Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced Treg differentiation via up-regulating Nr4a2

Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. While SRC1 inhibits the differentiation of regulatory T cells (Tregs) critical for establishing immune tolerance, we show here that SRC2 stimulates Treg differentiation. SRC2 is dispensable for the development of thymic Tregs, whereas naive CD4+ T cells from mice deficient of SRC2 specific in Tregs (SRC2fl/fl/Foxp3YFP-Cre) display defective Treg differentiation. Furthermore, the aged SRC2fl/fl/Foxp3YFP-Cre mice spontaneously develop autoimmune phenotypes including enlarged spleen and lung inflammation infiltrated with IFNγ-producing CD4+ T cells. SRC2fl/fl/Foxp3YFP-Cre mice also develop severer experimental autoimmune encephalomyelitis (EAE) due to reduced Tregs. Mechanically, SRC2 recruited by NFAT1 binds to the promoter and activates the expression of Nr4a2, which then stimulates Foxp3 expression to promote Treg differentiation. Members of SRC family coactivators thus play distinct roles in Treg differentiation and are potential drug targets for controlling immune tolerance.

[1]  N. McKenna,et al.  Steroid receptor coactivator 3 (SRC-3/AIB1) is enriched and functional in mouse and human Tregs , 2021, Scientific Reports.

[2]  N. Labrecque,et al.  Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology , 2021, Frontiers in Endocrinology.

[3]  Mark S. Sundrud,et al.  Genetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 driven inflammatory disorders , 2021, Nature Communications.

[4]  D. Bending,et al.  Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration , 2020, Cell reports.

[5]  B. O’Malley.  SRC-2 Coactivator: a role in human metabolic evolution and disease , 2020, Molecular medicine.

[6]  Hiroki Ishikawa,et al.  Transcriptional Regulation of Differentiation and Functions of Effector T Regulatory Cells , 2019, Cells.

[7]  Y. Gwack,et al.  SRC3 Is a Cofactor for RORγt in Th17 Differentiation but Not Thymocyte Development , 2019, The Journal of Immunology.

[8]  H. Nishikawa,et al.  Regulatory T cells in cancer immunosuppression — implications for anticancer therapy , 2019, Nature Reviews Clinical Oncology.

[9]  C. Leslie,et al.  Transcription factor Foxp1 regulates Foxp3 chromatin binding and coordinates regulatory T cell function , 2019, Nature Immunology.

[10]  A. Yoshimura,et al.  Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3. , 2018, Cell reports.

[11]  Y. Gwack,et al.  SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate RORγt activity in a PKC-θ–dependent manner , 2017, Proceedings of the National Academy of Sciences.

[12]  S. Zheng,et al.  A protocol to develop T helper and Treg cells in vivo , 2017, Cellular & Molecular Immunology.

[13]  Kathryn A. O’Donnell,et al.  SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer , 2017, PLoS genetics.

[14]  S. Sakaguchi,et al.  Regulatory T cells in cancer immunotherapy , 2016, Cell Research.

[15]  B. O’Malley,et al.  Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3 , 2016, Proceedings of the National Academy of Sciences.

[16]  R. Morita,et al.  Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells , 2015, The Journal of experimental medicine.

[17]  N. Fazilleau,et al.  Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors , 2015, Nature Immunology.

[18]  I. Rogatsky,et al.  Minireview: nuclear receptor coregulators of the p160 family: insights into inflammation and metabolism. , 2015, Molecular endocrinology.

[19]  C. Benner,et al.  Function of a Foxp3 cis-Element in Protecting Regulatory T Cell Identity , 2014, Cell.

[20]  D. Metzger,et al.  Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons , 2014, Neuroscience Letters.

[21]  I. Rogatsky,et al.  Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids , 2012, Proceedings of the National Academy of Sciences.

[22]  Zuoming Sun,et al.  Protein Kinase C-θ Inhibits Inducible Regulatory T Cell Differentiation via an AKT-Foxo1/3a–Dependent Pathway , 2012, The Journal of Immunology.

[23]  Jianming Xu,et al.  The Function of Steroid Receptor Coactivator-1 in Normal Tissues and Cancer , 2012, International journal of biological sciences.

[24]  V. Dixit,et al.  Signaling in innate immunity and inflammation. , 2012, Cold Spring Harbor perspectives in biology.

[25]  B. O’Malley,et al.  Steroid receptor coactivators 1, 2, and 3: Critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy , 2012, Molecular and Cellular Endocrinology.

[26]  P. Krammer,et al.  Molecular Mechanisms of Treg-Mediated T Cell Suppression , 2012, Front. Immun..

[27]  B. O’Malley,et al.  Small molecule inhibition of the steroid receptor coactivators, SRC-3 and SRC-1. , 2011, Molecular endocrinology.

[28]  Daniel Metzger,et al.  The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells , 2011, Nature communications.

[29]  David Baltimore,et al.  Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses , 2010, Cell.

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

[31]  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.

[32]  D. Vignali,et al.  How regulatory T cells work , 2008, Nature Reviews Immunology.

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

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

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

[36]  M. Farrar,et al.  Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. , 2008, Immunity.

[37]  Y. Shang,et al.  Regulation of SRC family coactivators by post-translational modifications. , 2007, Cellular signalling.

[38]  K. Honda,et al.  Type I Inteferon Gene Induction by the Interferon Regulatory Factor Family of Transcription Factors , 2006 .

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

[40]  D. Tatomer,et al.  Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression. , 2006, Molecular cell.

[41]  Xiaoyu Hu,et al.  The GRIP1:IRF3 interaction as a target for glucocorticoid receptor‐mediated immunosuppression , 2006, The EMBO journal.

[42]  K. Yamamoto,et al.  Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Yamamoto,et al.  Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase‐3 response element that mediates regulation by phorbol esters and hormones , 2001, The EMBO journal.

[44]  J. Gustafsson,et al.  Estradiol repression of tumor necrosis factor-alpha transcription requires estrogen receptor activation function-2 and is enhanced by coactivators. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Casanova,et al.  X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy , 2001, Nature Genetics.

[46]  H. Ochs,et al.  The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 , 2001, Nature Genetics.

[47]  D. Galas,et al.  Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse , 2001, Nature Genetics.