Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3

The molecular mechanisms that direct transcription of the gene encoding the transcription factor Foxp3 in CD4+ T cells remain ill-defined. We show here that deletion of the DNA-binding inhibitor Id3 resulted in the defective generation of Foxp3+ regulatory T cells (Treg cells). We identify two transforming growth factor-β1 (TGF-β1)-dependent mechanisms that were vital for activation of Foxp3 transcription and were defective in Id3−/− CD4+ T cells. Enhanced binding of the transcription factor E2A to the Foxp3 promoter promoted Foxp3 transcription. Id3 was required for relief of inhibition by the transcription factor GATA-3 at the Foxp3 promoter. Furthermore, Id3−/− T cells showed greater differentiation into the TH17 subset of helper T cells in vitro and in a mouse asthma model. Therefore, a network of factors acts in a TGF-β-dependent manner to control Foxp3 expression and inhibit the development of TH17 cells.

[1]  Chen Dong,et al.  Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. , 2008, Immunity.

[2]  C. Murre,et al.  Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. , 2000, Immunity.

[3]  G. Wang,et al.  Intron‐1 rs3761548 is related to the defective transcription of Foxp3 in psoriasis through abrogating E47/c‐Myb binding , 2010, Journal of cellular and molecular medicine.

[4]  Y. Zhuang,et al.  E2A and HEB Are Required to Block Thymocyte Proliferation Prior to Pre-TCR Expression1 , 2007, The Journal of Immunology.

[5]  M. Noris,et al.  Natural versus adaptive regulatory T cells. , 2005, Contributions to nephrology.

[6]  M. Nussenzweig,et al.  Inducing and expanding regulatory T cell populations by foreign antigen , 2005, Nature Immunology.

[7]  CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation , 2007, The Journal of Experimental Medicine.

[8]  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.

[9]  D. Baltimore,et al.  An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers , 1991, Cell.

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

[11]  Y. Zhuang,et al.  A T cell intrinsic role of Id3 in a mouse model for primary Sjogren's syndrome. , 2004, Immunity.

[12]  Hiroshi Kawamoto,et al.  E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment , 2006, The Journal of experimental medicine.

[13]  Y. Belkaid,et al.  Regulatory T cells in the control of host-microorganism interactions (*). , 2009, Annual review of immunology.

[14]  A. Rudensky,et al.  Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells , 2009, Nature Immunology.

[15]  C. Benoist,et al.  Treg cells: guardians for life , 2007, Nature Immunology.

[16]  K. Furuuchi,et al.  Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer , 2008, Nature Immunology.

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

[18]  M. A. Curotto de Lafaille,et al.  Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? , 2009, Immunity.

[19]  M. Greene,et al.  Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. , 2009, Immunity.

[20]  H. Boehmer,et al.  Mechanisms of suppression by suppressor T cells , 2005, Nature Immunology.

[21]  B. Ryffel,et al.  Interleukin-17 is a negative regulator of established allergic asthma , 2006, The Journal of experimental medicine.

[22]  A. Pierani,et al.  Requirement for RORgamma in thymocyte survival and lymphoid organ development. , 2000, Science.

[23]  C. Murre.  Helix-loop-helix proteins and lymphocyte development , 2005, Nature Immunology.

[24]  K. Kretschmer,et al.  Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines , 2009, The Journal of experimental medicine.

[25]  C. Peschle,et al.  Chromatin immunoselection defines a TAL‐1 target gene , 1998, The EMBO journal.

[26]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[27]  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.

[28]  A. Kulkarni,et al.  A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells , 2008, Nature Immunology.

[29]  R. Flavell,et al.  Cutting Edge: TGF-β Inhibits Th Type 2 Development Through Inhibition of GATA-3 Expression , 2000, The Journal of Immunology.

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

[31]  A. Rudensky,et al.  A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3 , 2005, Nature Immunology.

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

[33]  Y. Wan,et al.  Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Ethan M. Shevach,et al.  CD4+CD25+ suppressor T cells: more questions than answers , 2002, Nature Reviews Immunology.

[35]  H. Waldmann,et al.  Infectious tolerance and the long‐term acceptance of transplanted tissue , 2006, Immunological reviews.

[36]  S. Sakaguchi.  Regulatory T cells , 2006, Springer Seminars in Immunopathology.

[37]  J. Bluestone,et al.  Lethal Effect of CD3-Specific Antibody in Mice Deficient in TGF-β1 by Uncontrolled Flu-Like Syndrome1 , 2009, The Journal of Immunology.

[38]  I. Ghosh,et al.  DNA binding properties of basic helix-loop-helix fusion proteins of Tal and E47. , 2001, The journal of peptide research : official journal of the American Peptide Society.

[39]  J. Bluestone,et al.  CD3-specific antibody–induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells , 2008, Nature Medicine.

[40]  Y. Zhuang,et al.  A tamoxifen inducible knock-in allele for investigation of E2A function , 2009, BMC Developmental Biology.

[41]  C. Murre,et al.  Interplay between RORgammat, Egr3, and E proteins controls proliferation in response to pre-TCR signals. , 2006, Immunity.

[42]  Christopher Anderson,et al.  More questions than answers , 1991, Nature.

[43]  C. Murre,et al.  Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-β , 2001, Nature Immunology.

[44]  I. Homma,et al.  Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. , 2002, Immunity.

[45]  C. Heldin,et al.  Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling , 1997, Nature.

[46]  Y. Belkaid,et al.  Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells , 2010, The Journal of Immunology.

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

[48]  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.

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

[50]  H. Weiner,et al.  Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor , 2008, Nature.

[51]  B. Lambrecht,et al.  GATA3-Driven Th2 Responses Inhibit TGF-β1–Induced FOXP3 Expression and the Formation of Regulatory T Cells , 2007, PLoS biology.