Down-regulation of Gfi-1 expression by TGF-β is important for differentiation of Th17 and CD103+ inducible regulatory T cells

Growth factor independent 1 (Gfi-1), a transcriptional repressor, is transiently induced during T cell activation. Interleukin (IL) 4 further induces Gfi-1, resulting in optimal Th2 cell expansion. We report a second important function of Gfi-1 in CD4 T cells: prevention of alternative differentiation by Th2 cells, and inhibition of differentiation of naive CD4 T cells to either Th17 or inducible regulatory T (iTreg) cells. In Gfi1−/− Th2 cells, the Rorc, Il23r, and Cd103 loci showed histone 3 lysine 4 trimethylation modifications that were lacking in wild-type Th2 cells, implying that Gfi-1 is critical for epigenetic regulation of Th17 and iTreg cell–related genes in Th2 cells. Enforced Gfi-1 expression inhibited IL-17 production and iTreg cell differentiation. Furthermore, a key inducer of both Th17 and iTreg cell differentiation, transforming growth factor β, repressed Gfi-1 expression, implying a reciprocal negative regulation of CD4 T cell fate determination. Chromatin immunoprecipitation showed direct binding of the Gfi-1–lysine-specific demethylase 1 repressive complex to the intergenic region of Il17a/Il17f loci and to intron 1 of Cd103. T cell–specific Gfi1 conditional knockout mice displayed a striking delay in the onset of experimental allergic encephalitis correlated with a dramatic increase of Foxp3+CD103+ CD4 T cells. Thus, Gfi-1 plays a critical role both in enhancing Th2 cell expansion and in repressing induction of Th17 and CD103+ iTreg cells.

[1]  W. Paul,et al.  CD4 T cells: fates, functions, and faults. , 2008, Blood.

[2]  T. Hubbard,et al.  Large-Scale Mutagenesis in p19ARF- and p53-Deficient Mice Identifies Cancer Genes and Their Collaborative Networks , 2008, Cell.

[3]  Yuelei Shen,et al.  TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function , 2008, Nature.

[4]  D. Glass,et al.  Autoantigen-Specific TGFβ-Induced Foxp3+ Regulatory T Cells Prevent Autoimmunity by Inhibiting Dendritic Cells from Activating Autoreactive T Cells1 , 2007, The Journal of Immunology.

[5]  Jonghwan Kim,et al.  Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. , 2007, Molecular cell.

[6]  E. Shevach,et al.  Distinct Subsets of FoxP3 Regulatory T Cells Participate in the Control of Immune Responses , 2007 .

[7]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[8]  E. Shevach,et al.  Cutting Edge: IL-2 Is Essential for TGF-β-Mediated Induction of Foxp3+ T Regulatory Cells , 2007, The Journal of Immunology.

[9]  L. Hennighausen,et al.  Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. , 2007, Immunity.

[10]  R. D. Hatton,et al.  IL-17 family cytokines and the expanding diversity of effector T cell lineages. , 2007, Annual review of immunology.

[11]  Dragana Jankovic,et al.  Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion , 2006, Proceedings of the National Academy of Sciences.

[12]  R. J. Hocking,et al.  Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease , 2006, Nature Immunology.

[13]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[14]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[15]  R. D. Hatton,et al.  Transforming growth factor-β induces development of the TH17 lineage , 2006, Nature.

[16]  Y. Belkaid,et al.  Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens , 2006, The Journal of experimental medicine.

[17]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[18]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[19]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[20]  R. Geffers,et al.  The transcriptional repressor Gfi1 controls STAT3-dependent dendritic cell development and function. , 2005, Immunity.

[21]  S. Sakaguchi.  Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self , 2005, Nature Immunology.

[22]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[23]  Booki Min,et al.  Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses , 2004, Nature Immunology.

[24]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[25]  Hui Zeng,et al.  Transcription factor Gfi1 regulates self‐renewal and engraftment of hematopoietic stem cells , 2004, The EMBO journal.

[26]  T. Möröy,et al.  Gfi1:Green Fluorescent Protein Knock-in Mutant Reveals Differential Expression and Autoregulation of the Growth Factor Independence 1 (Gfi1) Gene during Lymphocyte Development* , 2004, Journal of Biological Chemistry.

[27]  W. Paul,et al.  Interleukin 2 plays a central role in Th2 differentiation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Pai,et al.  GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  H. Nawata,et al.  TGF-β1 Plays an Important Role in the Mechanism of CD4+CD25+ Regulatory T Cell Activity in Both Humans and Mice , 2004, The Journal of Immunology.

[30]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[31]  W. Paul,et al.  Stat5 activation plays a critical role in Th2 differentiation. , 2003, Immunity.

[32]  F. Powrie,et al.  Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells1 , 2003, The Journal of Immunology.

[33]  T. Möröy,et al.  The Transcriptional Repressor Gfi1 Affects Development of Early, Uncommitted c-Kit+ T Cell Progenitors and CD4/CD8 Lineage Decision in the Thymus , 2003, The Journal of experimental medicine.

[34]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[35]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2003 .

[36]  Kenneth M. Murphy,et al.  Decision making in the immune system: The lineage decisions of helper T cells , 2002, Nature Reviews Immunology.

[37]  Booki Min,et al.  Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. , 2002, Immunity.

[38]  T. Möröy,et al.  High levels of the onco-protein Gfi-1 accelerate T-cell proliferation and inhibit activation induced T-cell death in Jurkat T-cells , 2002, Oncogene.

[39]  Hui Zeng,et al.  Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1 , 2002, Nature Genetics.

[40]  A. Sher,et al.  T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  W. Paul,et al.  Stat6 Is Necessary and Sufficient for IL-4’s Role in Th2 Differentiation and Cell Expansion , 2001, The Journal of Immunology.

[42]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[43]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[44]  A. Ray,et al.  Transcription Factor GATA-3 Is Differentially Expressed in Murine Th1 and Th2 Cells and Controls Th2-specific Expression of the Interleukin-5 Gene* , 1997, The Journal of Biological Chemistry.

[45]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[46]  J. Jonkers,et al.  Characterization of pal-1, a common proviral insertion site in murine leukemia virus-induced lymphomas of c-myc and Pim-1 transgenic mice , 1997, Journal of virology.

[47]  P. Tsichlis,et al.  Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor , 1996, Molecular and cellular biology.

[48]  M. Kaplan,et al.  Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice , 1996, Nature.

[49]  P. Doherty,et al.  Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells , 1996, Nature.

[50]  W. Paul,et al.  Lymphocyte responses and cytokines , 1994, Cell.

[51]  A. Sher,et al.  Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[52]  C. Hsieh,et al.  Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. , 1993, Science.

[53]  C. Gilks,et al.  Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein , 1993, Molecular and cellular biology.

[54]  A. Weinberg,et al.  IL-4 directs the development of Th2-like helper effectors. , 1990, Journal of immunology.

[55]  W. Paul,et al.  Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4- producing cells , 1990, The Journal of experimental medicine.

[56]  R. D. Hatton,et al.  Transforming growth factor-beta induces development of the T(H)17 lineage. , 2006, Nature.

[57]  R. Geffers,et al.  The Transcriptional Repressor Gfi 1 Controls STAT 3-Dependent Dendritic Cell Development and Function , 2005 .

[58]  A. Rudensky,et al.  Foxp 3 programs the development and function of CD 4 + CD 25 + regulatory T cells , 2003 .

[59]  Scott Cameron,et al.  Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. , 2003, Immunity.

[60]  Andreas Radbruch,et al.  Regulation of expression of IL-4 alleles: analysis using a chimeric GFP/IL-4 gene. , 2001, Immunity.

[61]  A. Sher,et al.  T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. , 2001, Proceedings of the National Academy of Sciences of the United States of America.