In this report, we demonstrate that in mouse, Fli-1 overexpression retards the CD4(-) CD8(-) double-negative (DN) to CD4(+) CD8(+) double-positive (DP) transition by deregulating normal DN thymocyte development. Specifically, Fli-1 expression moderates the DN2 and DN3 developmental transitions. We further show that Fli-1 overexpression partially mimics strong TCR signals in developing DN thymocytes and thereby enhances ?? T-cell development. Conversely, Fli-1 knockdown by small hairpin RNA reverses the lineage bias from ?? T cells and directs DN cells to the ?? lineage by attenuating TCR signaling. Therefore, Fli-1 plays a critical role in both the DN2 to DN3 transition and ??/?? lineage commitment. PMID:24935715

  8. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo.

    PubMed

    Wang, Jyh-Chiang E; Livingstone, Alexandra M

    2003-12-15

    Recent studies have shown that CD4(+) T cell help is required for the generation of memory CD8(+) T cells that can proliferate and differentiate into effector cells on Ag restimulation. The importance of help for primary CD8(+) T cell responses remains controversial. It has been suggested that help is not required for the initial proliferation and differentiation of CD8(+) T cells in vivo and that classical models of helper-dependent responses describe impaired secondary responses to Ag in vitro. We have measured primary CD8(+) T cell responses to peptide-pulsed dendritic cells in mice by cytokine ELISPOT and tetramer staining. No responses were detected in the absence of help, either when normal dendritic cells were injected into MHC II-deficient mice or when MHC II-deficient dendritic cells were injected into normal mice. Thus, the primary in vivo CD8(+) T cell response depends absolutely on help from CD4(+) T cells in our experimental system. PMID:14662830

  9. Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells

    PubMed Central

    Zhu, Xuekai; Niedermann, Gabriele

    2015-01-01

    Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) holds great promise for cancer treatment. We recently developed CAR T cells targeting the prototypic cancer stem cell marker AC133 and showed that these CAR T cells killed AC133+ glioblastoma stem cells (GBM-SCs) in vitro and inhibited the growth of brain tumors initiated from GBM-SCs in xenograft mouse models in vivo. Upon coincubation with GBM-SCs, we observed strong upregulation of the T cell aging marker CD57, but other phenotypical or functional changes usually associated with terminal T cell differentiation could not immediately be detected. Here, we provide evidence suggesting that CD57 is rapidly and efficiently transferred from CD57+ GBM-SCs to preactivated T cells and that the transfer is greatly enhanced by specific CAR/ligand interaction. After separation from CD57+ tumor cells, CD57 epitope expression on T cells decreased only slowly over several days. We conclude that CD57 transfer from tumor cells to T cells may occur in patients with CD57+ tumors and that it may have to be considered in the interpretation of phenotyping results for tumor-infiltrating lymphocytes and perhaps also in the characterization of tumor-specific T cells from tumor or lymph node homogenates or peripheral blood mononuclear cells. PMID:26097880

  10. TGF-? Signalling Is Required for CD4+ T Cell Homeostasis But Dispensable for Regulatory T Cell Function

    PubMed Central

    ?ledzi?ska, Anna; Hemmers, Saskia; Mair, Florian; Gorka, Oliver; Ruland, Jürgen; Fairbairn, Lynsey; Nissler, Anja; Müller, Werner; Waisman, Ari

    2013-01-01

    TGF-? is widely held to be critical for the maintenance and function of regulatory T (Treg) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-? receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-?–driven peripheral tolerance is not regulated by TGF-? signalling on mature CD4+ T cells. Inducible TR2 ablation specifically on CD4+ T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4+ T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4+ T cells does not result in the collapse of the Treg cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-? signalling and the TR2–deficient Treg cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-? signalling on mature CD4+ T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice. PMID:24115907

  11. Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells.

    PubMed

    Zhu, Xuekai; Niedermann, Gabriele

    2015-01-01

    Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) holds great promise for cancer treatment. We recently developed CAR T cells targeting the prototypic cancer stem cell marker AC133 and showed that these CAR T cells killed AC133+ glioblastoma stem cells (GBM-SCs) in vitro and inhibited the growth of brain tumors initiated from GBM-SCs in xenograft mouse models in vivo . Upon coincubation with GBM-SCs, we observed strong upregulation of the T cell aging marker CD57, but other phenotypical or functional changes usually associated with terminal T cell differentiation could not immediately be detected. Here, we provide evidence suggesting that CD57 is rapidly and efficiently transferred from CD57+ GBM-SCs to preactivated T cells and that the transfer is greatly enhanced by specific CAR/ligand interaction. After separation from CD57+ tumor cells, CD57 epitope expression on T cells decreased only slowly over several days. We conclude that CD57 transfer from tumor cells to T cells may occur in patients with CD57+ tumors and that it may have to be considered in the interpretation of phenotyping results for tumor-infiltrating lymphocytes and perhaps also in the characterization of tumor-specific T cells from tumor or lymph node homogenates or peripheral blood mononuclear cells. PMID:26097880

  12. Transient T cell depletion causes regression of melanoma metastases

    Microsoft Academic Search

    Mary Ann Rasku; Amy L Clem; Sucheta Telang; Beverly Taft; Kelly Gettings; Hana Gragg; Daniel Cramer; Sheron C Lear; Kelly M McMasters; Donald M Miller; Jason Chesney

    2008-01-01

    BACKGROUND: Cognate immunity against neoplastic cells depends on a balance between effector T cells and regulatory T (Treg) cells. Treg cells prevent immune attack against normal and neoplastic cells by directly suppressing the activation of effector CD4+ and CD8+ T cells. We postulated that a recombinant interleukin 2\\/diphtheria toxin conjugate (DAB\\/IL2; Denileukin Diftitox; Ontak) may serve as a useful strategy

  13. Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein

    Microsoft Academic Search

    Kai W Wucherpfennig; Jack L Strominger

    1995-01-01

    Structural similarity between viral T cell epitopes and self-peptides could lead to the induction of an autoaggressive T cell response. Based on the structural requirements for both MHC class 11 binding and TCR recognition of an immunodominant myelin basic protein (MBP) peptide, criteria for a data base search were developed in which the degeneracy of amino acid side chains required

  14. Helper Function of Memory CD8+ T Cells: Heterologous CD8+ T Cells Support the Induction of Therapeutic Cancer Immunity

    Microsoft Academic Search

    Yutaro Nakamura; Julie Urban; Brian Sheridan; Adam Giermasz; Fumihiko Nishimura; Kotaro Sasaki; Rachel Cumberland; Ravikumar Muthuswamy; Robbie B. Mailliard; Adriana T. Larregina; Louis D. Falo; William Gooding; Walter J. Storkus; Hideho Okada; Robert L. Hendricks; Pawel Kalinski

    In contrast to the well-established efficacy of preventive vaccines, the effectiveness of therapeutic vaccines remains limited. To develop effective vaccination regimens against cancer, we have analyzed the effect of effector and memory CD8+ T cells on the ability of dendritic cells to mediate the immunologic and antitumor effects of vaccination. We show that in contrast to effector CD8+ T cells

  15. Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations.

    PubMed

    Deniger, Drew C; Yu, Jianqiang; Huls, M Helen; Figliola, Matthew J; Mi, Tiejuan; Maiti, Sourindra N; Widhopf, George F; Hurton, Lenka V; Thokala, Radhika; Singh, Harjeet; Olivares, Simon; Champlin, Richard E; Wierda, William G; Kipps, Thomas J; Cooper, Laurence J N

    2015-01-01

    T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3? and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with ?-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-? and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire. PMID:26030772

  16. Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations

    PubMed Central

    Deniger, Drew C.; Yu, Jianqiang; Huls, M. Helen; Figliola, Matthew J.; Mi, Tiejuan; Maiti, Sourindra N.; Widhopf, George F.; Hurton, Lenka V.; Thokala, Radhika; Singh, Harjeet; Olivares, Simon; Champlin, Richard E.; Wierda, William G.; Kipps, Thomas J.; Cooper, Laurence J. N.

    2015-01-01

    T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3? and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with ?-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-? and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire. PMID:26030772

  17. T CELL BASED THERAPIES FOR MALIGNANCY AND INFECTION IN CHILDHOOD

    PubMed Central

    Ahmed, Nabil; Heslop, Helen E.; Mackall, Crystal L.

    2009-01-01

    One major advance in T cell based immunotherapy in the last twenty years has been the molecular definition of numerous viral and tumor antigens. Adoptive T-cell transfer has shown definite clinical benefit in the prophylaxis and treatment of viral infections that develop in pediatric patients after allogeneic transplant and in Epstein–Barr virus-associated post-transplant lymphoproliferative disease. Developing adoptive T cell therapies for other malignancies presents additional challenges. This article describes the recent advances in T cell based therapies for malignancy and infection in childhood and strategies to enhance the effector functions of T cells and optimize the cellular product, including gene modification and modulation of the host environment. PMID:20307713

  18. Shaping the repertoire of tumor-infiltrating effector and regulatory T cells

    PubMed Central

    Savage, Peter A.; Leventhal, Daniel S.; Malchow, Sven

    2014-01-01

    Summary Many tumors express antigens that can be specifically or selectively recognized by T lymphocytes, suggesting that T cell-mediated immunity may be harnessed for the immunotherapy of cancer. However, since tumors originate from normal cells and evolve within the context of self tissues, the immune mechanisms that prevent the autoimmune attack of normal tissues function in parallel to restrict anti-tumor immunity. In particular, the purging of autoreactive T cells and the development of immune-suppressive regulatory T cells (Tregs) are thought to be major barriers impeding anti-tumor immune responses. Here, we discuss current understanding regarding the antigens recognized by tumor-infiltrating T cell populations, the mechanisms that shape the repertoire of these cells, and the role of the transcription factor autoimmune regulator (Aire) in these processes. Further elucidation of these principles is likely to be critical for optimizing emerging cancer immunotherapies, and for the rational design of novel therapies exhibiting robust anti-tumor activity with limited toxicity. PMID:24712470

  19. Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs

    PubMed Central

    Shrestha, Sharad; Yang, Kai; Wei, Jun; Karmaus, Peer W. F.; Neale, Geoffrey; Chi, Hongbo

    2014-01-01

    Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen reexposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells while promoting short-lived effector cell differentiation. Transcriptome analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation, and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated glycolytic and oxidative metabolism in response to IL-15 stimulation. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T-cell development and function. PMID:25271321

  20. Distinct contributions of CD4 and CD8 naive and memory T-cell subsets to overall T-cell-receptor repertoire complexity following transplantation of T-cell-depleted CD34-selected hematopoietic progenitor cells from unrelated donors

    Microsoft Academic Search

    Matthias Eyrich; Tanja Croner; Christine Leiler; Peter Lang; Peter Bader; Thomas Klingebiel; Dietrich Niethammer; Paul G. Schlegel

    2010-01-01

    Normalization of restricted T-cell-recep- tor (TCR) repertoire is critical following T-cell-depleted (TCD) stem cell transplan- tation. We present a prospective study analyzing respective contributions of na- ive and memory T-cell subsets within the CD4 and CD8 compartments to the evolution of overall TCR-repertoire com- plexity following transplantation of CD34- selected peripheral blood progenitor cells from unrelated donors. During the first

  1. STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function.

    PubMed

    Wilson, Robert P; Ives, Megan L; Rao, Geetha; Lau, Anthony; Payne, Kathryn; Kobayashi, Masao; Arkwright, Peter D; Peake, Jane; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; French, Martyn A; Fulcher, David A; Picard, Capucine; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Gray, Paul; Stepensky, Polina; Warnatz, Klaus; Freeman, Alexandra F; Rossjohn, Jamie; McCluskey, James; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Ma, Cindy S; Tangye, Stuart G; Deenick, Elissa K

    2015-06-01

    Unconventional T cells such as ?? T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not ?? T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor ROR?t. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFN? and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers. PMID:25941256

  2. Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells

    PubMed Central

    Rouse, Michael; Singh, Narendra P; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2013-01-01

    Background and Purpose Dietary indole derivatives, indole-3-carbinol (I3C) and diindolylmethane (DIM), possess anti-cancer properties and exhibit the characteristics of aryl hydrocarbon receptor (AhR) ligands. Because AhR activation has recently been shown to regulate T cell differentiation, we tested the hypothesis that I3C and DIM may mediate anti-inflammatory properties by promoting regulatory T cell (T-regs) differentiation while inhibiting Th17 cells. Experimental Approach We investigated the therapeutic efficacy of I3C and DIM against experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). The efficacy was evaluated based on clinical scores of paralysis, histopathology, serum cytokines and infiltration of T cells in the CNS. We next studied the mechanism of induction of T cells against myelin oligodendrocyte glycoprotein (MOG35–55) peptide, both in vivo and in vitro, specifically investigating the differentiation of T-regs and Th17 cells, and determined if indoles were acting through AhR. Key Results Pretreatment of EAE mice with I3C or DIM completely prevented the clinical symptoms and cellular infiltration into the CNS. Also, post-treatment of EAE with I3C or DIM proved highly effective in curtailing the overall severity of the disease. In addition, I3C or DIM promoted the generation of T-regs, while down-regulating the induction of MOG-specific Th17 cells. The regulation of FoxP3 induction and suppression of Th17 cells by indoles in vivo and in vitro were found to be AhR-dependent. Conclusions and Implications Together, our studies demonstrate for the first time that I3C and DIM may serve as novel therapeutics to suppress neuroinflammation seen during MS through activation of AhR. PMID:23586923

  3. The E3 ubiquitin ligase Cbl-b regulates expansion but not functional activity of self-reactive CD4 T cells.

    PubMed

    St Rose, Marie-Clare; Qui, Harry Z; Bandyopadhyay, Suman; Mihalyo, Marianne A; Hagymasi, Adam T; Clark, Robert B; Adler, Adam J

    2009-10-15

    Cbl-b is an E3 ubiquitin ligase that limits Ag responsiveness in T cells by targeting TCR-inducible signaling molecules. Cbl-b deficiency thus renders T cells hyperresponsive to antigenic stimulation and predisposes individuals toward developing autoimmunity. In part because Cbl-b(-/-) T cells do not require CD28 costimulation to become activated, and insufficient costimulation is a critical parameter that confers anergy induction over effector differentiation, it has been hypothesized that Cbl-b(-/-) T cells are resistant to anergy. This possibility has been supported in models in which anergy is normally induced in vitro, or in vivo following exposure to soluble Ag boluses. In the current study, we characterized the response of Cbl-b(-/-) CD4 T cells in an in vivo system in which anergy is normally induced by a constitutively expressed peripheral self-Ag. Cbl-b expression increased in self-Ag-induced anergic wild-type CD4 T cells, and Cbl-b(-/-) CD4 T cells underwent more robust proliferation and expansion upon initially encountering cognate self-Ag compared with wild-type counterparts. Nevertheless, both wild-type and Cbl-b(-/-) CD4 T cells ultimately developed the same impaired ability to respond to antigenic restimulation. The more extensive expansion that occurred during the initial induction of anergy did, however, allow the anergic CD4 T cells to expand to greater numbers when they were functionally resuscitated following replacement of the initial source of tolerizing self-Ag with a viral form of the same Ag. PMID:19801520

  4. The E3 Ubiquitin Ligase Cbl-b Regulates Expansion but Not Functional Activity of Self-Reactive CD4 T Cells1

    PubMed Central

    St. Rose, Marie-Clare; Qui, Harry Z.; Bandyopadhyay, Suman; Mihalyo, Marianne A.; Hagymasi, Adam T.; Clark, Robert B.; Adler, Adam J.

    2010-01-01

    Cbl-b is an E3 ubiquitin ligase that limits Ag responsiveness in T cells by targeting TCR-inducible signaling molecules. Cbl-b deficiency thus renders T cells hyperresponsive to antigenic stimulation and predisposes individuals toward developing autoimmunity. In part because Cbl-b?/? T cells do not require CD28 costimulation to become activated, and insufficient costimulation is a critical parameter that confers anergy induction over effector differentiation, it has been hypothesized that Cbl-b?/? T cells are resistant to anergy. This possibility has been supported in models in which anergy is normally induced in vitro, or in vivo following exposure to soluble Ag boluses. In the current study, we characterized the response of Cbl-b?/? CD4 T cells in an in vivo system in which anergy is normally induced by a constitutively expressed peripheral self-Ag. Cbl-b expression increased in self-Ag-induced anergic wild-type CD4 T cells, and Cbl-b?/? CD4 T cells underwent more robust proliferation and expansion upon initially encountering cognate self-Ag compared with wild-type counterparts. Nevertheless, both wild-type and Cbl-b?/? CD4 T cells ultimately developed the same impaired ability to respond to antigenic restimulation. The more extensive expansion that occurred during the initial induction of anergy did, however, allow the anergic CD4 T cells to expand to greater numbers when they were functionally resuscitated following replacement of the initial source of tolerizing self-Ag with a viral form of the same Ag. PMID:19801520

  5. Regulatory T cells and T cell depletion: role of immunosuppressive drugs.

    PubMed

    Noris, Marina; Casiraghi, Federica; Todeschini, Marta; Cravedi, Paolo; Cugini, Daniela; Monteferrante, Giuseppe; Aiello, Sistiana; Cassis, Linda; Gotti, Eliana; Gaspari, Flavio; Cattaneo, Dario; Perico, Norberto; Remuzzi, Giuseppe

    2007-03-01

    Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4(+)CD25(high) subset. Evidence exists that Treg expand after peritransplantation lymphopenia, inhibit graft rejection, and induce and maintain tolerance. Little, however, is known about the role of Treg in the clinical setting. IL-2 and activation by T cell receptor engagement are instrumental to generate and maintain Treg, but the influence of immunosuppressants on Treg homeostasis in humans in vivo has not been investigated. This study monitored Treg phenotype and function during immune reconstitution in renal transplant recipients who underwent profound T cell depletion with Campath-1H and received sirolimus or cyclosporine (CsA) as part of their maintenance immunosuppressive therapy. CD4(+)CD25(high) cells that expressed FOXP3 underwent homeostatic peripheral expansion during immune reconstitution, more intense in patients who received sirolimus than in those who were given CsA. T cells that were isolated from peripheral blood long term after transplantation were hyporesponsive to alloantigens in both groups. In sirolimus- but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic. Thus, lymphopenia and calcineurin-dependent signaling seem to be primary mediators of CD4(+)CD25(high) Treg expansion in renal transplant patients. These findings will be instrumental in developing "tolerance permissive" immunosuppressive regimens in the clinical setting. PMID:17287424

  6. Chapter 2. Normal Plant Appearance and Development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Most often, agronomists evaluate crop health by examining aboveground plant growth and canopy appearance. It is important to know when stresses occur relative to critical events in the development of the crop. This enables an agronomist to more effectively and efficiently employ management practices...

  7. Movie of normal C. elegans development

    NSDL National Science Digital Library

    PhD Bob Goldstein (UNC Chapel Hill Biology Dept,)

    2006-07-19

    C. elegans develops from a single cell, the fertilized egg, to a 558-celled worm in about 14 hours. The worm that crawls out of its eggshell has a functioning feeding apparatus, gut, nervous system and muscles. This movie shows that in time lapse.

  8. CRTAM is negatively regulated by ZEB1 in T cells.

    PubMed

    Rojas-Marquez, C; Valle-Rios, R; Lopez-Bayghen, E; Ortiz-Navarrete, V

    2015-08-01

    T cell activation leads to the induction of genes that are required for appropriate immune responses. This includes CRTAM (Class-I MHC-restricted T cell associated molecule), a protein that plays a key role in T cell development, proliferation, and generating cell polarity during activation. We previously characterized the CRTAM promoter and described how AP-1 family members are important for inducing CRTAM expression upon antigenic activation. Here, we show that CRTAM is a molecular target for ZEB1 (zinc finger E-box-binding protein), a homeodomain/Zn finger transcription factor. Overexpression of ZEB1 repressed CRTAM promoter activity, as well as endogenous CRTAM levels in human T cells. ZEB1-mediated transcriptional repression was abolished when E-box-like elements in the CRTAM promoter are mutated. In summary, ZEB1 functions as a transcriptional repressor for the CRTAM gene in both non-stimulated and stimulated T cells, thereby modulating adaptive immune responses. PMID:25910959

  9. Cytoskeletal forces during signaling activation in Jurkat T-cells

    PubMed Central

    Hui, King Lam; Balagopalan, Lakshmi; Samelson, Lawrence E.; Upadhyaya, Arpita

    2015-01-01

    T-cells are critical for the adaptive immune response in the body. The binding of the T-cell receptor (TCR) with antigen on the surface of antigen-presenting cells leads to cell spreading and signaling activation. The underlying mechanism of signaling activation is not completely understood. Although cytoskeletal forces have been implicated in this process, the contribution of different cytoskeletal components and their spatial organization are unknown. Here we use traction force microscopy to measure the forces exerted by Jurkat T-cells during TCR activation. Perturbation experiments reveal that these forces are largely due to actin assembly and dynamics, with myosin contractility contributing to the development of force but not its maintenance. We find that Jurkat T-cells are mechanosensitive, with cytoskeletal forces and signaling dynamics both sensitive to the stiffness of the substrate. Our results delineate the cytoskeletal contributions to interfacial forces exerted by T-cells during activation. PMID:25518938

  10. The emergence of T-bodies/CAR T cells.

    PubMed

    Eshhar, Zelig; Waks, Tova; Gross, Gideon

    2014-01-01

    The nickname "T-body" is used to denote a T cell expressing an antigen-specific or antibody-based chimeric receptor that combines antibody specificity with T-cell effector or regulatory function. Initially, we designed and constructed chimeric antibody-based receptors and expressed them in T cells to study the role of major histocompatibility complex in triggering T-cell activation. To this end, we replaced both variable domains (V? and V? of the native T-cell receptor chains) with antibody-derived VH and VL sequences. After transfection into T cells, the 2 chimeric chains paired, associated with the CD3 complex, and endowed transfectants with non-major histocompatibility complex-restricted antibody type specificity. In subsequent studies, we developed next generation of chimeric antibody-based receptors by fusing an antibody single-chain variable fragment to T-cell activation motifs. This modular configuration simplified gene transfer, avoided mixed pairing with endogenous T-cell receptor chains, and enabled simultaneous insertion of various domains as costimulatory moieties to generate T-bodies with efficient antitumor reactivity. PMID:24667957

  11. Human cytomegalovirus elicits fetal ?? T cell responses in utero

    PubMed Central

    Brouwer, Margreet; Donner, Catherine; Liesnard, Corinne; Tackoen, Marie; Van Rysselberge, Michel; Twité, Nicolas; Goldman, Michel; Marchant, Arnaud; Willems, Fabienne

    2010-01-01

    The fetus and infant are highly susceptible to viral infections. Several viruses, including human cytomegalovirus (CMV), cause more severe disease in early life compared with later life. It is generally accepted that this is a result of the immaturity of the immune system. ?? T cells are unconventional T cells that can react rapidly upon activation and show major histocompatibility complex–unrestricted activity. We show that upon CMV infection in utero, fetal ?? T cells expand and become differentiated. The expansion was restricted to V?9-negative ?? T cells, irrespective of their V? chain expression. Differentiated ?? T cells expressed high levels of IFN-?, transcription factors T-bet and eomes, natural killer receptors, and cytotoxic mediators. CMV infection induced a striking enrichment of a public V?8V?1-TCR, containing the germline-encoded complementary-determining-region-3 (CDR3) ?1–CALGELGDDKLIF/CDR3?8–CATWDTTGWFKIF. Public V?8V?1-TCR–expressing cell clones produced IFN-? upon coincubation with CMV-infected target cells in a TCR/CD3-dependent manner and showed antiviral activity. Differentiated ?? T cells and public V?8V?1-TCR were detected as early as after 21 wk of gestation. Our results indicate that functional fetal ?? T cell responses can be generated during development in utero and suggest that this T cell subset could participate in antiviral defense in early life. PMID:20368575

  12. Cytotoxic T Cells Mediate Pathology and Metastasis in Cutaneous Leishmaniasis

    PubMed Central

    Novais, Fernanda O.; Carvalho, Lucas P.; Graff, Joel W.; Beiting, Daniel P.; Ruthel, Gordon; Roos, David S.; Betts, Michael R.; Goldschmidt, Michael H.; Wilson, Mary E.; de Oliveira, Camila I.; Scott, Phillip

    2013-01-01

    Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8+ T cells following infection with the intracellular parasite Leishmania, CD8+ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8+ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8+ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8+ T cells. In mice with severe pathology, we visualized CD8+ T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8+ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8+ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis. PMID:23874205

  13. Loss of T cell precursors after spaceflight and exposure to vector-averaged gravity.

    PubMed

    Woods, Chris C; Banks, Krista E; Gruener, Raphael; DeLuca, Dominick

    2003-08-01

    Using fetal thymus organ culture (FTOC), we examined the effects of spaceflight and vector-averaged gravity on T cell development. Under both conditions, the development of T cells was significantly attenuated. Exposure to spaceflight for 16 days resulted in a loss of precursors for CD4+, CD8+, and CD4+CD8+ T cells in a rat/mouse xenogeneic co-culture. A significant decrease in the same precursor cells, as well as a decrease in CD4-CD8- T cell precursors, was also observed in a murine C57BL/6 FTOC after rotation in a clinostat to produce a vector-averaged microgravity-like environment. The block in T cell development appeared to occur between the pre-T cell and CD4+CD8+ T cell stage. These data indicate that gravity plays a decisive role in the development of T cells. PMID:12824295

  14. Loss of T cell precursors after spaceflight and exposure to vector-averaged gravity

    NASA Technical Reports Server (NTRS)

    Woods, Chris C.; Banks, Krista E.; Gruener, Raphael; DeLuca, Dominick

    2003-01-01

    Using fetal thymus organ culture (FTOC), we examined the effects of spaceflight and vector-averaged gravity on T cell development. Under both conditions, the development of T cells was significantly attenuated. Exposure to spaceflight for 16 days resulted in a loss of precursors for CD4+, CD8+, and CD4+CD8+ T cells in a rat/mouse xenogeneic co-culture. A significant decrease in the same precursor cells, as well as a decrease in CD4-CD8- T cell precursors, was also observed in a murine C57BL/6 FTOC after rotation in a clinostat to produce a vector-averaged microgravity-like environment. The block in T cell development appeared to occur between the pre-T cell and CD4+CD8+ T cell stage. These data indicate that gravity plays a decisive role in the development of T cells.

  15. Store-operated Ca2+ entry through ORAI1 is critical for T cell mediated autoimmunity and allograft rejection1

    PubMed Central

    McCarl, Christie-Ann; Khalil, Sara; Ma, Jian; Oh-hora, Masatsugu; Yamashita, Megumi; Roether, Jens; Kawasaki, Takumi; Jairaman, Amit; Sasaki, Yoshiteru; Prakriya, Murali; Feske, Stefan

    2010-01-01

    ORAI1 is the pore forming subunit of the Ca2+ release activated Ca2+ (CRAC) channel, which is responsible for store-operated Ca2+ entry (SOCE) in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1?/? mice but a detailed analysis of T cell mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1KI/KI) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1KI/KI mice die neonatally but Orai1KI/KI fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1KI/KI mice display severely impaired SOCE and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-? and TNF-? in CD4+ and CD8+ T cells. Cell mediated immune responses in vivo that depend on TH1, TH2 and TH17 cell function were severely attenuated in ORAI1 deficient mice. Orai1KI/KI mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wildtype mice. In addition, T cells from Orai1KI/KI mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide new insights into the in vivo functions of CRAC channels for T cell mediated immunity. PMID:20956344

  16. Pro-cognitive properties of T cells

    PubMed Central

    Kipnis, Jonathan; Gadani, Sachin; Derecki, Noël C.

    2014-01-01

    Interactions between the central nervous system and the immune system have been studied primarily in the context of pathology, popularizing the view that interplay between these two systems is inherently detrimental. However, recent experimental data have demonstrated productive neuroimmune interactions that occur under normal physiological conditions. In this Essay, we outline our current understanding of contemporary neuroimmunology, describe a working model of T cell function in support of learning and memory, and offer ideas regarding the selective advantages of immune-mediated effects on brain function. PMID:22903149

  17. Adolescent brain development in normality and psychopathology

    PubMed Central

    LUCIANA, MONICA

    2014-01-01

    Since this journal’s inception, the field of adolescent brain development has flourished, as researchers have investigated the underpinnings of adolescent risk-taking behaviors. Explanations based on translational models initially attributed such behaviors to executive control deficiencies and poor frontal lobe function. This conclusion was bolstered by evidence that the prefrontal cortex and its interconnections are among the last brain regions to structurally and functionally mature. As substantial heterogeneity of prefrontal function was revealed, applications of neuroeconomic theory to adolescent development led to dual systems models of behavior. Current epidemiological trends, behavioral observations, and functional magnetic resonance imaging based brain activity patterns suggest a quadratic increase in limbically mediated incentive motivation from childhood to adolescence and a decline thereafter. This elevation occurs in the context of immature prefrontal function, so motivational strivings may be difficult to regulate. Theoretical models explain this patterning through brain-based accounts of subcortical–cortical integration, puberty-based models of adolescent sensation seeking, and neurochemical dynamics. Empirically sound tests of these mechanisms, as well as investigations of biology–context interactions, represent the field’s most challenging future goals, so that applications to psychopathology can be refined and so that developmental cascades that incorporate neurobiological variables can be modeled. PMID:24342843

  18. A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency

    PubMed Central

    Hsieh, Jeremy; Ng, Spencer; Bosinger, Steve; Wu, Jian Hui; Tharp, Gregory K; Garcia, Anapatricia; Hossain, Mohammad S; Yuan, Shala; Waller, Edmund K; Galipeau, Jacques

    2015-01-01

    The competence of cellular immunity depends on a diverse T-cell receptor (TCR) repertoire arising from thymic output. Normal thymopoiesis arises from marrow-derived CD3?CD4?CD8? triple-negative T-cell progenitors (TN), which develop into mature single-positive (SP) CD4 or CD8 T cells after expressing both CD4 and CD8 (double-positive, DP) transiently, leading to de novo T-cell production. Interleukin-7 (IL7) is a singularly important common ?-chain IL involved in normal thymic development. Our previous work has demonstrated that ?c cytokines fused with granulocyte-macrophage colony stimulating factor (GMCSF) at the N-terminus acquire unheralded biological properties. Therefore, to enhance thymopoiesis, we developed a novel biopharmaceutical based on the fusion of GMCSF and IL7, hereafter GIFT7. Systemic administration of GIFT7 leads to cortical thymic hyperplasia including the specific expansion of CD44intCD25? double-negative 1 (DN1) thymic progenitors. During murine cytomegalovirus (mCMV) infection of aged animals, GIFT7-mediated neo-thymopoiesis led to increased absolute numbers of viral-specific CD8+ T cell. Our work demonstrated that thymic precursors can be therapeutically repopulated and its reconstitution leads to meaningful central and peripheral T-cell neogenesis, correcting immune dysfunction arising from age-associated thymic atrophy.

  19. Loss of T cell progenitor checkpoint control underlies leukemia initiation in Rag1-deficient NOD mice

    PubMed Central

    Yui, Mary A.; Feng, Ni; Zhang, Jingli A.; Liaw, Chen Yee; Rothenberg, Ellen V.; Longmate, Jeffrey A.

    2013-01-01

    NOD mice exhibit major defects in the earliest stages of T cell development in the thymus. Genome-wide genetic and transcriptome analyses were used to investigate the origins and consequences of an early T cell developmental checkpoint breakthrough in Rag1-deficient NOD mice. QTL analysis mapped the presence of checkpoint breakthrough cells to several known NOD diabetes susceptibility regions, particularly Idd9/11 on chromosome 4, suggesting common genetic origins for T cell defects affecting this trait and autoimmunity. Genome-wide RNA deep-sequencing of NOD and B6 Rag1-deficient thymocytes revealed the effects of genetic background prior to breakthrough, as well as the cellular consequences of the breakthrough. Transcriptome comparison between the two strains showed enrichment in differentially expressed signal transduction genes, prominently tyrosine kinase and actin-binding genes, in accord with their divergent sensitivities to activating signals. Emerging NOD breakthrough cells aberrantly expressed both stem cell-associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit which are normally repressed at the commitment checkpoint, and post-?-selection checkpoint genes including Cd2 and Cd5. Co-expression of genes characteristic of multi-potent progenitors and more mature T cells persists in the expanding population of thymocytes, and in the thymic leukemias that emerge with age in these mice. These results show that Rag1-deficient NOD thymocytes have T cell defects that can collapse regulatory boundaries at two early T cell checkpoints, which may predispose them to both leukemia and autoimmunity. PMID:23440410

  20. Gamma-delta T-cell lymphomas

    Microsoft Academic Search

    Emilio Iannitto; Ada Maria Florena; Carlo Ennio Pucillo; Pier Paolo Piccaluga; Vito Franco; Stefano Aldo Pileri; Claudio Tripodo

    2009-01-01

    Peripheral T-cell lymphomas (TCLs) are uncommon neoplasms, accounting for about 12% of all lymphoid tumors worldwide. TCLs in which ?? T-cell receptors are expressed (?? TCLs) are extremely aggressive and rare (<1% of lymphoid neoplasms). ?? TCLs originate from ?? T cells, a small subset of peripheral T cells with direct antigen recognition capability acting at the interface between innate

  1. Fish T cells: recent advances through genomics

    USGS Publications Warehouse

    Laing, Kerry J.; Hansen, John D.

    2011-01-01

    This brief review is intended to provide a concise overview of the current literature concerning T cells, advances in identifying distinct T cell functional subsets, and in distinguishing effector cells from memory cells. We compare and contrast a wealth of recent progress made in T cell immunology of teleost, elasmobranch, and agnathan fish, to knowledge derived from mammalian T cell studies. From genome studies, fish clearly have most components associated with T cell function and we can speculate on the presence of putative T cell subsets, and the ability to detect their differentiation to form memory cells. Some recombinant proteins for T cell associated cytokines and antibodies for T cell surface receptors have been generated that will facilitate studying the functional roles of teleost T cells during immune responses. Although there is still a long way to go, major advances have occurred in recent years for investigating T cell responses, thus phenotypic and functional characterization is on the near horizon.

  2. Activated CD4+ T cells enter the splenic T-cell zone and induce autoantibody-producing germinal centers through bystander activation

    PubMed Central

    Banczyk, David; Kalies, Kathrin; Nachbar, Lars; Bergmann, Lars; Schmidt, Philipp; Bode, Ulrike; Teegen, Bianca; Steven, Philipp; Lange, Tanja; Textor, Johannes; Ludwig, Ralf J; Stöcker, Winfried; König, Peter; Bell, Eric; Westermann, Jürgen

    2014-01-01

    CD4+ T (helper) cells migrate in huge numbers through lymphoid organs. However, little is known about traffic routes and kinetics of CD4+ T-cell subsets within different organ compartments. Such information is important because there are indications that CD4+ T cells may influence the function of microenvironments depending on their developmental stage. Therefore, we investigated the migration of resting (naïve), activated, and recently activated (memory) CD4+ T cells through the different compartments of the spleen. Resting and recently activated CD4+ T cells were separated from thoracic duct lymph and activated CD4+ T cells were generated in vitro by cross-linking the T-cell receptor and CD28. The present study shows that all three CD4+ T-cell subsets selectively accumulate in the T-cell zone of the spleen. However, only activated T cells induce the formation of germinal centers (GCs) and autoantibodies in rats and mice. Our results suggest that in a two-step process they first activate B cells independent of the T-cell receptor repertoire and CD40 ligand (CD154) expression. The activated B cells then form GCs whereby CD154-dependend T-cell help is needed. Thus, activated T cells may contribute to the development of autoimmune diseases by activating autoreactive B cells in an Ag-independent manner. PMID:24114675

  3. Thymic Deletion and Regulatory T Cells Prevent Antimyeloperoxidase GN

    PubMed Central

    Tan, Diana S.Y.; Gan, Poh Y.; O’Sullivan, Kim M.; Hammett, Maree V.; Summers, Shaun A.; Ooi, Joshua D.; Lundgren, Brita A.; Boyd, Richard L.; Scott, Hamish S.; Kitching, A. Richard; Chidgey, Ann P.

    2013-01-01

    Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo?/? mice, Aire?/? mice, and control littermates with MPO. Immunized Mpo?/? and Aire?/? mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire?/? mice had more severe renal disease than Aire+/+ mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell–mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN. PMID:23393320

  4. The roles of T cell subpopulations in allograft rejection.

    PubMed

    Mason, D

    1988-04-01

    In principle, cell-mediated allograft rejection can be brought about by cytotoxic T cells or by a DTH-like reaction. The first part of this article reviews the relative importance of these two mechanisms in graft rejection and concludes that the bulk of evidence points to cytotoxic T cells as being of major importance. In the discussion an operational definition of DTH is adopted--namely a mechanism that mediates bystander killing and depends on the existence of a radiation-sensitive effector mechanism. The rejection of skin and organ allografts in mammals is T cell dependent and the demonstration that such rejection can occur in heavily-irradiated T cell reconstituted animals and in the absence of demonstrable bystander effects leads to the conclusion drawn. This is not to imply that concomitant DTH reactions may not augment the rejection process nor to deny the possibility that in special circumstances DTH reactions may play an essential part. In the second part of this article, the roles in graft rejection of CD4+ and CD8+ cytotoxic T cells are considered. The classical collaborative interaction between class II-restricted CD4+ cells that play an inductive role, and class I restricted CD8+ cells that differentiate into cytotoxic effector cells, seems to be unnecessary in some allograft responses. Thus, not only can CD4+ T cells differentiate into class II-restricted cytotoxic T cells but CD8+ T cells, at least in some class I MHC-incompatible strain combinations, can develop into mature effector cells without an inductive signal from CD4+ T cells. This autonomy seems to be limited to MHC incompatibilities so that CD8+ cells alone are unable to mediate the rejection of minor-H incompatible grafts. For these latter types of grafts, CD4+ T cells can bring about graft rejection if multiple minor-H determinants are present, but for weak minor-H responses the classical collaborative scheme is necessary. PMID:3284050

  5. Regulatory T cells, tumour immunity and immunotherapy

    Microsoft Academic Search

    Weiping Zou

    2006-01-01

    Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment

  6. T-cell-receptor gene therapy

    Microsoft Academic Search

    Ton N. M. Schumacher

    2002-01-01

    T cells are tightly controlled cellular machines that monitor changes in epitope presentation. Although T-cell function is regulated by means of numerous interactions with other cell types and soluble factors, the T-cell receptor (TCR) is the only structure on the T-cell surface that defines its antigen-recognition potential. Consequently, the transfer of T-cell receptors into recipient cells can be used as

  7. Human T-cell activation deficiencies.

    PubMed

    Arnaiz-Villena, A; Timón, M; Rodríguez-Gallego, C; Pérez-Blas, M; Corell, A; Martín-Villa, J M; Regueiro, J R

    1992-07-01

    The increasing understanding of T-cell activation is paralleled by the recognition of a growing range of 'experiments of nature' that cause T-cell activation deficiencies. Analysis of these deficiencies is, in turn, contributing to the understanding of T-cell function in vivo. Here, José Regueiro, Antonio Arnaiz-Villena and colleagues review current knowledge of structural and functional T-cell defects and the implications of these for T-cell biology. PMID:1388653

  8. Occurrence of interleukin-5 production by CD4- CD8- (double-negative) T cells in lungs of both normal and congenitally athymic nude mice infected with Toxocara canis.

    PubMed Central

    Takamoto, M; Kusama, Y; Takatsu, K; Nariuchi, H; Sugane, K

    1995-01-01

    We studied cells in the lungs of BALB/c and BALB/c-nu/nu (nude) mice infected with Toxocara canis, which produced interleukin-5 (IL-5) in in vitro culture with larval excretory-secretory antigen (ESAg). The proportion of CD4+/CD8+/CD4- CD8- cells in lungs of both BALB/c and nude mice was unchanged before and after infection with T. canis. Panning and complement-mediated lysis using monoclonal antibody (mAb) to CD4 showed that CD4+ cells in the lung from both mice produced IL-5. Anti-CD4 mAb suppressed ESAg-stimulated IL-5 production in vitro. In vitro depletion or inhibition of CD8+ cells reduced IL-5 production significantly in some cases, suggesting involvement with IL-5 production. Anti-CD3 mAb enhanced IL-5 production when incubated with or without ESAg. Production of IL-5 was reduced by in vivo depletion of CD4+ cells only and both CD4+ and CD8+ T cells, by intraperitoneal injection with appropriate mAb; IL-5 production was stimulated by anti-CD3 mAb. In contrast, IL-5 production by lung cells of BALB/c mice decreased by more than 90% after simultaneous injection with anti-CD4, anti-CD8 and anti-CD3 mAb, and was not enhanced by anti-CD3 mAb. Similar results were obtained in nude mice. These results suggest that CD4- CD8- T cells, as well as CD4+ T cells, produce IL-5. PMID:7642218

  9. Developing Visualization Support System for Teaching/Learning Database Normalization

    ERIC Educational Resources Information Center

    Folorunso, Olusegun; Akinwale, AdioTaofeek

    2010-01-01

    Purpose: In tertiary institution, some students find it hard to learn database design theory, in particular, database normalization. The purpose of this paper is to develop a visualization tool to give students an interactive hands-on experience in database normalization process. Design/methodology/approach: The model-view-controller architecture…

  10. Multi-scale models of T cell activation

    E-print Network

    Zheng, Huan, Ph.D. Massachusetts Institute of Technology

    2010-01-01

    The overarching theme of this thesis is to develop and apply multi-scale computational techniques adopted from physical sciences to study a key phenomenon underlying the adaptive immune response: the activation of T cells. ...

  11. Natural killer and natural killer-T cells in psoriasis.

    PubMed

    Cameron, A L; Kirby, B; Fei, W; Griffiths, C E M

    2002-11-01

    Psoriasis is characterized by a dermal and epidermal infiltrate comprised predominantly of CD4(+) and CD8(+) T cells, respectively. These cells behave in an antigen-dependent manner, which suggests that psoriasis may be a T-cell-mediated autoimmune disease. Psoriasis shares certain immunological features with recognized autoimmune conditions such as type I diabetes mellitus and multiple sclerosis, in both of which a pathogenic role is postulated for natural killer (NK) cells and natural killer-like T (NK-T) cells. However, there are few studies assessing the role of NK and NK-T cells in psoriasis. We sought to determine whether NK and NK-T cells are present in psoriasis. Skin biopsies were taken from the active edge of a psoriasis plaque and from uninvolved skin at least 5 cm away from involved skin of ten patients with chronic plaque psoriasis. Skin from four normal subjects was used as controls. Using an immunoperoxidase technique, cryostat sections were stained using antibodies to T-cell markers CD2, CD3, CD4 and CD8; cutaneous leucocyte associated antigen; NK cell markers CD16, CD56, CD57, CD94 and CD158a; and the NK-T cell marker CD161. There were significantly more cells expressing T cell markers, NK cell markers CD16, CD57, CD94 and CD158a and NK-T cell marker CD161 in involved skin than in uninvolved or normal skin ( P<0.01). There was no difference in the number of cells expressing CD56. Cells expressing NK markers were found most commonly in the papillary dermis immediately subjacent to the dermoepidermal junction. Cells expressing CD57 were found in significantly higher numbers in the epidermis and reticular dermis of involved skin. This study demonstrates that cells expressing NK markers and NK-T cell markers are present in plaques of psoriasis. The exact roles of NK and NK-T cells in psoriasis are unclear, although they may modulate autoimmune inflammation and act as a source of Th(1) cytokines important in the psoriatic process. PMID:12420105

  12. Preferential effects of leptin on CD4 T cells in central and peripheral immune system are critically linked to the expression of leptin receptor

    SciTech Connect

    Kim, So Yong; Lim, Ju Hyun [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of)] [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of); Choi, Sung Won [Department of Molecular Biology, School of Arts and Sciences (S.W.C), Cornell University, Ithaca, NY 18450 (United States)] [Department of Molecular Biology, School of Arts and Sciences (S.W.C), Cornell University, Ithaca, NY 18450 (United States); Kim, Miyoung; Kim, Seong-Tae [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of)] [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of); Kim, Min-Seon; Cho, You Sook [Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-600 (Korea, Republic of)] [Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-600 (Korea, Republic of); Chun, Eunyoung, E-mail: chun.eunyoung@gmail.com [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of)] [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of); Lee, Ki-Young, E-mail: thylee@med.skku.ac.kr [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of)] [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of)

    2010-04-09

    Leptin can enhance thymopoiesis and modulate the T-cell immune response. However, it remains controversial whether these effects correlate with the expression of leptin receptor, ObR. We herein addressed this issue by using in vivo animal models and in vitro culture systems. Leptin treatment in both ob/ob mice and normal young mice induced increases of CD4 SP thymocytes in thymus and CD4 T cells in the periphery. Interestingly, expression of the long form ObR was significantly restricted to DN, DP and CD4 SP, but not CD8 SP thymocytes. Moreover, in the reaggregated DP thymocyte cultures with leptin plus TSCs, leptin profoundly induced differentiation of CD4 SP but not CD8 SP thymocytes, suggesting that the effects of leptin on thymocyte differentiation might be closely related to the expression of leptin receptor in developing thymocytes. Surprisingly, ObR expression was markedly higher in peripheral CD4 T cells than that in CD8 T cells. Furthermore, leptin treatment with or without IL-2 and PHA had preferential effects on cell proliferation of CD4 T cells compared to that of CD8 T cells. Collectively, these data provide evidence that the effects of leptin on differentiation and proliferation of CD4 T cells might be closely related to the expression of leptin receptor.

  13. Control of Experimental Autoimmune Encephalomyelitis by T Cells Responding to Activated T Cells

    NASA Astrophysics Data System (ADS)

    Lohse, Ansgar W.; Mor, Felix; Karin, Nathan; Cohen, Irun R.

    1989-05-01

    T cell vaccination against experimental autoimmune disease is herein shown to be mediated in part by anti-ergotypic T cells, T cells that recognize and respond to the state of activation of other T cells. The anti-ergotypic response thus combines with the previously shown anti-idiotypic T cell response to regulate autoimmunity.

  14. Role of IL-16 in CD4+ T cell-mediated regulation of relapsing multiple sclerosis.

    PubMed

    Skundric, Dusanka S; Cruikshank, William W; Drulovic, Jelena

    2015-01-01

    In an important article published in Nature Medicine, Liu and colleagues described a novel CD4(+) FoxA1(+) regulatory T (Treg) cell population as distinct regulators of relapsing-remitting multiple sclerosis (RRMS) and experimental autoimmune encephalomyelitis (EAE). CD4(+) FoxA1(+) Treg cells appear as key regulators of responsiveness to therapy with interferon beta (IFN-?) in RRMS patients. Data indicate that CD4(+)FoxA1(+) FOXP3(-) Treg cells develop within the central nervous system (CNS), and a potential of cerebellar granule neurons (CGN) in generation of CD4(+)FoxA1(+)PD-L1(hi)FOXP3(-) Treg cells from encephalitogenic CD4(+) T cells. A CD4 co-receptor specific ligand, IL-16, governs trafficking and biological properties of CD4(+) T cells irrespective of their activation state. Functions of IL-16, relevant to Treg cells, include expansion of CD4(+)CD25(+) T cells in long-term cultures with IL-2, de novo induction of FOXP-3 and migration of FOXP-3(+) T cells. IL-16 is highly conserved across species including human and mouse. CGN and neurons in hippocampus contain neuronal-IL-16 (NIL-16), splice variant of immune IL-16, and express CD4 molecule. In a CD4-dependent manner, IL-16 supports cultured CGN survival. Concomitant studies of RRMS lesions and corresponding MOG35-55-induced relapsing EAE in (B6 × JL)F1 (H-2(b/s)) mice discovered similar roles of IL-16 in regulation of relapsing disease. In RRMS and EAE relapse, peak levels of IL-16 and active caspase-3 correlated with CD4(+) T cell infiltration and levels of T-bet, Stat-1(Tyr(701)), and phosphorylated neurofilaments of axonal cytoskeleton [NF (M + H) P], suggesting a role of locally produced IL-16 in regulation of CD4(+) Th1 inflammation and axonal damage, respectively. IL-16 was abundantly present in CD4(+) T cells, followed by CD20(+) B, CD8(+) T, CD83(+) dendritic cells, and Mac-1(+) microglia. Apart from lesions, bioactive IL-16 was located in normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) in RRMS brain and spinal cord. A cytokine IL-16 emerges as an important regulator of relapsing MS and EAE. Better understanding of immune cell-neuron interactions mediated by IL-16 will foster development of more specific CD4(+) T cell subset-targeted therapies to prevent or ameliorate progression of neuroinflammation and axonal and neuronal damage. Translational studies necessitate corresponding EAE models. PMID:25896927

  15. Synthetic Niches for Stem Cell Differentiation into T cells

    Microsoft Academic Search

    Ankur Singh; Krishnendu Roy

    \\u000a T cell development from hematopoietic stem cells takes place in the thymus under precisely controlled intercellular signaling\\u000a between the stem cells and thymic stromal and epithelial cells. In vitro or ex vivo development of mature T cells from stem\\u000a cells faces two primary hurdles; one being the inability of culture conditions to provide a three dimensional thymic niche\\u000a with lineage-specific

  16. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

    PubMed Central

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

    2015-01-01

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

  17. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

    PubMed Central

    Harada, Yohsuke; Harada, Yasuyo; Elly, Chris; Ying, Ge; Paik, Ji-Hye; DePinho, Ronald A.

    2010-01-01

    The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4+ T cells from Cbl-b RING finger mutant knockin or Cbl-b–deficient mice show impaired TGF-?–induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-? signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b–deficient T cells, and Foxo3a deficiency results in defective TGF-?–driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation. PMID:20439537

  18. T Cell Responses during Influenza Infection: Getting and Keeping Control

    PubMed Central

    Kim, Taeg S.; Sun, Jie; Braciale, Thomas J.

    2011-01-01

    The 2009 influenza pandemic highlights the threat that type A influenza poses to human health. Thus there is an urgency to understand the pathobiology of influenza infection and the contribution of the host immune response to both virus elimination and the development of lung injury. This review focuses on the T cell arm of the adaptive host immune response to influenza and assesses recent developments in our understanding of the induction of primary influenza virus-specific T cell responses by antigen-presenting cells, the interaction of activated effector T cells with antigen-bearing cells in the infected lungs, and the contribution of influenza-specific effector T cells to the development and control of lung injury and inflammation during infection. PMID:21435950

  19. Defective function of Fas in T cells from paediatric patients with autoimmune thyroid diseases

    PubMed Central

    BONA, G; DEFRANCO, S; CHIOCCHETTI, A; INDELICATO, M; BIAVA, A; DIFRANCO, D; DIANZANI, I; RAMENGHI, U; CORRIAS, A; WEBER, G; DE SANCTIS, V; IUGHETTI, L; RADETTI, G; DIANZANI, U

    2003-01-01

    Triggering of the Fas receptor induces T cell apoptosis and is involved in shutting-off the immune response. Inherited defects impairing Fas function cause the autoimmune lymphoproliferative syndrome, and may play a role in other autoimmune diseases. The aim of this work was to analyse the Fas function in paediatric patients with thyroid autoimmunities. We found that T cells from 24/28 patients with Graves’ disease (GD) and 12/35 patients with Hashimoto's thyroiditis (HT) displayed defective Fas function. In HT, the defect was more frequent in patients requiring replacement therapy (11/20) than in those not requiring (1/15); moreover, in untreated HT the highest defect was displayed by patients with the highest levels of autoantibodies. Fas was always expressed at normal levels and no Fas mutations were detected. Analysis of the healthy parents of seven Fas-resistant patients showed that several of them were Fas-resistant, which suggests a genetic component. Fusion of Fas-resistant T cells with the Fas-sensitive HUT78 T cell line generated Fas-resistant hybrid cells, which suggests the presence of molecules exerting a dominant negative effect on Fas function. Analysis of Fas-induced activation of caspase-8 and -9 showed decreased activity of both caspases in HT, whereas activity of caspase-9 was increased and that of caspase-8 was decreased in GD. These data suggest that heterogeneous inherited defects impairing Fas function favour the development of thyroid autoimmunities. PMID:12930371

  20. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy?

    PubMed

    Klebanoff, Christopher A; Gattinoni, Luca; Restifo, Nicholas P

    2012-01-01

    CD8(+) T cells have been described as being naive or one of 4 antigen (Ag)-experienced subtypes representing a continuum of differentiation and maturation: T memory stem cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cells. In mice, adoptive cell transfer of less-differentiated naive T cells, T memory stem cell, and central memory T cell subsets have consistently demonstrated superior in vivo expansion, persistence, and antitumor capacities relative to the more differentiated effector memory T cell and effector T cell subsets. Retrospective analyses from human adoptive cell transfer trials have confirmed that transfer of less-differentiated T-cell subsets is highly correlated with objective clinical responses. These findings, combined with the recent ability to convey de novo Ag reactivity with high efficiency through genetic engineering of exogenous T-cell or chimeric Ag receptors, now challenge the field with 3 important questions: (1) how should less-differentiated T-cell subsets be isolated for human clinical trials?; (2) what is the best means of expanding T cells ex vivo in such a way as to not corrupt the beneficial traits of the younger subsets?; and (3) is it necessary to physically separate younger subsets from their more differentiated counterparts? Answering these questions will allow for the rational development of the next generation of highly effective and potentially curative T-cell therapies for the treatment of cancer. PMID:23090074

  1. Distinct Functions of Autoreactive Memory and Effector CD4+ T Cells in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Elyaman, Wassim; Kivisäkk, Pia; Reddy, Jay; Chitnis, Tanuja; Raddassi, Khadir; Imitola, Jaime; Bradshaw, Elizabeth; Kuchroo, Vijay K.; Yagita, Hideo; Sayegh, Mohamed H.; Khoury, Samia J.

    2008-01-01

    The persistence of human autoimmune diseases is thought to be mediated predominantly by memory T cells. We investigated the phenotype and migration of memory versus effector T cells in vivo in experimental autoimmune encephalomyelitis (EAE). We found that memory CD4+ T cells up-regulated the activation marker CD44 as well as CXCR3 and ICOS, proliferated more and produced more interferon-? and less interleukin-17 compared to effector T cells. Moreover, adoptive transfer of memory T cells into T cell receptor (TCR)???/? recipients induced more severe disease than did effector CD4+ T cells with marked central nervous system inflammation and axonal damage. The uniqueness of disease mediated by memory T cells was confirmed by the differential susceptibility to immunomodulatory therapies in vivo. CD28-B7 T cell costimulatory signal blockade by CTLA4Ig suppressed effector cell-mediated EAE but had minimal effects on disease induced by memory cells. In contrast, ICOS-B7h blockade exacerbated effector T cell-induced EAE but protected from disease induced by memory T cells. However, blockade of the OX40 (CD134) costimulatory pathway ameliorated disease mediated by both memory and effector T cells. Our data extend the understanding of the pathogenicity of autoreactive memory T cells and have important implications for the development of novel therapies for human autoimmune diseases. PMID:18583313

  2. The influence of CD4 T-cell subsets on control of CD4 T-cell-mediated graft-versus-host disease

    PubMed Central

    Moncrieffe, Halima; Coles, Mark; Stockinger, Brigitta

    2008-01-01

    In this study, we tested the effect of different T-cell subpopulations on antigen driven effector cell expansion in lymphopenic hosts, making use of an experimental model of graft-versus-host disease (GVHD). Fluorescence-activated cell sorted (FACS) naïve CD4 T cells from C57BL/6 mice, transferred into lymphopenic F1 (C57BL/6 × BALB/c) Rag-deficient hosts, proliferated extensively and migrated systemically causing acute GVHD within 4 weeks after transfer. Adoptive hosts of CD4 memory T cells on the other hand developed milder symptoms of GVHD with later onset. T-cell expansion and migration to peripheral sites as well as development of GVHD were prevented when naïve T cells were transferred together with CD4+ CD25+ T cells, but co-transfer of memory T cells with naïve T cells could not prevent GVHD, although its onset was delayed. OX40, a costimulatory marker that is upregulated at an early time point after T-cell activation and enhances T-cell proliferation, cytokine secretion and survival, was strongly upregulated during GVH responses. Naïve T cells deficient in OX40 expression caused markedly reduced GVH in onset and severity despite some level of expansion in the adoptive host, suggesting an important role of this molecule in the immune pathology of GVHD. PMID:18498346

  3. Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect

    PubMed Central

    Campbell, Katie; Viollet, Laurence; Wang, Wei; Gomez, Ana Maria; Walker, Christopher M.

    2013-01-01

    Abstract Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene transfer. In a trial of intramuscular adeno-associated virus (AAV)-mediated delivery of a therapeutic minidystrophin construct, we identified in two of six subjects the presence of a population of T cells that had been primed to recognize dystrophin epitopes before transgene delivery. As the presence of preexisting T cell immunity may have a significant effect on the success of therapeutic approaches for restoring dystrophin, we sought to determine the prevalence of such immunity within a DMD cohort from our Muscular Dystrophy Association clinic. Dystrophin-specific T cell immunity was evaluated in subjects with DMD who were either receiving the glucocorticoid steroid prednisone (n=24) or deflazacort (n=29), or who were not receiving steroids (n=17), as well as from normal age-matched control subjects (n=21). We demonstrate that increasing age correlates with an increased risk for the presence of anti-dystrophin T cell immunity, and that treatment with either corticosteroid decreases risk compared with no treatment, suggesting that steroid therapy in part may derive some of its benefit through modulation of T cell responses. The frequency of dystrophin-specific T cells detected by enzyme-linked immunospot assay was lower in subjects treated with deflazacort versus prednisone, despite similar overall corticosteroid exposure, suggesting that the effects of the two corticosteroids may not be identical in patients with DMD. T cells targeted epitopes upstream and downstream of the dystrophin gene mutation and involved the CD4+ helper and/or CD8+ cytotoxic subsets. Our data confirm the presence of preexisting circulating T cell immunity to dystrophin in a sizable proportion of patients with DMD, and emphasize the need to consider this in the design and interpretation of clinical gene therapy trials. PMID:24010700

  4. Bystander activation of CD4+ T cells.

    PubMed

    Boyman, Onur

    2010-04-01

    Bystander activation of T cells, i.e. the stimulation of unrelated (heterologous) T cells by cytokines during an Ag-specific T-cell response, has been best described for CD8(+) T cells. In the CD8(+) compartment, the release of IFN and IFN-inducers leads to the production of IL-15, which mediates the proliferation of CD8(+) T cells, notably memory-phenotype CD8(+) T cells. CD4(+) T cells also undergo bystander activation, however, the signals inducing this Ag-nonspecific stimulation of CD4(+) T cells are less well known. A study in this issue of the European Journal of Immunology sheds light on this aspect, suggesting that common gamma-chain cytokines including IL-2 might be involved in bystander activation of CD4(+) T cells. PMID:20309907

  5. Allelic variant in CTLA4 alters T cell phosphorylation patterns

    PubMed Central

    Maier, Lisa M.; Anderson, David E.; De Jager, Philip L.; Wicker, Linda S.; Hafler, David A.

    2007-01-01

    Little is known regarding the functional effects of common autoimmune susceptibility variants on human immune cells. The SNP CT60 (rs3087243; A/G) located in the 3? UTR of the CTLA4 gene has been associated with autoimmune diseases. We examined a cohort of healthy individuals stratified by genotypes at CTLA4 to gain insight into the functional effects of allelic variation on T cell signaling. Using phospho-site-specific mAbs, we tested the hypothesis that the CT60 genotype at CTLA4 is associated with altered T cell antigen receptor (TCR) signaling in naive and/or memory T cells. By normalizing for the extent of the initial TCR signaling event at CD3?, we observed that the relative responsiveness to TCR stimulation as assessed by phosphorylation levels of downstream signaling molecules was altered in naive (CD4+CD45RAhigh) and memory (CD4+CD45RAlow) T cells obtained from individuals with the disease-susceptibility allele at CTLA4. Thus, allelic variation associated with autoimmune disease can alter the signaling threshold of CD4+ T cells. These experiments provide a rational approach for the dissection of T cell-susceptibility genes in autoimmune diseases. PMID:18000051

  6. The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway.

    PubMed

    Sjölin-Goodfellow, Hanna; Frushicheva, Maria P; Ji, Qinqin; Cheng, Debra A; Kadlecek, Theresa A; Cantor, Aaron J; Kuriyan, John; Chakraborty, Arup K; Salomon, Arthur R; Weiss, Arthur

    2015-01-01

    T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The Src family kinase Lck and the Syk family kinase ZAP-70 (? chain-associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve as critical components of the TCR signaling machinery that leads to T cell activation. We performed a mass spectrometry-based phosphoproteomic study comparing the quantitative differences in the temporal dynamics of phosphorylation in stimulated and unstimulated T cells with or without inhibition of ZAP-70 catalytic activity. The data indicated that the kinase activity of ZAP-70 stimulates negative feedback pathways that target Lck and thereby modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ? chain components of the TCR and of signaling molecules downstream of Lck, including ZAP-70. We developed a computational model that provides a mechanistic explanation for the experimental findings on ITAM phosphorylation in wild-type cells, ZAP-70-deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model incorporated negative feedback regulation of Lck activity by the kinase activity of ZAP-70 and predicted the order in which tyrosines in the ITAMs of TCR ? chains must be phosphorylated to be consistent with the experimental data. PMID:25990959

  7. Identification of novel CD8+ T cell epitopes in human herpesvirus 6B U11 and U90

    PubMed Central

    Halawi, Mustafa; Khan, Naeem; Blake, Neil

    2015-01-01

    Human herpesvirus 6B (HHV6B) infects over 90% of the population, and normally establishes a latent infection, where episodes of reactivation are asymptomatic. However, in immunocompromised patients HHV6B reactivation is associated with high morbidity and mortality. Cellular immunotherapy has been utilised against other herpesvirus in immunocompromised settings. However, limited information on the immune response against HHV6B has hampered the development of immunotherapy for HHV6B-driven disease. In this study, we have analysed the cellular immune response against four HHV6B antigens in a panel of 30 healthy donors. We show that the base-line level of T cell reactivity in peripheral blood is very low to undetectable. A short-term reactivation step enabled expansion of T cell responses, and all donors responded to at least 1 antigen, but more commonly 3 or 4. A hierarchy of immunogenicity was determined with antigens U90 and U54 being co-dominant, followed by U11 and U39. Putative CD8+ T cell epitopes were mapped to U90 and U11, predicted to be presented in the context of HLA-A1, A29, B39 and C6. T cells reactive against these novel epitopes were able to recognise virus-infected cells. Our data is supportive of the application and on-going development of T cell immunotherapy against HHVB-driven disease in the immunocompromised host. PMID:26029371

  8. Effects of cigarette smoke extract on primary activated T cells

    PubMed Central

    Hernandez, Claudia P.; Morrow, Kevin; Velasco, Cruz; Wyczechowska, Dorota D.; Naura, Amarjit; Rodriguez, Paulo C.

    2013-01-01

    Tobacco smoking predisposes the development of diseases characterized by chronic inflammation and T cell dysfunction. In this study, we aimed to determine the direct effects of cigarette smoke on primary T cells and to identify the corresponding molecular mediators. Activated T cells cultured in the presence of cigarette smoke extract (CSE) displayed a dose-dependent decrease in cell proliferation, which associated with the induction of cellular apoptosis. T cell apoptosis by CSE was independent of caspases and mediated through reactive oxygen and nitrogen species endogenously contained within CSE. Additional results showed that exposure of T cells to CSE induced phosphorylation of the stress mediator eukaryotic-translation-initiation-factor 2 alpha (eIF2 ). Inhibition of the phosphorylation of eIF2 in T cells prevented the cellular apoptosis induced by CSE. Altogether, the results show the direct effects of CSE on T cells, which advance in the understanding of how cigarette smoking promotes chronic inflammation and immune dysfunction. PMID:23665673

  9. Macrophage and T Cell Produced IL-10 Promotes Viral Chronicity

    PubMed Central

    Richter, Kirsten; Perriard, Guillaume; Behrendt, Rayk; Schwendener, Reto A.; Sexl, Veronika; Dunn, Robert; Kamanaka, Masahito; Flavell, Richard A.; Roers, Axel; Oxenius, Annette

    2013-01-01

    Chronic viral infections lead to CD8+ T cell exhaustion, characterized by impaired cytokine secretion. Presence of the immune-regulatory cytokine IL-10 promotes chronicity of Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 infection, while absence of IL-10/IL-10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine producing T cells. IL-10 is produced by several cell types during LCMV infection but it is currently unclear which cellular sources are responsible for induction of viral chronicity. Here, we demonstrate that although dendritic cells produce IL-10 and overall IL-10 mRNA levels decrease significantly in absence of CD11c+ cells, absence of IL-10 produced by CD11c+ cells failed to improve the LCMV-specific T cell response and control of LCMV infection. Similarly, NK cell specific IL-10 deficiency had no positive impact on the LCMV-specific T cell response or viral control, even though high percentages of NK cells produced IL-10 at early time points after infection. Interestingly, we found markedly improved T cell responses and clearance of normally chronic LCMV Clone 13 infection when either myeloid cells or T cells lacked IL-10 production and mice depleted of monocytes/macrophages or CD4+ T cells exhibited reduced overall levels of IL-10 mRNA. These data suggest that the decision whether LCMV infection becomes chronic or can be cleared critically depends on early CD4+ T cell and monocyte/macrophage produced IL-10. PMID:24244162

  10. V?9V?2 T Cells in Human Legionellosis

    PubMed Central

    Kroca, Michal; Johansson, Anders; Sjöstedt, Anders; Tärnvik, Arne

    2001-01-01

    In humans, expansion of circulating V?9V?2 T cells seems to be a pathophysiological denominator shared by protozoan and intracellular bacterial diseases. The assumption was tested here on legionellosis, a condition conforming to the category but not yet described with respect to ?? T cells. Levels of V?9V?2 T cells in peripheral blood were measured at various intervals in 14 subjects undergoing a Pontiac fever-like disease, shown by serological investigation to be caused by Legionella micdadei. In samples obtained 4 to 6 days after the onset of the disease, the mean percentage (± the standard deviation) of V?9V?2+ T cells among CD3+ cells was 1.0% ± 0.5%, compared to 5.0% ± 3.9% in healthy control subjects (P < 0.001). Thereafter, a pronounced increase occurred and at 2 to 7 weeks after onset, mean peak levels were as high as ?15%. During the next 6 months, values slowly declined, although without reaching the normal range. Percentages of ??+ T cells expressing tumor necrosis factor alpha or gamma interferon in response to phorbol myristate acetate were assayed in vitro. At 14 to 16 days after the onset of disease, the expression of both cytokines was increased (P < 0.01), whereas at 5 to 7 weeks, the expression of tumor necrosis factor alpha was decreased (P < 0.05), possibly reflecting modulation of an inflammatory response. In conclusion, Pontiac fever was found to be associated with a pronounced and long-lasting expansion of V?9V?2 T cells, implying that the subset may also be pathophysiologically important in a mild and transient form of intracellular bacterial diseases. Surprisingly, the expansion was preceded by a depletion of circulatory V?9V?2 T cells. Possibly, V?9V?2 T cells are initially recruited to a site of infection before they expand in response to antigen and occur in high numbers in blood. PMID:11527809

  11. Decreased Expression of T-Cell Costimulatory Molecule CD28 on CD4 and CD8 T Cells of Mexican Patients with Pulmonary Tuberculosis

    PubMed Central

    Bernal-Fernandez, German; Espinosa-Cueto, Patricia; Leyva-Meza, Rosario; Mancilla, Nathalie; Mancilla, Raul

    2010-01-01

    Patients with tuberculosis frequently develop anergy, a state of T-cell hyporesponsiveness in which defective T-cell costimulation could be a factor. To know if the expression of T-cell costimulatory molecules was altered in tuberculosis, we analyzed the peripheral blood T-cell phenotype of 23 Mexican patients with pulmonary tuberculosis. There was severe CD4 (P < .001) and CD8 (P < .01) lymphopenia and upregulation of costimulatory molecule CD30 on CD4 and CD8 T cells (P < .05); this increase was higher in relapsing tuberculosis. The main finding was severe downregulation of the major costimulatory molecule CD28 on both CD8 and CD4 T cells (P < .001). Depletion of the CD4/CD28 subset, a hitherto undescribed finding, is relevant because CD4 T cells constitute the main arm of the cell-mediated antimycobacterial immune response. PMID:22567259

  12. Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells.

    PubMed

    Lord, James D; Hackman, Robert C; Moklebust, Amanda; Thompson, John A; Higano, Celestia S; Chielens, Deborah; Steinbach, Gideon; McDonald, George B

    2010-05-01

    Ipilimumab is a humanized antibody to CTLA4 and is used to treat cancers refractory to conventional treatment. We treated 21 patients with refractory melanoma or prostate cancer with anti-CTLA4 antibody (ipilimumab), with subsequent development of significant colitis in nine cases. Two of these nine did not respond rapidly to high-dose (2 mg kg(-1) day(-1)) glucocorticoids or infliximab. They required additional immunosuppression, and one ultimately died of opportunistic infection, representing a more refractory course than has previously been described complicating ipilimumab therapy. Both patients had received radiation to the pelvis for prostate cancer less than 1 year prior to receiving ipilimumab. We performed immunohistochemical analysis of colon biopsies from ipilimumab recipients to determine if colitis correlates with depletion of intramucosal FOXP3(+) regulatory T cells (Tregs), which normally express CTLA4. However, we found no evidence of FOXP3(+) T cell depletion in any of the nine patients who developed colitis. PMID:19507029

  13. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion.

    PubMed

    Hindley, James P; Jones, Emma; Smart, Kathryn; Bridgeman, Hayley; Lauder, Sarah N; Ondondo, Beatrice; Cutting, Scott; Ladell, Kristin; Wynn, Katherine K; Withers, David; Price, David A; Ager, Ann; Godkin, Andrew J; Gallimore, Awen M

    2012-11-01

    The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T-cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. PMID:22962270

  14. T Cell Trafficking Facilitated by High Endothelial Venules is Required for Tumor Control after Regulatory T Cell Depletion

    PubMed Central

    Hindley, James P.; Jones, Emma; Smart, Kathryn; Bridgeman, Hayley; Lauder, Sarah N.; Ondondo, Beatrice; Cutting, Scott; Ladell, Kristin; Wynn, Katherine K.; Withers, David; Price, David A.; Ager, Ann; Godkin, Andrew J.; Gallimore, Awen M.

    2012-01-01

    The evolution of immune blockades in tumors limits successful anti-tumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Tregs), a T cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have demonstrated that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T cell activation and proliferation following Treg depletion there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T cell infiltration and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. PMID:22962270

  15. Control of Murine Cytomegalovirus Infection by ?? T Cells

    PubMed Central

    Sell, Sabrina; Dietz, Monika; Schneider, Andrea; Holtappels, Rafaela; Mach, Michael; Winkler, Thomas H.

    2015-01-01

    Infections with cytomegalovirus (CMV) can cause severe disease in immunosuppressed patients and infected newborns. Innate as well as cellular and humoral adaptive immune effector functions contribute to the control of CMV in immunocompetent individuals. None of the innate or adaptive immune functions are essential for virus control, however. Expansion of ?? T cells has been observed during human CMV (HCMV) infection in the fetus and in transplant patients with HCMV reactivation but the protective function of ?? T cells under these conditions remains unclear. Here we show for murine CMV (MCMV) infections that mice that lack CD8 and CD4 ??-T cells as well as B lymphocytes can control a MCMV infection that is lethal in RAG-1-/- mice lacking any T- and B-cells. ?? T cells, isolated from infected mice can kill MCMV infected target cells in vitro and, importantly, provide long-term protection in infected RAG-1-/- mice after adoptive transfer. ?? T cells in MCMV infected hosts undergo a prominent and long-lasting phenotypic change most compatible with the view that the majority of the ?? T cell population persists in an effector/memory state even after resolution of the acute phase of the infection. A clonotypically focused V?1 and V?2 repertoire was observed at later stages of the infection in the organs where MCMV persists. These findings add ?? T cells as yet another protective component to the anti-CMV immune response. Our data provide clear evidence that ?? T cells can provide an effective control mechanism of acute CMV infections, particularly when conventional adaptive immune mechanisms are insufficient or absent, like in transplant patient or in the developing immune system in utero. The findings have implications in the stem cell transplant setting, as antigen recognition by ?? T cells is not MHC-restricted and dual reactivity against CMV and tumors has been described. PMID:25658831

  16. Nude mice produce a T cell-derived antigen-binding factor that mediates the early component of delayed-type hypersensitivity.

    PubMed

    Herzog, W R; Meade, R; Pettinicchi, A; Ptak, W; Askenase, P W

    1989-03-15

    The elicitation of delayed-type hypersensitivity (DTH) reactions in mice is caused by the sequential action of two different T cells. An early-acting, DTH-initiating T cell produces an Ag-specific T cell factor, that is analogous to IgE antibody and initiates DTH by sensitizing the local tissues for release of the vasoactive amine serotonin. In picryl chloride or oxazolone contact sensitivity, this T cell factor is Ag-specific, but MHC unrestricted. We, therefore, hypothesized that DTH-initiating T cells are primitive T cells with Ag receptors that can bind Ag without MHC restriction. In order to characterize the origin of this DTH-initiating T cell and the conditions that are necessary for its development, we contact-sensitized various strains of immunodeficient mice. Surprisingly, we found that the early phase of DTH was present in athymic nude mice. In contrast, the early component of DTH was absent in mice with severe combined immunodeficiency. These mice lack T and B cells, but have NK cells. These findings suggested that the early component of DTH was not caused by NK cells, and was caused by cells belonging to a lineage from a rearranging gene family. The early component of DTH in nude mice was Ag specific, was caused by MHC unrestricted Thy-1+ T cells, and was mediated by Ag-binding, Ag-specific T cell factors. We found that DTH-initiating, T cell-derived, Ag-binding molecules from nude mice and normal CBA/J mice had the same functional properties. The early component of DTH was elicited in two different systems (contact sensitivity and SRBC-specific DTH) in two strains of nude mice (BALB/c athymic nudes and CByB6F1/J-nu) from two different suppliers, but not in BALB/c and athymic nudes from a third supplier. From these findings we concluded that DTH-initiating T cells, which produce IgE-like Ag-specific T cell factors, are present in some strains of athymic nude mice and thus are relatively thymic independent T cells. PMID:2466077

  17. Synthesis in Human T Cells

    Microsoft Academic Search

    Randall N. Knibbs; Ronald A. Craig; Shunji Natsuka; Alfred Chang; Mark Cameron; John B. Lowe; Lloyd M. Stoolman

    Selectin-ligands on T cells contribute to the recruitment of circulating cells into chronic inflamma- tory lesions in the skin and elsewhere. This report pro- vides the first evidence that a single fucosyltransferase, termed FucT-VII, controls the synthesis of E-selectin ligands in human T-lymphoblasts. The FucT-IV trans- ferase (the ELFT enzyme), in contrast, constructs lower avidity E-selectin ligands and requires enzyme

  18. Cytokine network and T cell immunity in atherosclerosis

    Microsoft Academic Search

    Hafid Ait-Oufella; Soraya Taleb; Ziad Mallat; Alain Tedgui

    2009-01-01

    Atherosclerosis is a chronic inflammatory disease of the arterial wall where both innate and adaptive immune responses contribute\\u000a to disease initiation and progression. Recent studies established that subtypes of T cells, regulatory T cells (Tregs), actively\\u000a involved in the maintenance of immunological tolerance, inhibit the development and progression of atherosclerosis. Here,\\u000a we review the current knowledge on the Treg response

  19. Transcriptional repressor Blimp1 regulates T cell homeostasis and function

    Microsoft Academic Search

    Gislâine A Martins; Luisa Cimmino; Miriam Shapiro-Shelef; Matthias Szabolcs; Alan Herron; Erna Magnusdottir; Kathryn Calame

    2006-01-01

    The B lymphocyte–induced maturation protein 1 (Blimp-1) transcriptional repressor is required for terminal differentiation of B lymphocytes. Here we document a function for Blimp-1 in the T cell lineage. Blimp-1-deficient thymocytes showed decreased survival and Blimp-1-deficient mice had more peripheral effector T cells. Mice lacking Blimp-1 developed severe colitis as early as 6 weeks of age, and Blimp-1-deficient regulatory T

  20. B and CD4+ T cell expression of TLR2 are critical for optimal induction of a T cell-dependent humoral immune response to intact Streptococcus pneumoniae

    PubMed Central

    Vasilevsky, S.; Chattopadhyay, G.; Colino, Jesus; Yeh, T-J; Chen, Q.; Sen, G.; Snapper, C. M.

    2009-01-01

    Summary TLR2?/? mice immunized with Streptococcus pneumoniae (Pn) elicit normal IgM, but defective CD4+ T cell-dependent (TD) type 1 IgG isotype production, associated with a largely intact innate immune response. We studied the TD phosphorylcholine (PC)-specific IgG3 versus the T cell-independent IgM response to Pn to determine whether TLR2 signals directly via the adaptive immune system. Pn-activated TLR2?/? bone marrow dendritic cells (BMDC) have only a modest defect in cytokine secretion, undergo normal maturation, and when transferred into naive WT mice elicit a normal IgM and IgG3 anti-PC response, relative to WT BMDC. Pn synergizes with BCR and TCR signaling for DNA synthesis in purified WT B and CD4+ T cells, respectively, but is defective in cells lacking TLR2. Pn primes TLR2?/? mice for a normal CD4+ T cell IFN-? recall response. Notably, TLR2?/? B cells transferred into RAG-2?/? mice with WT CD4+ T cells, or TLR2?/? CD4+ T cells transferred into athymic nude mice, each elicit a defective IgG3, in contrast to normal IgM, anti-PC response relative to WT cells. These data are the first to demonstrate a major role for B cell and CD4+ T cell expression of TLR2 for eliciting an anti-bacterial humoral immune response. PMID:19003933

  1. Distinct contributions of CD4(+) and CD8(+) naive and memory T-cell subsets to overall T-cell-receptor repertoire complexity following transplantation of T-cell-depleted CD34-selected hematopoietic progenitor cells from unrelated donors.

    PubMed

    Eyrich, Matthias; Croner, Tanja; Leiler, Christine; Lang, Peter; Bader, Peter; Klingebiel, Thomas; Niethammer, Dietrich; Schlegel, Paul G

    2002-09-01

    Normalization of restricted T-cell-receptor (TCR) repertoire is critical following T-cell-depleted (TCD) stem cell transplantation. We present a prospective study analyzing respective contributions of naive and memory T-cell subsets within the CD4(+) and CD8(+) compartments to the evolution of overall TCR-repertoire complexity following transplantation of CD34-selected peripheral blood progenitor cells from unrelated donors. During the first year after transplantation, sorted CD4/45RA, CD4/45R0, CD8/45RA, and CD8/45R0 subsets were analyzed at 3-month intervals for TCR-repertoire complexity by CDR3 size spectratyping. Skew in TCR-repertoire was observed only in early memory-type T cells. CD4(+) and CD8(+) subsets differed in clonal distribution of CDR3 sizes, with rapid Gaussian normalization of bands in CD4/45R0(+) T cells. Naive T cells displayed normal repertoire complexity and contributed significantly to skew correction. Our data provide direct evidence for an important role of de novo maturation of naive T cells in normalization of an initially restricted TCR-repertoire following transplantation of CD34-selected, TCD-depleted peripheral blood progenitors from unrelated donors. PMID:12176918

  2. The NIH MRI study of normal brain development

    Microsoft Academic Search

    Alan C. Evans

    2006-01-01

    MRI is increasingly used to study normal and abnormal brain development, but we lack a clear understanding of “normal”. Previous studies have been limited by small samples, narrow age ranges and few behavioral measures. This multi-center project conducted epidemiologically based recruitment of a large, demographically balanced sample across a wide age range, using strict exclusion factors and comprehensive clinical\\/behavioral measures.A

  3. Developing visualization support system for teaching\\/learning database normalization

    Microsoft Academic Search

    Olusegun Folorunso; AdioTaofeek Akinwale

    2010-01-01

    Purpose – In tertiary institution, some students find it hard to learn database design theory, in particular, database normalization. The purpose of this paper is to develop a visualization tool to give students an interactive hands-on experience in database normalization process. Design\\/methodology\\/approach – The model-view-controller architecture is used to alleviate the black box syndrome associated with the study of algorithm

  4. Engager T cells: a new class of antigen-specific T cells that redirect bystander T cells.

    PubMed

    Iwahori, Kota; Kakarla, Sunitha; Velasquez, Mireya P; Yu, Feng; Yi, Zongzhen; Gerken, Claudia; Song, Xiao-Tong; Gottschalk, Stephen

    2015-01-01

    Adoptive immunotherapy with antigen-specific T cells has shown promise for the treatment of malignancies. However, infused T cells are unable to redirect resident T cells, limiting potential benefit. While the infusion of bispecific T-cell engagers can redirect resident T cells to tumors, these molecules have a short half-life, and do not self amplify. To overcome these limitations, we generated T cells expressing a secretable T-cell engager specific for CD3 and EphA2, an antigen expressed on a broad range of human tumors (EphA2-ENG T cells). EphA2-ENG T cells were activated and recognized tumor cells in an antigen-dependent manner, redirected bystander T cells to tumor cells, and had potent antitumor activity in glioma and lung cancer severe combined immunodeficiency (SCID) xenograft models associated with a significant survival benefit. This new class of tumor-specific T cells, with the unique ability to redirect bystander T cells, may be a promising alternative to current immunotherapies for cancer. PMID:25142939

  5. Frequency and function of HIV-specific CD8 + T Cells

    Microsoft Academic Search

    Stephen A Migueles; Mark Connors

    2001-01-01

    The virus-specific CD8+ T cell responses of 27 HIV-infected patients were studied, including a unique cohort of long term nonprogressors (LTNP) with normal CD4+ T cell counts, low levels of plasma viral RNA, strong proliferative responses to HIV antigens and an over-representation of the HLA B*5701 class I allele. The frequencies of CD8+ T cells specific to the majority of

  6. Quieting T cells with Slfn2

    PubMed Central

    Horton, Maureen R; Powell, Jonathan D

    2014-01-01

    The mechanisms that enforce T cell quiescence are incompletely understood. Slfn2 has now been identified as another participant in this process, functioning as a critical regulator of T cell– and monocyte-mediated immunity. PMID:20300134

  7. Regulatory T Cells Suppress T Cell Activation at the Pathologic Site of Human Visceral Leishmaniasis

    PubMed Central

    Rai, Ambak K.; Thakur, Chandreshwar P.; Singh, Amar; Seth, Tulika; Srivastava, Sandeep K.; Singh, Pushpendra; Mitra, Dipendra K.

    2012-01-01

    Suppression of T cell response is thought to be involved in the pathogenesis of visceral leishmaniasis (VL). Regulatory T cell (Treg) mediated immune-suppression is reported in animal models of Leishmania infection. However, their precise role among human patients still requires pathologic validation. The present study is aimed at understanding the frequency dynamics and function of Treg cells in the blood and bone marrow (BM) of VL patients. The study included 42 parasitologically confirmed patients, 17 healthy contact and 9 normal bone marrow specimens (NBM). We show i) the selective accumulation of Treg cells at one of the disease inflicted site(s), the BM, ii) their in vitro expansion in response to LD antigen and iii) persistence after successful chemotherapy. Results indicate that the Treg cells isolated from BM produces IL-10 and may inhibit T cell activation in IL-10 dependent manner. Moreover, we observed significantly higher levels of IL-10 among drug unresponsive patients, suggesting their critical role in suppression of immunity among VL patients. Our results suggest that IL-10 plays an important role in suppression of host immunity in human VL and possibly determines the efficacy of chemotherapy. PMID:22347492

  8. Normalization

    NSDL National Science Digital Library

    2008-05-09

    This PowerPoint lecture, by Jason Park of San Jose State University Department of Computer Science, offers students a quick introduction to database normalization, the "process of removing redundant data from your tables in to improve storage efficiency, data integrity, and scalability." Here, visitors will find information about database normalization history and applications. With information on the normal forms, field pioneer Edgar F. Codd, and problematic tables, this presentation will be helpful in any database programming and design classroom.

  9. The Yins of T Cell Activation

    NSDL National Science Digital Library

    Jun O. Liu (Johns Hopkins School of Medicine; Department of Pharmacology and Department of Neuroscience REV)

    2005-01-04

    The potentially destructive power of the immune response necessitates tight regulation of T cell activation, and this STKE review, with three figures, no tables, and 56 references, concerns negative regulators of T cell signaling. These negative regulators can be divided into two groups: Class 1 regulators help maintain the quiescent state of unstimulated T cells, whereas class 2 regulators are themselves transcriptionally induced in response to T cell signaling and serve to limit and terminate the activating signal.

  10. CD8+ T Cell Responses to Plasmodium and Intracellular Parasites

    PubMed Central

    Villarino, Nicolas; Schmidt, Nathan W.

    2013-01-01

    Parasitic protozoa are major threats to human health affecting millions of people around the world. Control of these infections by the host immune system relies on a myriad of immunological mechanisms that includes both humoral and cellular immunity. CD8+ T cells contribute to the control of these parasitic infections in both animals and humans. Here, we will focus on the CD8+ T cell response against a subset of these protozoa: Plasmodium, Toxoplasma gondii, Leishmania and Trypanosoma cruzi, with an emphasis on experimental rodent systems. It is evident a complex interaction occurs between CD8+ T cells and the invading protozoa. A detailed understanding of how CD8+ T cells mediate protection should provide the basis for the development of effective vaccines that prevent and control infections by these parasites. PMID:24741372

  11. A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin

    PubMed Central

    Fiorenza, Salvatore; Kenna, Tony J.; Comerford, Iain; McColl, Shaun; Steptoe, Raymond J.; Leggatt, Graham R.; Frazer, Ian H.

    2012-01-01

    Adoptive T cell therapy utilises the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. Here, we utilise a murine model of immunotherapy to optimise cell-mediated immunity in the skin. We show that in vitro derived central but not effector memory-like T cells bring about rapid regression of skin expressing cognate antigen as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist, imiquimod, subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development of in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity that is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8+ T cells with a central memory T cell phenotype are transferred and IL-2 is present with contemporaneous local inflammation. PMID:23144496

  12. Hepatic T cells and liver tolerance

    Microsoft Academic Search

    Ian Nicholas Crispe

    2003-01-01

    The T-cell biology of the liver is unlike that of any other organ. The local lymphocyte population is enriched in natural killer (NK) and NKT cells, which might have crucial roles in the recruitment of circulating T cells. A large macrophage population and the efficient trafficking of dendritic cells from sinusoidal blood to lymph promote antigen trapping and T-cell priming,

  13. Combinatorics T-cell repertoire maintenance

    E-print Network

    Haase, Markus

    T-cell repertoire mainte- nance Grant Lythe Cell death Survival stimuli Combinatorics T-cell repertoire mainte- nance Grant Lythe Cell death Survival stimuli Combinatorics Constant death rate Assumption Every T cell has a constant probability per unit time µ of dying, independent of all others. Consequence

  14. Strange brew: T cells in the liver

    Microsoft Academic Search

    I. Nicholas Crispe; Wajahat Z. Mehal

    1996-01-01

    The liver is a meeting place for thymus-dependent circulating T cells and thymus-independent T cells with natural-killer (NK)-cell markers. Here, Nick Crispe and Waj Mehal argue that interactions between these two T-cell pools might account for the distinctive immunological role of the liver as a focus of peripheral tolerance induction.

  15. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality.

    PubMed

    Kalathil, Suresh; Lugade, Amit A; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

    2013-04-15

    The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1(+)-exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-? producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations. PMID:23423978

  16. Databases for T-cell epitopes.

    PubMed

    Tung, Chun-Wei

    2014-01-01

    Modem immunology and vaccinology incorporate immunoinformatics techniques to give insights into immune systems and accelerate vaccine design. Databases managing epitope data in a structured form with immune-related annotations including sequences, alleles, source organisms, structures, and diseases could be the most crucial part of immunoinformatics offering data sources for the analysis of immune systems and development of prediction methods. This chapter provides an overview of publicly available databases of T-cell epitopes including general databases, pathogen- and tumor-specific databases, and 3D structure databases. PMID:25048121

  17. T cell metabolism. The protein LEM promotes CD8? T cell immunity through effects on mitochondrial respiration.

    PubMed

    Okoye, Isobel; Wang, Lihui; Pallmer, Katharina; Richter, Kirsten; Ichimura, Takahuru; Haas, Robert; Crouse, Josh; Choi, Onjee; Heathcote, Dean; Lovo, Elena; Mauro, Claudio; Abdi, Reza; Oxenius, Annette; Rutschmann, Sophie; Ashton-Rickardt, Philip G

    2015-05-29

    Protective CD8(+) T cell-mediated immunity requires a massive expansion in cell number and the development of long-lived memory cells. Using forward genetics in mice, we identified an orphan protein named lymphocyte expansion molecule (LEM) that promoted antigen-dependent CD8(+) T cell proliferation, effector function, and memory cell generation in response to infection with lymphocytic choriomeningitis virus. Generation of LEM-deficient mice confirmed these results. Through interaction with CR6 interacting factor (CRIF1), LEM controlled the levels of oxidative phosphorylation (OXPHOS) complexes and respiration, resulting in the production of pro-proliferative mitochondrial reactive oxygen species (mROS). LEM provides a link between immune activation and the expansion of protective CD8(+) T cells driven by OXPHOS and represents a pathway for the restoration of long-term protective immunity based on metabolically modified cytotoxic CD8(+) T cells. PMID:25883318

  18. Development, organization and function of the thymic medulla in normal, immunodeficient or autoimmune mice

    Microsoft Academic Search

    Philippe Naquet; Marianne Naspetti; Richard Boyd

    1999-01-01

    Thymopoiesis is initiated by the colonisation of the epithelial rudiment with blood-borne hemopoietic precursors. Their subsequent differentiation to the functionally mature T cell subsets is exquisitely linked to sequential interaction with a diverse array of thymic epithelial cells which form discrete microenvironments. The development and organisation of the epithelium, however, is in turn controlled by thymocyte subsets. In particular the

  19. BLT-humanized C57BL/6 Rag2-/-?c-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection.

    PubMed

    Lavender, Kerry J; Pang, Wendy W; Messer, Ronald J; Duley, Amanda K; Race, Brent; Phillips, Katie; Scott, Dana; Peterson, Karin E; Chan, Charles K; Dittmer, Ulf; Dudek, Timothy; Allen, Todd M; Weissman, Irving L; Hasenkrug, Kim J

    2013-12-12

    The use of C57BL/6 Rag2(-/-)?c(-/-) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRP? does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)?c(-/-) background negates the requirement for CD47-signal recognition protein ? (SIRP?) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis. Importantly, these mice have an intact complement system and showed no signs of graft-versus-host disease (GVHD) out to 29 weeks after transplantation. Sustained, high-level HIV-1 infection was observed via either intrarectal or intraperitoneal inoculation. TKO-BLT mice exhibited hallmarks of human HIV infection including CD4(+) T-cell depletion, immune activation, and development of HIV-specific B- and T-cell responses. The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens. PMID:24021673

  20. Abundant expression of HMGB1 in human T-cell lymphotropic virus type I-infected T-cell lines and high plasma levels of HMGB1 in patients with adult T-cell leukemia

    PubMed Central

    KIMURA, RYUICHIRO; MORI, NAOKI

    2014-01-01

    High mobility group box 1 (HMGB1) functions as a chromatin-associated nuclear protein and an extracellular signaling molecule. The concentration of HMGB1 protein and the expression of HMGB1 mRNA were analyzed by ELISA and polymerase chain reaction (PCR), respectively. The present study reports high plasma HMGB1 levels in patients with adult T-cell leukemia [ATL; which is caused by infection with human T-cell lymphotropic virus type I (HTLV-I)] compared with normal controls. In addition, HMGB1 was highly expressed in HTLV-I-infected T-cell lines compared with uninfected T-cell lines. The HTLV-I oncoprotein, Tax, induced extracellular release of HMGB1 in T cells. The results suggest that HMGB1 is a potential biomarker and a therapeutic target for ATL. PMID:24944700

  1. NF-?B signaling mediates homeostatic maturation of new T cells

    PubMed Central

    Silva, Ana; Cornish, Georgina; Ley, Steven C.; Seddon, Benedict

    2014-01-01

    Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. IL-7 receptor ? ( IL-7R?) expression is subject to developmental regulation and new T cells induce expression as they leave the thymus, which is essential for their long-term survival. It is not understood how this expression is regulated. Here, we identify a role for the Nuclear Factor ?-B (NF-?B) signaling pathway in controlling expression of IL-7R? in new T cells. Perturbations to NF-?B signaling, either by deletion of Inhibitor of Kappa-B Kinase-2 (IKK2) or by inhibiting Rel dimer activity, prevented normal IL-7R? expression in new T cells. Defective IL-7R? expression resulted in impaired survival and homeostatic cell division responses by T cells that could be attributed to their failure to express IL-7R? normally. Surprisingly, NF-?B signaling was only required transiently in new T cells to allow their normal expression of IL-7R?, because IKK2 deletion in mature T cells had no effect on IL-7R? expression or their normal homeostatic responsiveness. Therefore, we identify a developmental function for NF-?B signaling in the homeostatic maturation of new T cells, by regulating IL-7R? expression. PMID:24550492

  2. CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity.

    PubMed

    Mayer, Christian T; Floess, Stefan; Baru, Abdul Mannan; Lahl, Katharina; Huehn, Jochen; Sparwasser, Tim

    2011-03-01

    "Suppressor T cells" were historically defined within the CD8(+) T-cell compartment and recent studies have highlighted several naturally occurring CD8(+) Foxp3(-) Treg populations. However, the relevance of CD8(+) Foxp3(+) T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8(+) Foxp3(-) T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8(+) Foxp3(+) T cells fail to develop in TCR-transgenic mice with Rag1(-/-) background, similar to classical CD4(+) Foxp3(+) Tregs. Notably, both naturally occurring and induced CD8(+) Foxp3(+) T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-? production upon restimulation when compared with their CD8(+) Foxp3(-) counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3(+) cells by eGFP reporter expression, we demonstrate that induced CD8(+) Foxp3(+) T cells similar to activated CD8(+) Foxp3(-) T cells only mildly suppress T-cell proliferation and IFN-? production. We therefore categorize CD8(+) Foxp3(+) T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4(+) Foxp3(+) Tregs, but lacking potent suppressive activity. PMID:21312192

  3. Thyroid stem cells: lessons from normal development and thyroid cancer

    Microsoft Academic Search

    Dolly Thomas; Susan Friedman; Reigh-Yi Lin

    Ongoing advances in stem cell research have opened new avenues for therapy for many human disorders. Until recently, however, thyroid stem cells have been relatively understudied. Here, we review what is known about thyroid stem cells and explore their utility as models of normal and malignant biological development. We also discuss the cellular origin of thyroid cancer stem cells and

  4. 1FALL 2005, VOL. 16, #3 N NORMALLY DEVELOPING INFANTS,

    E-print Network

    1FALL 2005, VOL. 16, #3 N NORMALLY DEVELOPING INFANTS, the five plates of the skull are loosely. The fusion restricts growth and the brain is forced to expand into other areas, resulting in a skull-shape the skull. In addition to having joints, an infant's skull plates are also soft. Another malformation

  5. The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells

    PubMed Central

    Muro, Ryunosuke; Nitta, Takeshi; Okada, Toshiyuki; Ideta, Hitoshi; Tsubata, Takeshi; Suzuki, Harumi

    2015-01-01

    The Ras-mitogen-activated protein kinase (MAPK) pathway is crucial for T cell receptor (TCR) signaling in the development and function of T cells. The significance of various modulators of the Ras-MAPK pathway in T cells, however, remains to be fully understood. Ras-activating protein-like 3 (Rasal3) is an uncharacterized member of the SynGAP family that contains a conserved Ras GTPase-activating protein (GAP) domain, and is predominantly expressed in the T cell lineage. In the current study, we investigated the function and physiological roles of Rasal3. Our results showed that Rasal3 possesses RasGAP activity, but not Rap1GAP activity, and represses TCR-stimulated ERK phosphorylation in a T cell line. In systemic Rasal3-deficient mice, T cell development in the thymus including positive selection, negative selection, and ?-selection was unaffected. However, the number of naive, but not effector memory CD4 and CD8 T cell in the periphery was significantly reduced in Rasal3-deficient mice, and associated with a marked increase in apoptosis of these cells. Indeed, survival of Rasal3 deficient naive CD4 T cells in vivo by adoptive transfer was significantly impaired, whereas IL-7-dependent survival of naive CD4 T cells in vitro was unaltered. Collectively, Rasal3 is required for in vivo survival of peripheral naive T cells, contributing to the maintenance of optimal T cell numbers. PMID:25793935

  6. T cell immune abnormalities in immune thrombocytopenia.

    PubMed

    Ji, Xuebin; Zhang, Liping; Peng, Jun; Hou, Ming

    2014-01-01

    Immune thrombocytopenia is an autoimmune disease with abnormal T cell immunity. Cytotoxic T cells, abnormal T regulatory cells, helper T cell imbalance, megakaryocyte maturation abnormalities and abnormal T cell anergy are involved in the pathogenesis of this condition. The loss of T cell-mediated immune tolerance to platelet auto-antigens plays a crucial role in immune thrombocytopenia. The induction of T cell tolerance is an important mechanism by which the pathogenesis and treatment of immune thrombocytopenia can be studied. Studies regarding the roles of the new inducible costimulator signal transduction pathway, the ubiquitin proteasome pathway, and the nuclear factor kappa B signal transduction pathway in the induction of T cell tolerance can help improve our understanding of immune theory and may provide a new theoretical basis for studying the pathogenesis and treatment of immune thrombocytopenia. PMID:25274611

  7. Distinct Effects of IL18 on the Engraftment and Function of Human Effector CD8+ T Cells and Regulatory T Cells

    Microsoft Academic Search

    Richard G. Carroll; Carmine Carpenito; Xiaochuan Shan; Gwenn Danet-Desnoyers; Ronghua Liu; Shuguang Jiang; Steven M. Albelda; Tatiana Golovina; George Coukos; James L. Riley; Zdenka L. Jonak; Carl H. June; Derya Unutmaz

    2008-01-01

    IL-18 has pleotropic effects on the activation of T cells during antigen presentation. We investigated the effects of human IL-18 on the engraftment and function of human T cell subsets in xenograft mouse models. IL-18 enhanced the engraftment of human CD8+ effector T cells and promoted the development of xenogeneic graft versus host disease (GVHD). In marked contrast, IL-18 had

  8. Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis.

    PubMed

    Afzal, Samia; Hao, Zhenyue; Itsumi, Momoe; Abouelkheer, Yasser; Brenner, Dirk; Gao, Yunfei; Wakeham, Andrew; Hong, Claire; Li, Wanda Y; Sylvester, Jennifer; Gilani, Syed O; Brüstle, Anne; Haight, Jillian; You-Ten, Annick J; Lin, Gloria H Y; Inoue, Satoshi; Mak, Tak W

    2015-01-27

    UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell-specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell-specific loss of UVRAG dampened CD8(+) T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis. PMID:25583492

  9. ?4?7 independent pathway for CD8+ T cell–mediated intestinal immunity to rotavirus

    PubMed Central

    Kuklin, Nelly A.; Rott, Lusijah; Darling, Jama; Campbell, James J.; Franco, Manuel; Feng, Ningguo; Müller, Werner; Wagner, Norbert; Altman, John; Butcher, Eugene C.; Greenberg, Harry B.

    2000-01-01

    Rotavirus (RV), which replicates exclusively in cells of the small intestine, is the most important cause of severe diarrhea in young children worldwide. Using a mouse model, we show that expression of the intestinal homing integrin ?4?7 is not essential for CD8+ T cells to migrate to the intestine or provide immunity to RV. Mice deficient in ?7 expression (?7–/–) and unable to express ?4?7 integrin were found to clear RV as quickly as wild-type (wt) animals. Depletion of CD8+ T cells in ?7–/– animals prolonged viral shedding, and transfer of immune ?7–/– CD8+ T cells into chronically infected Rag-2–deficient mice resolved RV infection as efficiently as wt CD8+ T cells. Paradoxically, ?4?7hi memory CD8+ T cells purified from wt mice that had been orally immunized cleared RV more efficiently than ?4?7low CD8+ T cells. We explained this apparent contradiction by demonstrating that expression of ?4?7 on effector CD8+ T cells depends upon the site of initial antigen exposure: oral immunization generates RV-specific CD8+ T cells primarily of an ?4?7hi phenotype, but subcutaneous immunization yields both ?4?7hi and ?4?7low immune CD8+ T cells with anti-RV effector capabilities. Thus, ?4?7 facilitates normal intestinal immune trafficking to the gut, but it is not required for effective CD8+ T cell immunity. PMID:11120761

  10. Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis

    PubMed Central

    Afzal, Samia; Hao, Zhenyue; Itsumi, Momoe; Abouelkheer, Yasser; Brenner, Dirk; Gao, Yunfei; Wakeham, Andrew; Hong, Claire; Li, Wanda Y.; Sylvester, Jennifer; Gilani, Syed O.; Brüstle, Anne; Haight, Jillian; You-Ten, Annick J.; Lin, Gloria H. Y.; Inoue, Satoshi; Mak, Tak W.

    2015-01-01

    UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell–specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell–specific loss of UVRAG dampened CD8+ T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis. PMID:25583492

  11. Molecular Hallmarks of Adult T Cell Leukemia

    PubMed Central

    Yamagishi, Makoto; Watanabe, Toshiki

    2012-01-01

    The molecular hallmarks of adult T cell leukemia (ATL) comprise outstanding deregulations of signaling pathways that control the cell cycle, resistance to apoptosis, and proliferation of leukemic cells, all of which have been identified by early excellent studies. Nevertheless, we are now confronted the therapeutic difficulties of ATL that is a most aggressive T cell leukemia/lymphoma. Using next-generation strategies, emerging molecular characteristics such as specific surface markers and an additional catalog of signals affecting the fate of leukemic cells have been added to the molecular hallmarks that constitute an organizing principle for rationalizing the complexities of ATL. Although human T cell leukemia virus type 1 is undoubtedly involved in ATL leukemogenesis, most leukemic cells do not express the viral protein Tax. Instead, cellular gene expression changes dominate homeostasis disorders of infected cells and characteristics of ATL. In this review, we summarize the state of the art of ATL molecular pathology, which supports the biological properties of leukemic cells. In addition, we discuss the recent discovery of two molecular hallmarks of potential generality; an abnormal microRNA pattern and epigenetic reprogramming, which strongly involve the imbalance of the molecular network of lymphocytes. Global analyses of ATL have revealed the functional impact of crosstalk between multifunctional pathways. Clinical and biological studies on signaling inhibitory agents have also revealed novel oncogenic drivers that can be targeted in future. ATL cells, by deregulation of such pathways and their interconnections, may become masters of their own destinies. Recognizing and understanding of the widespread molecular applicability of these concepts will increasingly affect the development of novel strategies for treating ATL. PMID:23060864

  12. Developmental Regulation of Lck Targeting to the CD8 Coreceptor Controls Signaling in Naive and Memory T Cells

    PubMed Central

    Bachmann, Martin F.; Gallimore, Awen; Linkert, Susanne; Cerundolo, Vincenzo; Lanzavecchia, Antonio; Kopf, Manfred; Viola, Antonella

    1999-01-01

    The question of whether enhanced memory T cell responses are simply due to an increased frequency of specific cells or also to an improved response at the single cell level is widely debated. In this study, we analyzed T cell receptor (TCR) transgenic memory T cells and bona fide memory T cells isolated from virally infected normal mice using the tetramer technology. We found that memory T cells are qualitatively different from naive T cells due to a developmentally regulated rearrangement of the topology of the signaling machinery. In naive cytotoxic T cells, only a few CD8 molecules are associated with Lck and the kinase is homogeneously distributed inside the cell. However, in vivo priming of naive T cells induces the targeting of Lck to the CD8 coreceptor in the cell membrane and the consequent organization of a more efficient TCR signaling machinery in effector and memory cells. PMID:10330431

  13. T cell stimulator cells, an efficient and versatile cellular system to assess the role of costimulatory ligands in the activation of human T cells.

    PubMed

    Leitner, Judith; Kuschei, Werner; Grabmeier-Pfistershammer, Katharina; Woitek, Ramona; Kriehuber, Ernst; Majdic, Otto; Zlabinger, Gerhard; Pickl, Winfried F; Steinberger, Peter

    2010-10-31

    It is well established that full activation of T cells requires the interaction of the TCR complex with the peptide-MHC complex (Signal 1) and additional signals (Signal 2). These second signals are generated by the interaction of costimulatory ligands expressed on antigen presenting cells with activating receptors on T cells. In addition, T cell responses are negatively regulated by inhibitory costimulatory pathways. Since professional antigen presenting cells (APC) harbour a plethora of stimulating and inhibitory surface molecules, the contribution of individual costimulatory molecules is difficult to assess on these cells. We have developed a system of stimulator cells that can give signal 1 to human T cells via a membrane bound anti-CD3 antibody fragment. By expressing human costimulatory ligands on these cells, their role in T cell activation processes can readily be analyzed. We demonstrate that T cell stimulator cells are excellent tools to study various aspects of human T cell costimulation, including the effects of immunomodulatory drugs or how costimulatory signals contribute to the in vitro expansion of T cells. T cell stimulator cells are especially suited for the functional evaluation of ligands that are implicated in costimulatory processes. In this study we have evaluated the role of the CD2 family member CD150 (SLAM) and the TNF family member TL1A (TNFSF15) in the activation of human T cells. Whereas our results do not point to a significant role of CD150 in T cell activation we found TL1A to potently costimulate human T cells. Taken together our results demonstrate that T cell stimulator cells are excellent tools to study various aspects of costimulatory processes. PMID:20858499

  14. T cell regulation of Bacteroides fragilis-induced intraabdominal abscesses.

    PubMed

    Crabb, J H; Finberg, R; Onderdonk, A B; Kasper, D L

    1990-01-01

    Intraabdominal abscesses (IAA) caused by Bacteroides fragilis are a major sequela to colonic spillage into the peritoneum. The development of an animal model that closely reproduces the disease observed in humans permitted careful inspection of the cellular and/or humoral contributions to the development and control of this disease. The results obtained thus far describe an immunoregulatory T cell circuit that governs both the development of and the immunity against these abscesses. T cells of CD4+8+ phenotype induce the development of IAA in response to B. fragilis. CD8+ T cells generated in response to immunization with the B. fragilis capsular polysaccharide confer protection against the development of IAA. These cells elaborate an antigen-specific factor that mediates the observed protection by these cells. Moreover, a third type of T cell, a CD8+ cell that is also present in nonimmune individuals, is required for the immune T cell or its factor to confer protection. Thus, in the specific disease process of IAA induced by the encapsulated microorganism B. fragilis, immunity proceeds by cellular and not humoral mechanisms. PMID:2406870

  15. How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia.

    PubMed

    Ruella, Marco; Gill, Saar

    2015-06-01

    Antigen-specific T cell-based immunotherapy is getting its day in the sun. The contemporaneous development of two potent CD19-specific immunotherapeutic modalities for the treatment of B-cell malignancies provides exciting opportunities for patients, physicians and scientists alike. Patients with relapsed, refractory or poor-risk B-cell acute lymphoblastic leukemia (ALL) previously had few therapeutic options and now have two potential new lifelines. Physicians will have the choice between two powerful modalities and indeed could potentially enroll some patients on trials exploring both modalities if needed. For scientists interested in tumor immunology, the advent of chimeric antigen receptor T-cell therapy and of bispecific T-cell engagers (BiTEs) provides unprecedented opportunities to explore the promise and limitations of antigen-specific T-cell therapy in the context of human leukemia. In this article, we compare chimeric antigen receptor T cells and BiTEs targeting CD19 in B-cell ALL in the setting of the available clinical literature. PMID:25640460

  16. Abnormal immunomodulatory ability on memory T cells in humans with severe aplastic anemia

    PubMed Central

    Zheng, Mengying; Liu, Chunyan; Fu, Rong; Wang, Huaquan; Wu, Yuhong; Li, Lijuan; Liu, Hui; Ding, Shaoxue; Shao, Zonghong

    2015-01-01

    Severe aplastic anemia (SAA) is a bone marrow failure disease induced by hyperfunctional autoimmunic Th1 lymphocytes. Memory T cells (TM) are a component of the adaptive immune system. They ensure the host of more aggressive and faster immune response to efficiently eliminate the specific antigens after re-exposure and thus play a key role in T-cell functions. In this study we investigate the quantities and functions of memory T cells in SAA patients before and after immunosuppressive therapy (IST) to further clarify the mechanism of SAA apoptosis of bone marrow hematopoietic cells. Results showed that the percentage of CD4+ effector T cells in peripheral blood and bone marrow lymphocytes was decreased in SAA patients. The ratio of CD4+ memory T lymphocytes to CD8+ memory T subsets (CD4+/CD8+TM) in SAA patients was also lower. The percentage of CD8+ effector T cells in peripheral blood and CD8+ central memory T cells in the bone marrow lymphocytes was significantly higher in newly diagnosed patients. Furthermore, the median expressions of perforin and granzyme B on memory T cells were higher in SAA patients compared to those in normal controls. After IST, the quantities and functions of memory T cells return to normal level. Therefore, we concluded that the abnormal immunomodulatory ability on memory T cells may contribute to the imbalance of Th1/Th2 subsets and thus lead to over-function of T lymphocytes and hematopoiesis failure in SAA. PMID:26097547

  17. Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing

    PubMed Central

    Massaad, Michel J.; Oyoshi, Michiko K.; Kane, Jennifer; Koduru, Suresh; Alcaide, Pilar; Nakamura, Fumihiko; Ramesh, Narayanaswamy; Luscinskas, Francis W.; Hartwig, John

    2014-01-01

    The Wiskott-Aldrich syndrome protein (WASp) is important for actin polymerization in T cells and for their migration. WASp-interacting protein (WIP) binds to and stabilizes WASp and also interacts with actin. Cytoskeletal and functional defects are more severe in WIP?/? T cells, which lack WASp, than in WASp?/? T cells, suggesting that WIP interaction with actin may be important for T cell cytoskeletal integrity and function. We constructed mice that lack the actin-binding domain of WIP (WIP?ABD mice). WIP?ABD associated normally with WASp but not F-actin. T cells from WIP?ABD mice had normal WASp levels but decreased cellular F-actin content, a disorganized actin cytoskeleton, impaired chemotaxis, and defective homing to lymph nodes. WIP?ABD mice exhibited a T cell intrinsic defect in contact hypersensitivity and impaired responses to cutaneous challenge with protein antigen. Adoptively transferred antigen-specific CD4+ T cells from WIP?ABD mice had decreased homing to antigen-challenged skin of wild-type recipients. These findings show that WIP binding to actin, independently of its binding to WASp, is critical for the integrity of the actin cytoskeleton in T cells and for their migration into tissues. Disruption of WIP binding to actin could be of therapeutic value in T cell-driven inflammatory diseases. PMID:25246631

  18. TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer

    PubMed Central

    Sakuishi, Kaori; Ngiow, Shin Foong; Sullivan, Jenna M.; Teng, Michele W. L.; Kuchroo, Vijay K.; Smyth, Mark J.; Anderson, Ana C.

    2013-01-01

    T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8+ T cells arising in chronic diseases such as cancer. In addition to exhausted CD8+ T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3+ Tregs express TIM3. TIM3+ Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co-blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3+ Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3+ Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8+ T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8+ T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue-resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer. PMID:23734331

  19. SH2D2A Modulates T Cell Mediated Protection to a B Cell Derived Tumor in Transgenic Mice

    PubMed Central

    Berge, Tone; Grønningsæter, Ingrid Helene Bø; Lorvik, Kristina Berg; Abrahamsen, Greger; Granum, Stine; Sundvold-Gjerstad, Vibeke; Corthay, Alexandre; Bogen, Bjarne; Spurkland, Anne

    2012-01-01

    Background T cell specific adapter protein (TSAd), encoded by the SH2D2A gene, modulates signaling downstream of the T cell receptor (TCR). Young, unchallenged SH2D2A-deficient C57BL/6 mice exhibit a relatively normal immune phenotype. To address whether SH2D2A regulates physiologic immune responses, SH2D2A-deficient TCR-transgenic BALB/c mice were generated. The transgenic TCR recognizes a myeloma-derived idiotypic (Id) peptide in the context of the major histocompatibility complex (MHC) class II molecule I-Ed, and confers T cell mediated resistance to transplanted multiple myeloma development in vivo. Principal Findings The immune phenotype of SH2D2A-deficient C57BL/6 and BALB/c mice did not reveal major differences compared to the corresponding wild type mice. When challenged with myeloma cells, Id-specific TCR-transgenic BALB/c mice lacking SH2D2A displayed increased resistance towards tumor development. Tumor free TCR-transgenic SH2D2A-deficient mice had higher numbers of Id-specific single positive CD4+ thymocytes compared to TCR-transgenic wild-type mice. Conclusion Our results suggest a modulatory role for SH2D2A in T cell mediated immune surveillance of cancer. However, it remains to be established whether its effect is T-cell intrinsic. Further studies are required to determine whether targeting SH2D2A function in T cells may be a potential adjuvant in cancer immunotherapy. PMID:23144743

  20. Development of attentional processes in ADHD and normal children.

    PubMed

    Gupta, Rashmi; Kar, Bhoomika R

    2009-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is a developmental disorder. Typical development of attentional processes is rapid during early childhood. ADHD results in impairment in response inhibition, error monitoring, attentional disengagement, executive attention, and delay aversion and may effect the ongoing development of these processes during childhood. We examined the development of attentional processes in children with ADHD and normal children. Two hundred forty children (120 in each group) in the age range of 6-9 years participated in the study. Four tasks: Stop-Signal, attentional disengagement, attention network, and choice delay task were administered. Stop signal reaction time, switch costs, conflict effect, and percentage choice of short delay reward was higher in ADHD group compared to normal group. Post error of slowing was less in ADHD children. Endogenous orienting effect was more in normal children compared to ADHD children. Different developmental trajectories were observed for control functions in normal children. Major development in response inhibition occurred in 7-8 years, error monitoring in 6-9 years, and attentional disengagement in 7-9 years. Late development in alerting network was observed in normal children at age 9 years. No developmental changes occurred on these control functions in ADHD children aged 6-9 years. Age related changes were observed on delay aversion between 6 and 9 years in normal children, while it changed between 6 and 7 years in ADHD children. Performance was not changed on orienting and conflict attentional networks in both the children except conflict effect reduced between 7 and 9 years in ADHD children under double cue condition. Conflict network was interacted with the alerting and orienting network in normal children; specifically conflict network interacted with the orienting network in younger children (age 6 years) and with alerting network in older children (age 9 years). In ADHD group interaction between alerting and conflict network was observed only in the double cue condition. Together these results indicated that the deficits in control processes accumulate with age in ADHD children Present study favors the conceptual view of ADHD as a stable deficit in cognitive control functions, which are implicated in the pathology of ADHD. These results have theoretical implication for the theories of executive control and ADHD. PMID:19733762

  1. Control of HPV-associated tumors by innovative therapeutic HPV DNA vaccine in the absence of CD4+ T cells

    PubMed Central

    2014-01-01

    Human papillomavirus (HPV) infections are particularly problematic for HIV + and solid organ transplant patients with compromised CD4+ T cell-dependent immunity as they produce more severe and progressive disease compared to healthy individuals. There are no specific treatments for chronic HPV infection, resulting in an urgent unmet need for a modality that is safe and effective for both immunocompromised and otherwise normal patients with recalcitrant disease. DNA vaccination is attractive because it avoids the risks of administration of live vectors to immunocompromised patients, and can induce potent HPV-specific cytotoxic T cell responses. We have developed a DNA vaccine (pNGVL4a-hCRTE6E7L2) encoding calreticulin (CRT) fused to E6, E7 and L2 proteins of HPV-16, the genotype associated with approximately 90% vaginal, vulvar, anal, penile and oropharyngeal HPV-associated cancers and the majority of cervical cancers. Administration of the DNA vaccine by intramuscular (IM) injection followed by electroporation induced significantly greater HPV-specific immune responses compared to IM injection alone or mixed with alum. Furthermore, pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation of mice carrying an intravaginal HPV-16 E6/E7-expressing syngeneic tumor demonstrated more potent therapeutic effects than IM vaccination alone. Of note, administration of the DNA vaccine by IM injection followed by electroporation elicited potent E6 and E7-specific CD8+ T cell responses and antitumor effects despite CD4+ T cell-depletion, although no antibody response was detected. While CD4+ T cell-depletion did reduce the E6 and E7-specific CD8+ T cell response, it remained sufficient to prevent subcutaneous tumor growth and to eliminate circulating tumor cells in a model of metastatic HPV-16+ cancer. Thus, the antibody response was CD4-dependent, whereas CD4+ T cell help enhanced the E6/E7-specific CD8+ T cell immunity, but was not required. Taken together, our data suggest that pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation warrants testing in otherwise healthy patients and those with compromised CD4+ T cell immunity to treat HPV-16-associated anogenital disease and cancer. PMID:24594273

  2. Molecular signatures of T-cell inhibition in HIV-1 infection

    PubMed Central

    2013-01-01

    Cellular immune responses play a crucial role in the control of viral replication in HIV-infected individuals. However, the virus succeeds in exploiting the immune system to its advantage and therefore, the host ultimately fails to control the virus leading to development of terminal AIDS. The virus adopts numerous evasion mechanisms to hijack the host immune system. We and others recently described the expression of inhibitory molecules on T cells as a contributing factor for suboptimal T-cell responses in HIV infection both in vitro and in vivo. The expression of these molecules that negatively impacts the normal functions of the host immune armory and the underlying signaling pathways associated with their enhanced expression need to be discussed. Targets to restrain the expression of these molecular markers of immune inhibition is likely to contribute to development of therapeutic interventions that augment the functionality of host immune cells leading to improved immune control of HIV infection. In this review, we focus on the functions of inhibitory molecules that are expressed or secreted following HIV infection such as BTLA, CTLA-4, CD160, IDO, KLRG1, LAG-3, LILRB1, PD-1, TRAIL, TIM-3, and regulatory cytokines, and highlight their significance in immune inhibition. We also highlight the ensemble of transcriptional factors such as BATF, BLIMP-1/PRDM1, FoxP3, DTX1 and molecular pathways that facilitate the recruitment and differentiation of suppressor T cells in response to HIV infection. PMID:23514593

  3. The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells.

    PubMed

    Richard, Arianne C; Tan, Cuiyan; Hawley, Eric T; Gomez-Rodriguez, Julio; Goswami, Ritobrata; Yang, Xiang-Ping; Cruz, Anthony C; Penumetcha, Pallavi; Hayes, Erika T; Pelletier, Martin; Gabay, Odile; Walsh, Matthew; Ferdinand, John R; Keane-Myers, Andrea; Choi, Yongwon; O'Shea, John J; Al-Shamkhani, Aymen; Kaplan, Mark H; Gery, Igal; Siegel, Richard M; Meylan, Françoise

    2015-04-15

    The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9. PMID:25786692

  4. Innate and virtual memory T cells in man.

    PubMed

    Van Kaer, Luc

    2015-07-01

    A hallmark of the antigen-specific B and T lymphocytes of the adaptive immune system is their capacity to "remember" pathogens long after they are first encountered, a property that forms the basis for effective vaccine development. However, studies in mice have provided strong evidence that some naive T cells can develop characteristics of memory T cells in the absence of foreign antigen encounters. Such innate memory T cells may develop in response to lymphopenia or the presence of high levels of the cytokine IL-4, and have also been identified in unmanipulated animals, a phenomenal referred to as "virtual memory." While the presence of innate memory T cells in mice is now widely accepted, their presence in humans has not yet been fully validated. In this issue of the European Journal of Immunology, Jacomet et al. [Eur. J. Immunol. 2015. 45:1926-1933] provide the best evidence to date for innate memory T cells in humans. These findings may contribute significantly to our understanding of human immunity to microbial pathogens and tumors. PMID:26013879

  5. IL-15-secreting ??T cells induce memory T cells in experimental allergic encephalomyelitis (EAE) mice.

    PubMed

    Wang, Xiaoqian; Wei, Yinxiang; Liu, Xiaoling; Xing, Chen; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Dambuza, Ivy M; Shen, Beifen; Li, Yan; Xiao, He; Wang, Renxi

    2015-08-01

    With the most recent data suggesting ??T cells as primary producers of the pro-inflammatory autoimmune-associated cytokine, the relationship between ??T cells and Th17 in experimental allergic encephalitis (EAE) mice requires more extensive investigation. By flow cytometry and qPCR, we identified a new subset of IL-15-secreting ??T (??T15) cells that increased in EAE mice. The capacity of IL-15-secreting ??T cells inducing memory T cells and memory T cells inducing IL-17(+)Th17 was examined by transferring into EAE mice and 7-week-old female nude mice, respectively. We found that ??T15 induced CD44(hi) memory T cells by secreting IL-15. ??T15-induced memory T cells induced EAE by transforming into pathogenic Th17 cells. The data suggest that a new subset of IL-15-secreting ??T cells mediated the production of memory T cells which transformed into pathogenic Th17 cells in EAE mice. PMID:25974878

  6. Activation-induced T cell apoptosis by monocytes from stem cell products

    Microsoft Academic Search

    Kazuhiko Ino; Ana G Ageitos; Rakesh K Singh; James E Talmadge

    2001-01-01

    We recently found that mobilized peripheral blood stem cell (PSC) products (from both cancer patients and normal donors) contain high levels of CD14+ monocytes, which can inhibit the proliferation of allogeneic and autologous T cells. We found in our studies that using CD14+ monocytes from mobilized PSC products (from normal and cancer patient donors), normal apheresis products or normal peripheral

  7. Role of programmed death ligands in effective T-cell interactions in extranodal natural killer/T-cell lymphoma

    PubMed Central

    HAN, LIJUAN; LIU, FEIFEI; LI, RUPING; LI, ZHAOMING; CHEN, XINFENG; ZHOU, ZHIYUAN; ZHANG, XUDONG; HU, TENGPENG; ZHANG, YI; YOUNG, KEN; SUN, SUKE; WEN, JIANGUO; ZHANG, MINGZHI

    2014-01-01

    Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficiency that may influence the capacity of T cells to extract an efficient antitumor immune response. It has been confirmed that the B7-CD28 pathway may promote tumor immune evasion by providing a negative regulatory signal. The current study analyzed the expression of programmed death 1 (PD-1)/programmed death ligand (PD-L) in ENKL cell lines and tissues. The functional studies were performed to analyze the functional activity of PD-L1 interacting with effective T cells in ENKL. PD-L1 and PD-L2 mRNA levels in ENKL cell lines were markedly upregulated compared with those in normal natural killer cells. The proteins constitutively expressed in the 30 ENKL specimens were significantly higher than in the 20 rhinitis specimens. In addition, PD-L1 and PD-L2 expression were found to closely correlate with certain clinical histopathological parameters. Furthermore, the count of PD-1+ tumor-infiltrating T lymphocytes was found to negatively correlate with the expression of PD-L1 and PD-L2. The PD-1 expression in the CD4+ and CD8+ T-cell subsets of 20 ENKL patients prior to therapy were significantly higher than that of the 10 healthy volunteers. In the functional studies, the cytokines (interleukin-2 and interferon-?) secreted by CD8+ T cells were inhibited by PD-L1 expression in SNK-6 cells and this was restored with the presence of the PD-L1 blocking antibody. However no direct effect of PD-L1 was identified on CD8+ T-cell apoptosis and CD8+ T-cell cytotoxicity, as assessed by the proliferation of SNK-6 cells in the presence or absence of the neutralizing anti-PD-L1 antibody. The results of the current study revealed that PD-Ls and PD-1 are aberrantly expressed in ENKL and, furthermore, PD-L1 expression in SNK-6 cells was found to inhibit the activity of CD8+ T-cell cytokine secretion. This indicated that the PD-Ls may prevent effective antitumor immunity in vivo by interacting with tumor T cells, which provides important evidence to delineate the cellular immune deficiency mechanism in ENKL. Therefore, PD-1/PD-Ls are predicted to become novel targets for ENKL immunotherapy. PMID:25202350

  8. Adult T-cell leukemia-lymphoma.

    PubMed Central

    Neely, S M

    1989-01-01

    Adult T-cell leukemia-lymphoma, an aggressive T-cell leukemia, is characterized by the presence in the peripheral blood of malignant T cells that have highly indented or lobulated nuclei. Phenotypically the cells are usually helper T cells, but functionally they behave as suppressor cells. Patients have skin and lung involvement, hepatosplenomegaly, moderate lymphadenopathy sparing the mediastinum, and various metabolic abnormalities such as hypercalcemia. The clinical course may be chronic or acute, usually followed by a rapidly progressive terminal course. Adult T-cell leukemia-lymphoma is now known to be caused by human T-cell lymphotropic virus type I, which has been identified in the cells of patients with the disease. PMID:2662614

  9. Immunologic Self-Tolerance Maintained by CD25 1 CD4 1 Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte-associated Antigen 4

    Microsoft Academic Search

    Takeshi Takahashi; Tomoyuki Tagami; Sayuri Yamazaki; Toshimitsu Uede; Jun Shimizu; Noriko Sakaguchi; Tak W. Mak; Shimon Sakaguchi

    This report shows that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) plays a key role in T cell-mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific au- toimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25 1

  10. Anti-leukemia T cells in AML

    PubMed Central

    Flörcken, Anne; van Lessen, Antje; Terwey, Theis H.; Dörken, Bernd; Arnold, Renate; Pezzutto, Antonio; Westermann, Jörg

    2013-01-01

    Leukemia-associated antigens such as proteinase-3 (PR3) and Wilms´ tumor protein-1 (WT-1) are potential targets of T-cell responses, which can be monitored by T-cell assays within vaccination trials and after allogeneic stem cell transplantation (SCT). In chronic myeloid leukemia (CML) an aberrant cytokine profile of antigen-specific T-cells with predominant TNF-a secretion has previously been described. The aim of this study was to investigate whether these TNF-?+/IFN-?- CD8+ T-cells can also be observed in AML patients after SCT. Eight HLA-A2+ AML patients at different time points after SCT were evaluated for HLA-A2-restricted CD8+ T-cell responses against PR3, WT-1 and influenza-A using pentamer staining and different cytokine-based T-cell assays. Antigen-specific T-cell immune responses against influenza-A and PR3 were observed in 4/8 patients, WT-1-specific T-cells could be detected in in 3/8 patients. Interestingly, four different cytokine secretion profiles of antigen-specific T-cells were detected:1 IFN-?+/TNF-?+,2 IFN-?+/TNF-?-,3 TNF-?+/ IFN-?- and4 IFN-?-/TNF-?-. TNF-?+/ IFN-?- CD8+ T-cells are an interesting biological phenomenon which can obviously be observed also in AML patients. This finding has important implications for both T-cell biology and monitoring within immunotherapy trials. The functional characterization of these TNF-?+/ IFN-?- CD8+ T-cells needs further investigations. PMID:23571180

  11. Evolving Insights in the Pathogenesis and Therapy of Cutaneous T-cell lymphoma (Mycosis Fungoides and Sezary Syndrome)

    PubMed Central

    Wong, Henry K.; Mishra, Anjali; Hake, Timothy; Porcu, Pierluigi

    2015-01-01

    Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin-homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T-cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T-cells; and reviews the latest advances in MF and SS treatment. PMID:21883142

  12. A vaccine strategy protects against genital herpes by establishing local memory T cells

    PubMed Central

    Shin, Haina; Iwasaki, Akiko

    2012-01-01

    The majority of successful existing vaccines rely on neutralizing antibodies, which may not require specific anatomical localization of B cells. However, efficacious vaccines that rely on T cells for protection have been difficult to develop, as robust systemic memory T cell responses do not necessarily correlate with host protection1. In peripheral sites, tissue-resident memory T cells provide superior protection compared to circulating memory T cells2,3. Here, we describe a simple and non-inflammatory vaccine strategy that enables the establishment of a protective memory T cell pool within peripheral tissue. The female genital tract, which is a portal of entry for sexually transmitted infections (STIs), is an immunologically restrictive tissue that prevents entry of activated T cells in the absence of inflammation or infection4. To overcome this obstacle, we explored a vaccine strategy we term “prime and pull” to establish local tissue-resident memory T cells at a site of potential viral exposure. This approach relies on two steps: 1) conventional parenteral vaccination to elicit systemic T cell responses (prime), followed by 2) recruitment of activated T cells via topical chemokine application to the restrictive genital tract (pull), where such T cells establish a long-term niche and mediate protective immunity. Prime and pull protocol reduces the spread of infectious HSV-2 into the sensory neurons and prevents development of clinical disease. These results reveal a promising vaccination strategy against HSV-2, and potentially against other STIs such as HIV-1. PMID:23075848

  13. ?? T cell activation by bispecific antibodies.

    PubMed

    Oberg, Hans-Heinrich; Kellner, Christian; Gonnermann, Daniel; Peipp, Matthias; Peters, Christian; Sebens, Susanne; Kabelitz, Dieter; Wesch, Daniela

    2015-07-01

    Bispecific antibodies have been successfully introduced into clinical application. ?? T cells are of special interest for tumor immunotherapy, due to their recognition of pyrophosphates that are overproduced by many tumor cells resulting in HLA-nonrestricted tumor cell killing. Here we describe in detail a [(Her2)2×V?9] tribody construct that targets human V?9 T cells to HER2-expressing tumor cells. The direct comparison with other selective V?9 T cell agonists including phosphoantigens and nitrogen-containing bisphosphonates revealed the superiority of the [(Her2)2×V?9] tribody in triggering ?? T cell-mediated tumor cell killing with negligible induction of ?? T cell death. In contrast, phosphoantigens and bisphosphonates are potent inducers of ?? T cell proliferation but less efficient enhancers of ?? T cell-mediated tumor cell killing. Collectively, our data identify unique properties of a ?? T cell-targeting [(Her2)2×V?9] tribody which make it an attractive candidate for clinical application in ?? T cell-based tumor immunotherapy. PMID:25979810

  14. Genetically Modified T Cells to Target Glioblastoma

    PubMed Central

    Krebs, Simone; Rodríguez-Cruz, Tania G.; DeRenzo, Christopher; Gottschalk, Stephen

    2013-01-01

    Despite advances in surgical procedures, radiation, and chemotherapy the outcome for patients with glioblastoma (GBM) remains poor. While GBM cells express antigens that are potentially recognized by?T cells, GBMs prevent the induction of GBM-specific immune responses by creating an immunosuppressive microenvironment. The advent of gene transfer has allowed the rapid generation of antigen-specific?T cells as well as?T cells with enhanced effector function. Here we review recent advances in the field of cell therapy with genetically modified?T cells and how these advances might improve outcomes for patients with GBM in the future. PMID:24427741

  15. Normal development of hindgut and anorectum in human embryo

    Microsoft Academic Search

    Tao Zhang; Hai Lan Zhang; Da Jia Wang; Xiao Bing Tang; Hui Min Jia; Yu Zuo Bai; Zheng Wei Yuan; Wei Lin Wang

    2011-01-01

    Purpose  The aim of the present analysis is to examine the morphological changes, the spatiotemporal distribution of apoptosis\\/proliferation\\u000a in the human embryonic anorectum, to reveal the normal development of human anorectum, and investigate the possible roles\\u000a of apoptosis\\/proliferation during anorectal development.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and methods  The embryos were sectioned serially and sagittally, stained with hematoxylin and eosin (H & E) between the third

  16. Optimal T-cell receptor affinity for inducing autoimmunity

    PubMed Central

    Koehli, Sabrina; Naeher, Dieter; Galati-Fournier, Virginie; Zehn, Dietmar; Palmer, Ed

    2014-01-01

    T-cell receptor affinity for self-antigen has an important role in establishing self-tolerance. Three transgenic mouse strains expressing antigens of variable affinity for the OVA transgenic-I T-cell receptor were generated to address how TCR affinity affects the efficiency of negative selection, the ability to prime an autoimmune response, and the elimination of the relevant target cell. Mice expressing antigens with an affinity just above the negative selection threshold exhibited the highest risk of developing experimental autoimmune diabetes. The data demonstrate that close to the affinity threshold for negative selection, sufficient numbers of self-reactive T cells escape deletion and create an increased risk for the development of autoimmunity. PMID:25411315

  17. X Chromosome Abnormalities and Cognitive Development: Implications for Understanding Normal Human Development.

    ERIC Educational Resources Information Center

    Walzer, Stanley

    1985-01-01

    Argues that knowledge from studies of individuals with sex chromosome abnormalities can further understanding of aspects of normal human development. Studies of XO girls, XXY boys, XXX girls, and males with a fragile X chromosome are summarized to demonstrate how results contribute to knowledge about normal cognitive development and about…

  18. Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta.

    PubMed

    Adams, Catherine O; Housley, William J; Bhowmick, Sourojit; Cone, Robert E; Rajan, Thiruchandurai V; Forouhar, Faripour; Clark, Robert B

    2010-08-15

    Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b(-/-) mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b(-/-) mice are not yet clear, we have reported that Cbl-b(-/-) CD4(+)CD25(-) effector T cells (Teffs) are resistant to CD4(+)CD25(+) regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b(-/-) Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b(-/-) Teffs. Additionally, we show that Cbl-b(-/-) Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b(-/-) mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-beta sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b(-/-) mice are able to mount a normal Th17 response in vivo. As Cbl-b(-/-) Teffs have been shown to be insensitive to the suppressive effects of TGF-beta in other in vivo models, the present results suggest that Cbl-b(-/-) Teffs demonstrate a context-dependent sensitivity to TGF-beta in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b(-/-) mice offer unique approaches for studying the interrelationships between Treg function, TGF-beta-mediated responses, and the development of autoimmunity. PMID:20624942

  19. Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis.

    PubMed Central

    Goronzy, J J; Bartz-Bazzanella, P; Hu, W; Jendro, M C; Walser-Kuntz, D R; Weyand, C M

    1994-01-01

    Clonal expansion of T cell specificities in the synovial fluid of patients has been taken as evidence for a local stimulation of T cells. By studying the T cell receptor (TCR) repertoire of CD4+ T cells in the synovial and peripheral blood compartments of patients with early rheumatoid arthritis (RA), we have identified clonally expanded CD4+ populations. Expanded clonotypes were present in the peripheral blood and the synovial fluid but were not preferentially accumulated in the joint. Dominant single clonotypes could not be isolated from CD4+ cells of HLA-DRB1*04+ normal individuals. Clonal expansion involved several distinct clonotypes with a preference for V beta 3+, V beta 14+, and V beta 17+CD4+ T cells. A fraction of clonally related T cells expressed IL-2 receptors, indicating recent activation. The frequencies of clonally expanded V beta 17+CD4+ T cells fluctuated widely over a period of one year. Independent variations in the frequencies of two distinct clonotypes in the same patient indicated that different mechanisms, and not stimulation by a single arthritogenic antigen, were involved in clonal proliferation. These data support the concept that RA patients have a grossly imbalanced TCR repertoire. Clonal expansion may result from intrinsic defects in T cell generation and regulation. The dominance of expanded clonotypes in the periphery emphasizes the systemic nature of RA and suggests that T cell proliferation occurs outside of the joint. Images PMID:7962553

  20. Phenotypic and functional characterization of T cells from patients with myasthenia gravis.

    PubMed Central

    Mokhtarian, F; Pino, M; Ofosu-Appiah, W; Grob, D

    1990-01-01

    A study of cell surface phenotypes of PBL of myasthenia gravis (MG) patients showed that their T cells had a significantly higher percentage of 4B4+ T cells (the helper/inducer subset) than age- and sex-matched controls. The PBL of MG patients proliferated significantly higher than those of normal subjects (NS) in response to the purified alpha chain of the acetylcholine receptor (AChR). Anti-AChR antibody was present in sera of 88% of MG and none of the NS. The PBL B cells from MG only, when cultured with autologous T cells and stimulated with either pokeweed mitogen (69%), or AChR-alpha chain (38%), secreted antibody to AChR-alpha chain, whereas T and B cells alone secreted no antibody. T cells from PBL of MG patients were more readily cloned than T cells of NS, by limiting dilution, in the presence of recombinant IL-2 and in the absence of AChR-alpha chain. About 50% of T cell clones from MG patients, compared to none from NS, proliferated to AChR-alpha chain. This response was HLA-DR restricted. MG T cell clones did not display significant cytotoxic activity, as compared to control T cell clones. Our results indicate that in MG, 4B4+ regulatory T cells play their role in the pathogenesis of MG, not by cytotoxicity, but more likely by their ability to stimulate specific antibody production by B cells. Images PMID:1979338

  1. Cd81 Interacts with the T Cell Receptor to Suppress Signaling

    PubMed Central

    Cevik, Safak Isil; Keskin, Nazli; Belkaya, Serkan; Ozlu, Meral Ilcim; Deniz, Emre; Tazebay, Uygar Halis; Erman, Batu

    2012-01-01

    CD81 (TAPA-1) is a ubiquitously expressed tetraspanin protein identified as a component of the B lymphocyte receptor (BCR) and as a receptor for the Hepatitis C Virus. In an effort to identify trans-membrane proteins that interact with the T-cell antigen receptor (TCR), we performed a membrane yeast two hybrid screen and identified CD81 as an interactor of the CD3delta subunit of the TCR. We found that in the absence of CD81, in thymocytes from knockout mice, TCR engagement resulted in stronger signals. These results were recapitulated in T cell lines that express low levels of CD81 through shRNA mediated silencing. Increased signaling did not result from alterations in the levels of TCR on the surface of T lymphocytes. Although CD81 is not essential for normal T lymphocyte development, it plays an important role in regulating TCR and possibly pre-TCR signal transduction by controlling the strength of signaling. CD81 dependent alterations in thymocyte signaling are evident in increased CD5 expression on CD81 deficient double positive (DP) thymocytes. We conclude that CD81 interacts with the T cell receptor to suppress signaling. PMID:23226274

  2. T Cells in Cryptopatch Aggregates Share TCR Variable Region Junctional Sequences with T Cells in the Small Intestinal Epithelium of Mice1

    Microsoft Academic Search

    Bradley S. Podd; Joseph Thoits; Nicholas Whitley; Hao-Yuan Cheng; Kimberly L. Kudla; Hiroko Taniguchi; Joanna Halkias; Kerstin Goth; Victoria Camerini

    The role of cryptopatch aggregates in the development of intestinal intraepithelial lymphocytes (IEL) is a matter of controversy. Therefore, an important question is whether T cells in cryptopatch aggregates are lineally related to IEL. We hypothesized that if IEL derive from T cells in cryptopatch aggregates, then a clonal relationship would exist between the two populations. To test this hypothesis,

  3. B7-H1 expressed by activated CD8 T cells is essential for their survival

    PubMed Central

    Pulko, Vesna; Harris, Kimberley J.; Liu, Xin; Gibbons, Rachel M.; Harrington, Susan M.; Krco, Christopher J.; Kwon, Eugene D.; Dong, Haidong

    2011-01-01

    An immuno-inhibitory role of B7-H1 expressed by non-T cells has been established, however, the function of B7-H1 expressed by T cells is not clear. Peak expression of B7-H1 on antigen-primed CD8 T cells was observed during the contraction phase of an immune response. Unexpectedly, B7-H1 blockade at this stage reduced the numbers of effector CD8 T cells, suggesting B7-H1 blocking antibody may disturb an unknown function of B7-H1 expressed by CD8 T cells. To exclusively examine the role of B7-H1 expressed by T cells, we introduced B7-H1 deficiency into TCR transgenic (OT-1) mice. Naive B7-H1 deficient CD8 T cells proliferated normally following antigen stimulation, however once activated, they underwent more robust contraction in vivo and more apoptosis in vitro. In addition, B7-H1 deficient CD8 T cells were more sensitive to Ca-dependent and Fas ligand-dependent killing by cytotoxic T lymphocytes. Activation-induced Bcl-xL expression was lower in activated B7-H1 deficient CD8 T cells, while Bcl-2 and Bim expression were comparable to the wild type. Transfer of effector B7-H1 deficient CD8 T cells failed to suppress tumor growth in vivo. Thus, up-regulation of B7-H1 on primed T cells helps effector T cells survive the contraction phase and consequently generate optimal protective immunity. PMID:22025548

  4. T Cell Activation Threshold Regulated by E3 Ubiquitin Ligase Cbl-b Determines Fate of Inducible Regulatory T Cells

    PubMed Central

    Qiao, Guilin; Zhao, Yixia; Li, Zhenping; Tang, Peter Q.; Langdon, Wallace Y; Yang, Tianlan; Zhang, Jian

    2013-01-01

    E3 ubiquitin ligase Cbl-b is critical for establishing the threshold for T cell activation, and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of inducible CD4+CD25+ regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naïve CD4+CD25? T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is down-regulated in vitro. Using TCR transgenic Rag?/? mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation. PMID:23749633

  5. T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells.

    PubMed

    Qiao, Guilin; Zhao, Yixia; Li, Zhenping; Tang, Peter Q; Langdon, Wallace Y; Yang, Tianlan; Zhang, Jian

    2013-07-15

    E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR-transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation. PMID:23749633

  6. Harnessing the Heterogeneity of T Cell Differentiation Fate to Fine-Tune Generation of Effector and Memory T Cells

    PubMed Central

    Gong, Chang; Linderman, Jennifer J.; Kirschner, Denise

    2014-01-01

    Recent studies show that naïve T cells bearing identical T cell receptors experience heterogeneous differentiation and clonal expansion processes. The factors controlling this outcome are not well characterized, and their contributions to immune cell dynamics are similarly poorly understood. In this study, we develop a computational model to elaborate mechanisms occurring within and between two important physiological compartments, lymph nodes and blood, to determine how immune cell dynamics are controlled. Our multi-organ (multi-compartment) model integrates cellular and tissue level events and allows us to examine the heterogeneous differentiation of individual precursor cognate naïve T cells to generate both effector and memory T lymphocytes. Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection. Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct “sweet spots” of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes. This has important implications for vaccine development and immunotherapy. PMID:24600448

  7. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice

    PubMed Central

    Muto, H; Sakata-Yanagimoto, M; Nagae, G; Shiozawa, Y; Miyake, Y; Yoshida, K; Enami, T; Kamada, Y; Kato, T; Uchida, K; Nanmoku, T; Obara, N; Suzukawa, K; Sanada, M; Nakamura, N; Aburatani, H; Ogawa, S; Chiba, S

    2014-01-01

    TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30–83%) or peripheral T-cell lymphoma, not otherwise specified (10–49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2gt/gt) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans. PMID:25501021

  8. Increased interleukin-10 production by ASC-deficient CD4+ T cells impairs bystander T-cell proliferation.

    PubMed

    Narayan, Sharmal; Kolly, Laeticia; So, Alexander; Busso, Nathalie

    2011-09-01

    Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important component of the inflammasome, functioning as an adaptor protein that facilitates the recruitment and activation of procaspases that in turn promote the maturation of interleukin-1? (IL-1?) and IL-18. Despite initial focus on the inflammatory properties of ASC there is emerging evidence that highlights the importance of ASC in facilitating adaptive immune responses. However, the cellular and molecular basis for the involvement of ASC in adaptive immunity remains largely unexplored. We have previously demonstrated that activated ASC-deficient T cells have dampened proliferative responses. We have therefore explored the underlying cellular mechanism(s) by which ASC regulates T-cell proliferation. We show that under activating conditions (anti-CD3/CD28 stimulation) in bulk T-cell cultures the presence of ASC(-/-) CD4(+) T cells is sufficient to suppress the proliferative responses of neighbouring T cells. Furthermore, ASC(-/-) CD4(+) T cells upon activation exhibit a suppressive cytokine profile, with elevated production of IL-10 and reduced secretion of T helper type 1 cytokines, interferon-? and IL-2. This increase in IL-10 secretion within the activated ASC(-/-) CD4(+) T-cell compartment was not associated with a proportional increase in conventional Foxp3(+) regulatory T (Treg) cells. Interestingly, when equal numbers of fluorescence-activated cell sorted ASC(+/+) and ASC(-/-) Treg cells (CD4(+) CD44(intermediate/high) CD25(+)) were activated in vitro, the ASC(-/-) fraction produced significantly more IL-10 than their wild-type counterparts, suggesting that ASC(-/-) Treg cells have greater suppressive capacity. Collectively, these results imply that the ASC may influence the development and functioning of Treg cells. PMID:21718313

  9. Unexpected Phenotype of Mice Lacking Shcbp1, a Protein Induced during T Cell Proliferation

    PubMed Central

    Buckley, Monica W.; Arandjelovic, Sanja; Trampont, Paul C.; Kim, Taeg S.; Braciale, Thomas J.; Ravichandran, Kodi S.

    2014-01-01

    T cell development and activation are highly regulated processes, and their proper execution is important for a competent immune system. Shc SH2-domain binding protein-1 (Shcbp1) is an evolutionarily conserved protein that binds to the adaptor protein ShcA. Studies in Drosophila and in cell lines have strongly linked Shcbp1 to cell proliferation, embryonic development, growth factor signaling, and tumorigenesis. Here we show that Shcbp1 expression is strikingly upregulated during the ?-selection checkpoint in thymocytes, and that its expression tightly correlates with proliferative stages of T cell development. To evaluate the role for Shcbp1 during thymic selection and T cell function in vivo, we generated mice with global and conditional deletion of Shcbp1. Surprisingly, the loss of Shcbp1 expression did not have an obvious effect during T cell development. However, in a mouse model of experimental autoimmune encephalomyelitis (EAE), which depends on CD4+ T cell function and mimics multiple features of the human disease multiple sclerosis, Shcbp1 deficient mice had reduced disease severity and improved survival, and this effect was T cell intrinsic. These data suggest that despite the striking upregulation of Shcbp1 during T cell proliferation, loss of Shcbp1 does not directly affect T cell development, but regulates CD4+ T cell effector function in vivo. PMID:25153088

  10. Diacylglycerol metabolism attenuates T-cell receptor signaling and alters thymocyte differentiation

    PubMed Central

    Almena, M; Andrada, E; Liebana, R; Merida, I

    2013-01-01

    Diacylglycerol (DAG) metabolism has a critical function in Ras-regulated functions in mature T cells, but causal data linking defects in DAG-based signals with altered thymus development are missing. To study the effect of increased DAG metabolism in T-cell development, we engineered a membrane-targeted constitutive active version of DAG kinase-? (DGK?). We show that transgenic expression of constitutive active DGK leads to developmental defects in T cells, with a marked accumulation of immature CD8 thymocytes and a reduction in positive selected populations. These alterations are reflected in the periphery by a CD4/CD8 cell imbalance and general T-cell lymphopenia. The results link DAG metabolism to T-cell homeostasis, and show that correctly controlled generation and consumption of this lipid at the plasma membrane ensure T-cell passage through quality-control checkpoints during differentiation. PMID:24201811

  11. Novel autoantigens for diabetogenic CD4 T cells in autoimmune diabetes

    PubMed Central

    Delong, Thomas; Baker, Rocky L; He, Jing; Haskins, Kathryn

    2013-01-01

    Autoreactive CD4 T cells play a central role in the development of type 1 diabetes. The BDC-panel of diabetogenic T cell clones was originally isolated from non-obese diabetic (NOD) mice and has been used to study the role of autoreactive CD4 T cells and T cell autoantigens in the development of diabetes. Recent studies by our group have led to the identification of two new target antigens for clones of this panel. This review describes the proteomic strategy used for antigen identification, the antigens identified, and the potential contribution of post-translational modification to autoantigen generation. In addition, we compare peptide epitopes for the T cell clones and discuss their potential applications in investigating the role of T cell autoantigens in the pathogenesis and regulation of disease. PMID:22971988

  12. T-Cell Signaling Regulated by the Tec Family Kinase, Itk

    PubMed Central

    Andreotti, Amy H.; Schwartzberg, Pamela L.; Joseph, Raji E.; Berg, Leslie J.

    2010-01-01

    The Tec family tyrosine kinases regulate lymphocyte development, activation, and differentiation. In T cells, the predominant Tec kinase is Itk, which functions downstream of the T-cell receptor to regulate phospholipase C-?. This review highlights recent advances in our understanding of Itk kinase structure and enzymatic regulation, focusing on Itk protein domain interactions and mechanisms of substrate recognition. We also discuss the role of Itk in the development of conventional versus innate T-cell lineages, including both ?? and ?? T-cell subsets. Finally, we describe the complex role of Itk signaling in effector T-cell differentiation and the regulation of cytokine gene expression. Together, these data implicate Itk as an important modulator of T-cell signaling and function. PMID:20519342

  13. L-Myc expression by dendritic cells is required for optimal T-cell priming

    PubMed Central

    Wumesh, KC; Satpathy, Ansuman T.; Rapaport, Aaron S.; Briseño, Carlos G.; Wu, Xiaodi; Albring, Jörn C.; Russler-Germain, Emilie V.; Kretzer, Nicole M.; Durai, Vivek; Persaud, Stephen P.; Edelson, Brian T.; Loschko, Jakob; Cella, Marina; Allen, Paul M.; Nussenzweig, Michel C.; Colonna, Marco; Sleckman, Barry P.; Murphy, Theresa L.; Murphy, Kenneth M.

    2014-01-01

    The transcription factors c-Myc and N-Myc encoded by Myc and Mycn, respectively, regulate cellular growth1 and are required for embryonic development2,3. A third paralog, Mycl1, is dispensable for normal embryonic development but its normal biologic function has remained unclear4. To examine the in vivo function of Mycl1, we generated an inactivating Mycl1gfp allele that also reports Mycl1 expression. We found that Mycl1 was selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression was initiated in the common DC progenitor5 (CDP) concurrent with reduction in c-Myc expression. Mature DCs lacked expression of c-Myc and N-Myc, but maintained L-Myc expression even in the presence of inflammatory signals, such as GM-CSF. All DC subsets developed in Mycl1-deficient mice, but several DC subsets, such as migratory CD103+ cDCs in the lung and liver, were significantly reduced at steady state. Importantly, loss of L-Myc by DCs caused a significant decrease in the in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming6. PMID:24509714

  14. Glucose Metabolism Regulates T Cell Activation, Differentiation, and Functions

    PubMed Central

    Palmer, Clovis S.; Ostrowski, Matias; Balderson, Brad; Christian, Nicole; Crowe, Suzanne M.

    2014-01-01

    The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation, and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The “Warburg effect” originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here, we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1?. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases. PMID:25657648

  15. Aging is associated with increased regulatory T-cell function

    PubMed Central

    Garg, Sanjay K; Delaney, Colin; Toubai, Tomomi; Ghosh, Amiya; Reddy, Pavan; Banerjee, Ruma; Yung, Raymond

    2014-01-01

    Regulatory T-cell (Treg, CD4+CD25+) dysfunction is suspected to play a key role in immune senescence and contributes to increased susceptibility to diseases with age by suppressing T-cell responses. FoxP3 is a master regulator of Treg function, and its expression is under control of several epigenetically labile promoters and enhancers. Demethylation of CpG sites within these regions is associated with increased FoxP3 expression and development of a suppressive phenotype. We examined differences in FoxP3 expression between young (3–4 months) and aged (18–20 months) C57BL/6 mice. DNA from CD4+ T cells is hypomethylated in aged mice, which also exhibit increased Treg numbers and FoxP3 expression. Additionally, Treg from aged mice also have greater ability to suppress effector T-cell (Teff) proliferation in vitro than Tregs from young mice. Tregs from aged mice exhibit greater redox remodeling–mediated suppression of Teff proliferation during coculture with DCs by decreasing extracellular cysteine availability to a greater extent than Tregs from young mice, creating an adverse environment for Teff proliferation. Tregs from aged mice produce higher IL-10 levels and suppress CD86 expression on DCs more strongly than Tregs from young mice, suggesting decreased T-cell activity. Taken together, these results reveal a potential mechanism of higher Treg-mediated activity that may contribute to increased immune suppression with age. PMID:24325345

  16. Cbl-b and itch: key regulators of peripheral T-cell tolerance.

    PubMed

    Venuprasad, K

    2010-04-15

    E3 ligases Cbl-b and Itch have emerged as dominant "tolerogenic" regulators of T cells because their deficiency results in severe autoimmune diseases. Cbl-b and Itch ligase activity regulate T-cell anergy and development of Foxp3+ regulatory T cells (Treg) in the periphery by modulating key components of T-cell receptor (TCR) and transforming growth factor-beta (TGF-beta) signaling. Manipulation of Cbl-b and Itch activities may provide unique opportunities to develop future therapies for immune disorders such as autoimmunity and cancer. PMID:20395198

  17. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells

    PubMed Central

    Fahey, Laura M.; Wilson, Elizabeth B.; Elsaesser, Heidi; Fistonich, Chris D.; McGavern, Dorian B.

    2011-01-01

    CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection. PMID:21536743

  18. Transforming growth factor-? in T-cell biology

    Microsoft Academic Search

    Leonid Gorelik; Richard A. Flavell

    2002-01-01

    Strict control of T-cell homeostasis is required to permit normal immune responses and prevent undesirable self-targeted responses. Transforming growth factor-? (TGF-?) has been shown to have an essential role in that regulation. Owing to its broad expression, and inhibitory effects on multiple cell types of the immune system, TGF-? regulation is complex. Through advances in cell-specific targeting of TGF-? signalling

  19. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease

    Microsoft Academic Search

    Silke Paust; Linrong Lu; Nami McCarty; Harvey Cantor

    2004-01-01

    Although there is considerable evidence that a subpopulation of regulatory CD4+CD25+ T cells can suppress the response of autoreactive T cells, the underlying molecular mechanism is not understood. We find that transmission of a suppressive signal by CD4CD25+ regulatory cells requires engagement of the B7 molecule expressed on target T cells. The response of T cells from B7-deficient mice is

  20. The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection

    Microsoft Academic Search

    Guangping Sun; Xiaolong Liu; Peter Mercado; S Rhiannon Jenkinson; Magdalini Kypriotou; Lionel Feigenbaum; Philippe Galéra; Rémy Bosselut

    2005-01-01

    The genetic programs directing CD4 or CD8 T cell differentiation in the thymus remain poorly understood. While analyzing gene expression during intrathymic T cell selection, we found that Zfp67, encoding the zinc finger transcription factor cKrox, was upregulated during the differentiation of CD4+ but not CD8+ T cells. Expression of a cKrox transgene impaired CD8 T cell development and caused

  1. Coinfection with Heligmosomoides polygyrus Fails To Establish CD8+ T-Cell Immunity against Toxoplasma gondii

    Microsoft Academic Search

    Imtiaz A. Khan; Rubeena Hakak; Karen Eberle; Peter Sayles; Louis M. Weiss; Joseph F. Urban

    2008-01-01

    CD8 T-cell immunity is important for long-term protection against Toxoplasma gondii infection. However, a Th1 cytokine environment, especially the presence of gamma interferon (IFN-), is essential for the devel- opment of primary CD8 T-cell immunity against this obligate intracellular pathogen. Earlier studies from our laboratory have demonstrated that mice lacking optimal IFN- levels fail to develop robust CD8 T-cell immunity

  2. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell

    E-print Network

    Parker, Ian

    T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell, CO, and approved November 25, 2003 (received for review October 3, 2003) Dendritic cells (DCs) ingest cell follicles but vigorously extended long agile dendrites. Encounters between T cells and DCs arose

  3. Ecological developmental biology: environmental signals for normal animal development.

    PubMed

    Gilbert, Scott F

    2012-01-01

    The environment plays instructive roles in development and selective roles in evolution. This essay reviews several of the instructive roles whereby the organism has evolved to receive cues from the environment in order to modulate its developmental trajectory. The environmental cues can be abiotic (such as temperature or photoperiod) or biotic (such as those emanating from predators, conspecifics, or food), and the "alteration" produces a normal, not a pathological, phenotype, that is appropriate for the environment. In addition, symbiotic organisms can produce important signals during normal development. Environmental cues can be obligatory, such that the organism cannot develop without the environmental cue. These cues often permit and instruct the organism to proceed from one developmental stage to another, as when larvae receive cues to settle and undergo metamorphosis from substrates. Such obligatory cues can also be given by symbionts, as when Wolbachia bacteria prevent apoptosis in developing ovaries of some wasps. Other environmental cues can be used facultatively, allowing organisms to follow different developmental trajectories depending on whether the cue is present or not. This can be seen in the temperature-dependent determination of sex in many reptiles and in the determination of thermotolerance in aphids by their symbiotic bacteria. Signaling from the environment is essential in development, and co-development appears to be normative between symbionts and their hosts. Here, one sees the reciprocal induction of gene expression, just as within the embryonic organism. The ability of organisms to respond to environmental cues by producing different phenotypes may be critically important in evolution, and it may be an essential feature that can facilitate or limit evolution. PMID:23016971

  4. Pathogenic CD8(+) T cells in experimental cerebral malaria.

    PubMed

    Howland, Shanshan Wu; Claser, Carla; Poh, Chek Meng; Gun, Sin Yee; Rénia, Laurent

    2015-05-01

    Cerebral malaria (CM) is one the major complications occurring during malaria infection. The mechanisms leading to this syndrome are still not completely understood. Although it is clear that parasite sequestration is the key initiation factor, the downstream pathological processes are still highly debated. The experimental cerebral malaria (ECM) model, in which susceptible mice are infected with Plasmodium berghei ANKA, has led to the identification of CD8(+) T cells as the major mediator of ECM death. In this review, we discuss the recent advances and future developments in the understanding of the role of CD8(+) T cells in CM. PMID:25772948

  5. Thrombopoietin in normal and neoplastic stem cell development

    PubMed Central

    Kaushansky, Kenneth; Ranney, Helen M.

    2009-01-01

    It has been known for some time that thrombopoietin acts on megakaryocytic progenitor cells to stimulate platelet production. It has recently been discovered that it also stimulates the self-renewal and expansion of normal murine and human hematopoietic stem cells (HSCs) by acting on its cognate receptor, the product of the c-MPL proto-oncogene. c-MPL may also play an important role in the development of human myeloproliferative disorders, essential thrombocythemia, myelofibrosis, and polycythemia vera, cooperating with the dysregulated Janus kinase JAK2 V617F. PMID:19959099

  6. Evaluation of normal brain development by prenatal MR imaging

    Microsoft Academic Search

    L. Manganaro; A. Perrone; S. Savelli; M. Di Maurizio; C. Maggi; L. Ballesio; L. M. Porfiri; C. De Felice; E. Marinoni; M. Marini

    2007-01-01

    Purpose.  The aim of this study was to describe the normal pattern\\u000a of development and maturation of the foetal brain with respect to\\u000a gestational age as assessed with magnetic resonance imaging (MRI)\\u000a and to provide an overview of the possibilities of the technique.\\u000a \\u000a \\u000a \\u000a Materials and methods.  Foetal cerebral MRI was performed on 56\\u000a pregnant women between 19 and 37 weeks of gestation.

  7. Pediatric sexuality: promoting normal sexual development in children.

    PubMed

    Smith, M

    1993-08-01

    Since the sexual revolution of the 1960s there has been an openness regarding sexual exploration that has resulted in an increase of sexually transmitted diseases and teenage pregnancies. Clinicians can mitigate the unhealthy results of such exploration through a therapeutic relationship with their patients. This article provides practical ways to approach and educate the pediatric patient and parent regarding normal sexual growth and development and the promotion of healthy, responsible sexual behavior. Using developmental theories as a foundation, sexuality is examined from birth through the adolescent years. PMID:8233152

  8. Targeting regulatory T cells in cancer.

    PubMed

    Byrne, William L; Mills, Kingston H G; Lederer, James A; O'Sullivan, Gerald C

    2011-11-15

    Infiltration of tumors by regulatory T cells confers growth and metastatic advantages by inhibiting antitumor immunity and by production of receptor activator of NF-?B (RANK) ligand, which may directly stimulate metastatic propagation of RANK-expressing cancer cells. Modulation of regulatory T cells can enhance the efficacy of cancer immunotherapy. Strategies include depletion, interference with function, inhibition of tumoral migration, and exploitation of T-cell plasticity. Problems with these strategies include a lack of specificity, resulting in depletion of antitumor effector T cells or global interruption of regulatory T cells, which may predispose to autoimmune diseases. Emerging technologies, such as RNA interference and tetramer-based targeting, may have the potential to improve selectivity and efficacy. PMID:22068034

  9. Divergent behavior of mucosal memory T cells.

    PubMed

    Pham, O H; McSorley, S J

    2015-07-01

    Memory CD4 T cells are strategically positioned at mucosal surfaces to initiate a robust adaptive immune response. The detection of specific antigen via the T-cell receptor causes these memory T cells to unleash a potent antimicrobial response that includes rousing local innate immune populations for tissue-specific defense. Paradoxically, these same memory T cells can also be stimulated by nonantigen-specific signals that are generated by the activity of local innate immune cells. This versatility of mucosal memory T cells in both the initiation and the sensing of local innate immunity could be a vitally important asset during pathogen defense but alternatively could be responsible for initiating and maintaining chronic inflammation in sensitive mucosal tissues. PMID:26059005

  10. Placing Ion Channels into a Signaling Network of T Cells: From Maturing Thymocytes to Healthy T Lymphocytes or Leukemic T Lymphoblasts

    PubMed Central

    Delgado-Enciso, Iván; Best-Aguilera, Carlos; Rojas-Sotelo, Rocío Monserrat; Pottosin, Igor

    2015-01-01

    T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting “leukemogenic” signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility. PMID:25866806

  11. Generation of Fas-independent CD4+ cytotoxic T-cell clone specific for p190 minor bcr-abl fusion peptide.

    PubMed

    Tanaka, Yuji; Takahashi, Tsuyoshi; Nieda, Mie; Masuda, Shigeo; Kashiwase, Koichi; Takahashi, Tokiharu; Ogawa, Seishi; Chiba, Shigeru; Juji, Takeo; Hirai, Hisamaru

    2002-03-01

    In the majority of Ph+ALL patients, p190 bcr-abl fusion protein is generated in the Philadelphia chromosome. The fusion protein may serve as a leukemia antigen because it is not expressed in normal cells and hardly in any other malignancy. From a healthy donor, we have established a p190 bcr-abl fusion peptide-specific CD4+ cytotoxic T-cell clone, activation of which depends on HLA-DRB1*1501. This T-cell clone has a strong cytotoxic activity against autologus MoDCs pulsed with e1a2 peptide and its cytotoxicity is not mediated by Fas/Fas ligand or perforin pathway. Success in establishment of the p190 bcr-abl fusion peptide-specific T-cell clone encourages us to develop a new approach to an effective immunotherapy for Ph+ALL. PMID:11792422

  12. ?? TCR+ T Cells, but Not B Cells, Promote Autoimmune Keratitis in B10 Mice Lacking ?? T Cells

    PubMed Central

    Chain, Jennifer L.; Aydintug, M. Kemal; Bohrer-Kunter, Dawn; Huang, Yafei; Hardy, Ian R.; Cambier, John C.; Lahmers, Kevin; Nuhsbaum, Tanja; Davidson, Richard; Sun, Deming; Born, Willi K.

    2012-01-01

    Purpose. To investigate additional factors in the spontaneous development of keratitis previously reported in B10.TCR??/? female mice. Methods. The study tested whether susceptible B10.TCR??/? mice have dry eyes compared with resistant B6.TCR??/? females and also rederived the B10.TCR??/? strain to test for the role of an infectious agent. Also assessed was whether adoptive transfer of ?? T cells from autoimmune mice induced keratitis in resistant mice. In addition, a potential role was examined for B cells or autoantibodies by B-cell inactivation, and the role of female hormones was tested by ovariectomy. Finally, the study investigated whether adoptive transfer of V?1+ ?? T cells confers protection. Results. Tear production in B10.TCR??/? females was actually higher than in B6.TCR??/? controls. Rederived B10.TCR??/? mice still developed keratitis. Keratitis was induced in resistant mice after adoptive transfer of ?? T cells from keratitic donors. Inactivation of B cells from susceptible mice had no effect on the development of keratitis. Ovariectomy did not significantly reduce disease in B10.TCR??/? females. Adoptive transfer of V?1+ cells from wild-type donors reduced keratitis in B10.TCR??/? females. Conclusions. Neither low tear levels nor ovarian hormones contribute to spontaneous keratitis in B10.TCR??/? female mice, nor does it appear to depend on an infectious agent carried vertically in this strain. However, ?? T cells from keratitic hosts are sufficient to induce disease in the resistant B10.TCR??/???/? strain. Autoaggressive ?? T cells in the absence of V?1+ T cells in B10.TCR??/? mice may be insufficiently checked to prevent disease. PMID:22199243

  13. Inhibitory Receptors Beyond T Cell Exhaustion

    PubMed Central

    Fuertes Marraco, Silvia A.; Neubert, Natalie J.; Verdeil, Grégory; Speiser, Daniel E.

    2015-01-01

    Inhibitory receptors (iRs) are frequently associated with “T cell exhaustion”. However, the expression of iRs is also dependent on T cell differentiation and activation. Therapeutic blockade of various iRs, also referred to as “checkpoint blockade”, is showing ­unprecedented results in the treatment of cancer patients. Consequently, the clinical potential in this field is broad, calling for increased research efforts and rapid refinements in the understanding of iR function. In this review, we provide an overview on the significance of iR expression for the interpretation of T cell functionality. We summarize how iRs have been strongly associated with “T cell exhaustion” and illustrate the parallel evidence on the importance of T cell differentiation and activation for the expression of iRs. The differentiation subsets of CD8 T cells (naïve, effector, and memory cells) show broad and inherent differences in iR expression, while activation leads to strong upregulation of iRs. Therefore, changes in iR expression during an immune response are often concomitant with T cell differentiation and activation. Sustained expression of iRs in chronic infection and in the tumor microenvironment likely reflects a specialized T cell differentiation. In these situations of prolonged antigen exposure and chronic inflammation, T cells are “downtuned” in order to limit tissue damage. Furthermore, we review the novel “checkpoint blockade” treatments and the potential of iRs as biomarkers. Finally, we provide recommendations for the immune monitoring of patients to interpret iR expression data combined with parameters of activation and differentiation of T cells.

  14. Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X.

    PubMed

    Naik, Edwina; Webster, Joshua D; DeVoss, Jason; Liu, Jinfeng; Suriben, Rowena; Dixit, Vishva M

    2014-09-22

    The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell-specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance. PMID:25200027

  15. Effector V?9V?2 T cells dominate the human fetal ?? T-cell repertoire.

    PubMed

    Dimova, Tanya; Brouwer, Margreet; Gosselin, Françoise; Tassignon, Joël; Leo, Oberdan; Donner, Catherine; Marchant, Arnaud; Vermijlen, David

    2015-02-10

    ?? T cells are unconventional T cells recognizing antigens via their ?? T-cell receptor (TCR) in a way that is fundamentally different from conventional ?? T cells. ?? T cells usually are divided into subsets according the type of V? and/or V? chain they express in their TCR. T cells expressing the TCR containing the ?-chain variable region 9 and the ?-chain variable region 2 (V?9V?2 T cells) are the predominant ?? T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, V?9V?2 T cells are the predominant blood subset in the second-trimester fetus, whereas V?1(+) and V?3(+) ?? T cells are present only at low frequencies at this gestational time. Fetal blood V?9V?2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the V?9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3?2. Furthermore, these fetal blood V?9V?2 T cells are functionally preprogrammed (e.g., IFN-? and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine ?? T cells than is usually articulated. PMID:25617367

  16. TGF? in T cell biology and tumor immunity: Angel or devil?

    PubMed

    Tu, Eric; Chia, Pei Zhi Cheryl; Chen, Wanjun

    2014-08-01

    The evolutionally conserved transforming growth factor ? (TGF?) affects multiple cell types in the immune system by either stimulating or inhibiting their differentiation and function. Studies using transgenic mice with ablation of TGF? or its receptor have revealed the biological significance of TGF? signaling in the control of T cells. However, it is now clear that TGF? is more than an immunosuppressive cytokine. Disruption of TGF? signaling pathway also leads to impaired generation of certain T cell populations. Therefore, in the normal physiological state, TGF? actively maintains T cell homeostasis and regulates T cell function. However, in the tumor microenvironment, TGF? creates an immunosuppressive milieu that inhibits antitumor immunity. Here, we review recent advances in our understanding of the roles of TGF? in the regulation of T cells and tumor immunity. PMID:25156420

  17. In vitro expansion of gamma delta T cells with anti-myeloma cell activity by Phosphostim and IL-2 in patients with multiple myeloma

    E-print Network

    Boyer, Edmond

    T cells from MM patients, and the efficient and stable killing of human myeloma cells by T cells. 2 collection or in relapsing patients expanded less efficiently. Expanded T cells killed 13/14 myeloma cell lines as well as primary myeloma cells, but not normal CD34 cells. Their killing efficiency

  18. Nature versus nurture in T cell cytokine production

    Microsoft Academic Search

    David R. Fitzpatrick; Anne Kelso

    Abstract: Both extrinsic and intrinsic factors influ- ence the development of cytokine expression pat- terns in T lymphocytes. The models proposed to accommodate these factors are often separated into two types: deterministic (or instructional) and probabilistic (or stochastic). In this review we compare these two types of models and examine how they account for different stages of T cell cytokine

  19. Expansions of NK-like ??T cells with chronologic aging: novel lymphocyte effectors that compensate for functional deficits of conventional NK cells and T cells.

    PubMed

    Vallejo, Abbe N; Mueller, Robert G; Hamel, David L; Way, Amanda; Dvergsten, Jeffrey A; Griffin, Patricia; Newman, Anne B

    2011-07-01

    As the repertoire of ??T