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ABSTRACT: A balanced immune response requires combating infectious assaults while striving to maintain quiescence towards the self. One of the central players in this process is the pleiotropic cytokine TGFβ, whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGFβ is to regulate the peripheral immune homeostasis, particularly in the microbe and antigen rich environment of the gut. To maintain intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that inhabit the gut secrete TGFβ, which acts in both paracrine and autocrine fashions to activate its signal transducers, the SMAD transcription factors. The SMAD pathway regulates the production of IgA by B cells, maintains the protective mucosal barrier and promotes the balanced differentiation of CD4(+) T cells into inflammatory Th17 cells and suppressive FOXP3(+) T regulatory cells. While encounters with pathogenic microbes activate SMAD proteins to evoke a protective inflammatory immune response, SMAD activation and synergism with immunoregulatory factors such as Vitamin A metabolite Retinoic Acid enforce immunosuppression toward commensal microbes and innocuous food antigens. Such complementary context-dependent functions of TGFβ are achieved by the cooperation of SMAD proteins with distinct dominant transcription activators and accessory chromatin modifiers. This review highlights recent advances in unravelling the molecular basis for the multifaceted functions of TGFβ in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners. © 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.
Immunology 01/2013; · 3.32 Impact Factor
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ABSTRACT: Various innate-like T cell subsets preferentially reside in specific epithelial tissues as the first line of defense. However, mechanisms regulating their tissue-specific development are poorly understood. Using the prototypical skin intraepithelial γδT cells (sIELs) as a model, we show in this study that a TCR-mediated selection plays an important role in promoting acquisition of a specific skin-homing property by fetal thymic sIEL precursors for their epidermal location, and the skin-homing potential is intrinsically programmed even before the selection. In addition, once localized in the skin, the sIEL precursors develop into sIELs without the requirement of further TCR-ligand interaction. These studies reveal that development of the tissue-specific lymphocytes is a hard-wired process that targets them to specific tissues for proper functions.
The Journal of Immunology 11/2010; 185(12):7156-60. · 5.79 Impact Factor
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ABSTRACT: TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is required for the efficient differentiation and maintenance of CD4(+)FOXP3(+) T cells that inhibit immune responses. Conversely, in conjunction with the inflammatory cytokine IL-6, TGFβ promotes Th17 cell differentiation. The mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates receptor SMADs, SMAD2 and SMAD3, which associate with a variety of nuclear factors to regulate gene transcription. Defining relative contributions of distinct SMAD molecules for CD4 T cell differentiation is critical for mapping the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities to the state of host interaction with pathogens. We show here that SMAD2 is essential for Th17 cell differentiation and that it acts in part by modulating the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in T cells do not develop spontaneous lymphoproliferative autoimmunity, Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in vivo, and they are more pathogenic than controls when transferred into lymphopenic mice. These results demonstrate that SMAD2 is uniquely essential for TGFβ signaling in CD4(+) T effector cell differentiation.
Journal of Biological Chemistry 09/2010; 285(38):29044-8. · 4.77 Impact Factor
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ABSTRACT: TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is required for the efficient differentiation and
maintenance of CD4+FOXP3+ T cells that inhibit immune responses. Conversely, in conjunction with the inflammatory cytokine IL-6, TGFβ promotes Th17
cell differentiation. The mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates receptor SMADs, SMAD2 and SMAD3, which associate with
a variety of nuclear factors to regulate gene transcription. Defining relative contributions of distinct SMAD molecules for
CD4 T cell differentiation is critical for mapping the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities
to the state of host interaction with pathogens. We show here that SMAD2 is essential for Th17 cell differentiation and that
it acts in part by modulating the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in T cells do not
develop spontaneous lymphoproliferative autoimmunity, Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in vivo, and they are more pathogenic than controls when transferred into lymphopenic mice. These results demonstrate that SMAD2
is uniquely essential for TGFβ signaling in CD4+ T effector cell differentiation.
Journal of Biological Chemistry 09/2010; 285(38):29044-29048. · 4.77 Impact Factor
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ABSTRACT: The mechanism of T cell precursor commitment to the gammadelta or alphabeta T cell lineage remains unclear. While TCR signal strength has emerged as a key factor in lineage commitment based on TCR transgenic models, the entire TCR repertoire may not possess the same discriminatory power. A counterbalance to the TCR as the lineage determinant is the pre-existing heterogeneity in gene expression among precursors, which suggests that single precursors are unlikely to respond homogeneously to a given instructive signal.
Seminars in Immunology 05/2010; 22(4):222-7. · 6.39 Impact Factor
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ABSTRACT: Immune protection from intracellular pathogens depends on the generation of terminally differentiated effector and of multipotent memory precursor CD8 T cells, which rapidly regenerate effector and memory cells during recurrent infection. The identification of factors and pathways involved in CD8 T cell differentiation is of obvious importance to improve vaccination strategies. Here, we show that mice lacking T cell factor 1 (Tcf-1), a nuclear effector of the canonical Wingless/Integration 1 (Wnt) signaling pathway, mount normal effector and effector memory CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV). However, Tcf-1-deficient CD8 T cells are selectively impaired in their ability to expand upon secondary challenge and to protect from recurrent virus infection. Tcf-1-deficient mice essentially lack CD8 memory precursor T cells, which is evident already at the peak of the primary response, suggesting that Tcf-1 programs CD8 memory cell fate. The function of Tcf-1 to establish CD8 T cell memory is dependent on the catenin-binding domain in Tcf-1 and requires the Tcf-1 coactivators and Wnt signaling intermediates beta-catenin and gamma-catenin. These findings demonstrate that the canonical Wnt signaling pathway plays an essential role for CD8 central memory T cell differentiation under physiological conditions in vivo. They raise the possibility that modulation of Wnt signaling may be exploited to improve the generation of CD8 memory T cells during vaccination or for therapies designed to promote sustained cytotoxic CD8 T cell responses against tumors.
Proceedings of the National Academy of Sciences 05/2010; 107(21):9777-82. · 9.68 Impact Factor
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ABSTRACT: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both is unclear. We show here that lack of CTLA-4 in regulatory T cells leads to aberrant activation and expansion of conventional T cells. However, CTLA-4 expression in conventional T cells prevents aberrantly activated T cells from infiltrating and fatally damaging nonlymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell tolerance: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells prevents the harmful accumulation of self-reactive pathogenic T cells in vital organs.
Proceedings of the National Academy of Sciences 01/2010; 107(4):1524-8. · 9.68 Impact Factor
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ABSTRACT: FOXP3-expressing regulatory T (Treg) cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. In this study we show that in mouse peripheral lymphocytes the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFbeta responses, is exclusively expressed in FOXP3+ regulatory T cells. Dab2 is a direct target of FOXP3, and regulatory T cells lacking DAB2 are functionally impaired in vitro and in vivo. However, not all aspects of Treg cell function are perturbed, and DAB2 appears to be dispensable for Treg cell function in maintaining naive T cell homeostasis.
The Journal of Immunology 10/2009; 183(7):4192-6. · 5.79 Impact Factor
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ABSTRACT: In conventional alphabeta T cells, the Tec family tyrosine kinase Itk is required for signaling downstream of the T cell receptor (TCR). Itk also regulates alphabeta T cell development, lineage commitment, and effector function. A well established feature of Itk(-/-) mice is their inability to generate T helper type 2 (Th2) responses that produce IL-4, IL-5, and IL-13; yet these mice have spontaneously elevated levels of serum IgE and increased numbers of germinal center B cells. Here we show that the source of this phenotype is gammadelta T cells, as normal IgE levels are observed in Itk(-/-)Tcrd(-/-) mice. When stimulated through the gammadelta TCR, Itk(-/-) gammadelta T cells produce high levels of Th2 cytokines, but diminished IFNgamma. In addition, activated Itk(-/-) gammadelta T cells up-regulate costimulatory molecules important for B cell help, suggesting that they may directly promote B cell activation and Ig class switching. Furthermore, we find that gammadelta T cells numbers are increased in Itk(-/-) mice, most notably the Vgamma1.1(+)Vdelta6.3(+) subset that represents the dominant population of gammadelta NKT cells. Itk(-/-) gammadelta NKT cells also have increased expression of PLZF, a transcription factor required for alphabeta NKT cells, indicating a common molecular program between alphabeta and gammadelta NKT cell lineages. Together, these data indicate that Itk signaling regulates gammadelta T cell lineage development and effector function and is required to control IgE production in vivo.
Proceedings of the National Academy of Sciences 06/2009; 106(20):8308-13. · 9.68 Impact Factor
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ABSTRACT: Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.
Journal of Experimental Medicine 03/2009; 206(2):421-34. · 13.85 Impact Factor
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The Journal of Immunology 02/2009; 182(1):5-7. · 5.79 Impact Factor
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ABSTRACT: The Wnt-beta-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt-Ca(2+) signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of alphabeta lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4(+)CD8(+) thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting beta-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of beta-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt-Ca(2+) pathway alters canonical Wnt signaling and is critical for normal T cell development.
Journal of Experimental Medicine 01/2008; 204(13):3077-84. · 13.85 Impact Factor
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ABSTRACT: The divergence of alphabeta and gammadelta T cells from a common precursor in the thymus is regulated by multiple cell-intrinsic and cell-extrinsic factors, most of which are not well defined. Recent studies have provided crucial data regarding the precise timing of lineage commitment and some clarification on the extent of the involvement of Notch and T-cell receptor signaling in this process. Combined with new insights into the differential regulation of molecular pathways active in alphabeta and gammadelta precursors, these data have led to the generation of a revised model of lineage commitment.
Current Opinion in Immunology 05/2007; 19(2):169-75. · 9.52 Impact Factor
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ABSTRACT: ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p37(Ing1), a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37(Ing1)-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity. The results show that endogenous levels of p37(Ing1) inhibit the proliferation of p53-wild-type and p53-deficient fibroblasts, and that p53 functions are unperturbed in p37(Ing1)-deficient cells. In addition, loss of p37(Ing1) induces Bax expression and increases DNA damage-induced apoptosis in primary cells and mice irrespective of p53 status. Finally, p37(Ing1) suppresses the formation of spontaneous follicular B-cell lymphomas in mice. These results indicate that p53 does not require p37(Ing1) to negatively regulate cell growth and offers genetic proof that Ing1 suppresses cell growth and tumorigenesis. Furthermore, these data reveal that p37(Ing1) can negatively regulate cell growth and apoptosis in a p53-independent manner.
Cancer Research 04/2007; 67(5):2054-61. · 7.86 Impact Factor
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ABSTRACT: Morphogens, a class of secreted proteins that regulate gene expression in a concentration-dependent manner, are responsible for directing nearly all lineage fate choices during embryogenesis. In the thymus, morphogen signal pathways consisting of WNT, Hedgehog, and the transforming growth factor-beta superfamily are active and have been implicated in various developmental processes including proliferation, survival, and differentiation of maturing thymocytes. Intriguingly, it has been inferred that some of these morphogen signal pathways differentially affect gammadelta and alphabeta T-cell development or maintenance, but their role in T-cell lineage commitment has not been directly probed. We have recently identified a modulator of morphogen signaling that significantly influences binary gammadelta versus alphabeta T-cell lineage diversification. In this review, we summarize functions of morphogens in the thymus and provide a highly speculative model of integrated morphogen signals, potentially directing the gammadelta versus alphabeta T-cell fate determination process.
Immunological Reviews 03/2007; 215:32-45. · 11.15 Impact Factor
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ABSTRACT: Morphogens, a class of secreted proteins that regulate gene expression in a concentration-dependent manner, are responsible for directing nearly all lineage fate choices during embryogenesis. In the thymus, morphogen signal pathways consisting of WNT, Hedgehog, and the transforming growth factor-β superfamily are active and have been implicated in various developmental processes including proliferation, survival, and differentiation of maturing thymocytes. Intriguingly, it has been inferred that some of these morphogen signal pathways differentially affect γδ and αβ T-cell development or maintenance, but their role in T-cell lineage commitment has not been directly probed. We have recently identified a modulator of morphogen signaling that significantly influences binary γδ versus αβ T-cell lineage diversification. In this review, we summarize functions of morphogens in the thymus and provide a highly speculative model of integrated morphogen signals, potentially directing the γδ versus αβ T-cell fate determination process.
Immunological Reviews 02/2007; 215(1):32 - 45. · 11.15 Impact Factor
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ABSTRACT: alphabeta and gammadelta T cells originate from a common, multipotential precursor population in the thymus, but the molecular mechanisms regulating this lineage-fate decision are unknown. We have identified Sox13 as a gammadelta-specific gene in the immune system. Using Sox13 transgenic mice, we showed that this transcription factor promotes gammadelta T cell development while opposing alphabeta T cell differentiation. Conversely, mice deficient in Sox13 expression exhibited impaired development of gammadelta T cells but not alphabeta T cells. One mechanism of SOX13 function is the inhibition of signaling by the developmentally important Wnt/T cell factor (TCF) pathway. Our data thus reveal a dominant pathway regulating the developmental fate of these two lineages of T lymphocytes.
Science 02/2007; 315(5809):230-3. · 31.20 Impact Factor
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ABSTRACT: The gammadelta T cells are prevalent in the mucosal epithelia and are postulated to act as 'sentries' for maintaining tissue integrity. What these gammadelta T cells recognize is poorly defined, but given the restricted T cell receptor (TCR) repertoire, the idea that they are selected by self antigens of low complexity has been widely disseminated. Here we present data showing that the generation of the restricted TCR variable gamma-region gene repertoire of intestinal intraepithelial lymphocytes was regulated by interleukin 15, which induced local chromatin modifications specific for the variable gamma-region gene segment and enhanced accessibility conducive to subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation probably reflects distinct TCR repertoire selection criteria for gammadelta and alphabeta T cell lineages adopted for different antigen-recognition strategies.
Nature Immunology 01/2006; 6(12):1263-71. · 26.01 Impact Factor
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ABSTRACT: Two models have been considered to account for the differentiation of γδ and αβ T cells from a common hematopoietic progenitor cell. In one model, progenitor cells commit to a lineage before T cell receptor (TCR) rearrangement occurs. In the other model, progenitor cells first undergo rearrangement of TCRγ, δ, or both genes, and cells that succeed in generating a functional receptor commit to the γδ lineage, while those that do not proceed to attempt complete β and subsequently α gene rearrangements. A prediction of the latter model is that TCRγ rearrangements present in αβ T cells will be nonproductive. We tested this hypothesis by examining Vγ2-Jγ1Cγ1 rearrangements, which are commonly found in αβ T cells. The results indicate that Vγ2-Jγ1Cγ1 rearrangements in purified αβ T cell populations are almost all nonproductive. The low frequency of productive rearrangements of Vγ2 in αβ T cells is apparently not due to a property of the rearrangement machinery, because a transgenic rearrangement substrate, in which the Vγ2 gene harbored a frame-shift mutation that prevents expression at the protein level, was often rearranged in a productive configuration in αβ T cells. The results suggest that progenitor cells which undergo productive rearrangement of their endogenous Vγ2 gene are selectively excluded from the αβ T cell lineage.
European Journal of Immunology 11/2005; 25(9):2706 - 2709. · 5.10 Impact Factor
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ABSTRACT: Diverse cytokines necessary for normal lymphopoiesis and lymphocyte homeostasis activate STAT5 in responder cells. Although STAT5 has been suggested to be a central molecular effecter of IL-7 function, its essential role during IL-7-dependent T cell development in vivo remained unclear. Using Stat5(-/-) mice we now show that STAT5 is essential for various functions ascribed to IL-7 in vivo. STAT5 is required for embryonic thymocyte production, TCRgamma gene transcription, and Peyer's patch development. In sharp contrast, normal STAT5 is dispensable for adult thymopoiesis. In peripheral lymphocytes, STAT5 is primarily required for the generation and/or maintenance of gammadelta T cells and TCRgammadelta(+) intraepithelial lymphocytes. Collectively, these results demonstrate that STAT5 is critical for many, but not all, aspects of steady state lymphoid lineage development and maintenance and suggest the existence of previously undocumented cytokine signaling traits and/or cytokine milieu during adult thymopoiesis.
The Journal of Immunology 09/2004; 173(4):2307-14. · 5.79 Impact Factor
