The Role of the Basic Helix-Loop-Helix Transcription Factor Dec1 in the Regulatory T Cells

Naturally occurring regulatory T (Treg) cells play a central role in the maintenance of immune homeostasis and in restraining the development of spontaneous inflammatory responses. However, the underlying mechanisms of Treg homeostasis remain incompletely understood. Of particular note, the IL-2Rα (CD25) is crucial for the homeostasis of Treg cells and the prevention of lymphoproliferative autoimmune disease. In this paper, we report that the basic helix-loop-helix transcription factor Dec1 is involved in the homeostasis of Treg cells and plays a role in their survival or expansion after adoptive transfer to lymphopenic recipients. Hence, it is crucial for the suppression of effector T cell-mediated inflammatory responses. Enforced expression of Dec1 upregulates CD25 expression during thymocyte development and increases the number of Treg cells in the periphery. Dec1 binds the transcription factor Runx1 and colocalizes with Runx1 in Treg cells. Specifically, we demonstrate that in Treg cells the Dec1/Runx1 complex binds to regulatory elements present in the Il-2rα locus. Collectively, these data show how Dec1 mechanistically acts in Treg cells.

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

[2]  T. Nomura,et al.  Indispensable role of the Runx1-Cbfbeta transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells. , 2009, Immunity.

[3]  R. Nurieva,et al.  Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment , 2009, Nature Immunology.

[4]  A. Rudensky,et al.  Control of regulatory T cell lineage commitment and maintenance. , 2009, Immunity.

[5]  E. Shevach.  Mechanisms of foxp3+ T regulatory cell-mediated suppression. , 2009, Immunity.

[6]  B. Malissen,et al.  Heterogeneity of natural Foxp3+ T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity , 2009, Proceedings of the National Academy of Sciences.

[7]  D. Littman,et al.  RUNX proteins in transcription factor networks that regulate T-cell lineage choice , 2009, Nature Reviews Immunology.

[8]  Tadashi Tsubota,et al.  Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts , 2008, Nature Cell Biology.

[9]  G. Mayrhofer,et al.  Recent thymic origin, differentiation, and turnover of regulatory T cells , 2008, Journal of leukocyte biology.

[10]  T. Nomura,et al.  CTLA-4 Control over Foxp3+ Regulatory T Cell Function , 2008, Science.

[11]  G. Eichele,et al.  Disturbed Clockwork Resetting in Sharp-1 and Sharp-2 Single and Double Mutant Mice , 2008, PloS one.

[12]  T. Nomura,et al.  Regulatory T Cells and Immune Tolerance , 2008, Cell.

[13]  H. Kawamoto,et al.  Thymocyte proliferation induced by pre-T cell receptor signaling is maintained through polycomb gene product Bmi-1-mediated Cdkn2a repression. , 2008, Immunity.

[14]  C. Hsieh,et al.  A two-step process for thymic regulatory T cell development. , 2008, Immunity.

[15]  S. Ishihara,et al.  CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells , 2007, Nature Immunology.

[16]  R. E. Tillman,et al.  The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells , 2007, The Journal of experimental medicine.

[17]  L. Hennighausen,et al.  Nonredundant roles for Stat5a/b in directly regulating Foxp3. , 2007, Blood.

[18]  T. Nomura,et al.  Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1 , 2007, Nature.

[19]  T. Chatila,et al.  Regulatory T cell development in the absence of functional Foxp3 , 2007, Nature Immunology.

[20]  A. Rudensky,et al.  Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3 , 2007, Nature Immunology.

[21]  Edgar Schmitt,et al.  Epigenetic Control of the foxp3 Locus in Regulatory T Cells , 2007, PLoS biology.

[22]  M. Farrar,et al.  IL-2 Receptor β-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells1 , 2007, The Journal of Immunology.

[23]  Jean Imbert,et al.  Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. , 2006, Cytokine & growth factor reviews.

[24]  Shimon Sakaguchi,et al.  Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease , 2006, Immunological reviews.

[25]  Isaac Engel,et al.  Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[28]  A. Rudensky,et al.  A function for interleukin 2 in Foxp3-expressing regulatory T cells , 2005, Nature Immunology.

[29]  A. Rudensky,et al.  TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells , 2005, The Journal of experimental medicine.

[30]  Shimon Sakaguchi,et al.  Homeostatic maintenance of natural Foxp3 + CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization , 2005, The Journal of experimental medicine.

[31]  A. Chiocchetti,et al.  Role of inherited defects decreasing Fas function in autoimmunity. , 2003, Life sciences.

[32]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

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

[34]  T. Kawamoto,et al.  Identification of Functional Hypoxia Response Elements in the Promoter Region of the DEC1 and DEC2 Genes* , 2002, The Journal of Biological Chemistry.

[35]  S. Egan,et al.  Stra13 Homodimers Repress Transcription through Class B E-box Elements* , 2002, The Journal of Biological Chemistry.

[36]  T. Kawamoto,et al.  Dec1 and Dec2 are regulators of the mammalian molecular clock , 2002, Nature.

[37]  J. Lafaille,et al.  Interleukin 2 Signaling Is Required for CD4+ Regulatory T Cell Function , 2002, The Journal of experimental medicine.

[38]  K. Kinzler,et al.  DEC1 is a downstream target of TGF-β with sequence-specific transcriptional repressor activities , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Flavell,et al.  Defective T cell activation and autoimmune disorder in Stra13-deficient mice , 2001, Nature Immunology.

[40]  S. Ito,et al.  Overexpression of AML1 renders a T hybridoma resistant to T cell receptor-mediated apoptosis , 1998, Oncogene.

[41]  P. Chambon,et al.  Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix-loop-helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells. , 1997, Genes & development.

[42]  H. Dadi,et al.  Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor , 1997 .

[43]  M. Nehls,et al.  Identification of interaction partners for the basic-helix – loop – helix protein E47 , 1997, Oncogene.

[44]  H. Weintraub,et al.  Specificity for the hairy/enhancer of split basic helix-loop-helix (bHLH) proteins maps outside the bHLH domain and suggests two separable modes of transcriptional repression , 1995, Molecular and cellular biology.

[45]  F. Alt,et al.  Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. , 1995, Immunity.

[46]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[47]  N. Copeland,et al.  Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis , 1992, Nature.

[48]  F. Ruscetti.  Biology of interleukin-2 , 1984, Survey of immunologic research.

[49]  鬼頭 昭彦.  Indispensable role of the Runx1-Cbfβ transcription complex for in vivo-suppressive function of FoxP3[+] regulatory T cells , 2010 .

[50]  H. Aburatani,et al.  Transforming growth factor-beta promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1. , 2007, Cancer research.

[51]  Supporting Online Material , 2002 .