The transcriptional repressor HIC1 regulates intestinal immune homeostasis

The intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T-cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T-cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

[1]  J. Lukas,et al.  HIC1 attenuates Wnt signaling by recruitment of TCF‐4 and β‐catenin to the nuclear bodies , 2006, The EMBO journal.

[2]  S. Rutz,et al.  Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells , 2014, Nature.

[3]  P. Chambon,et al.  Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. , 2008, Immunity.

[4]  Charlotte L. Scott,et al.  Intestinal CD103+ dendritic cells: master regulators of tolerance? , 2011, Trends in immunology.

[5]  D. Leprince,et al.  Generation of two modified mouse alleles of the Hic1 tumor suppressor gene , 2011, Genesis.

[6]  W. Leonard,et al.  Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells , 2015, Proceedings of the National Academy of Sciences.

[7]  William W. Agace,et al.  Functional specialization of gut CD103 dendritic cells in the regulation of tissue-selective T cell homing , 2005 .

[8]  Subhashis Banerjee,et al.  Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. , 2012, The New England journal of medicine.

[9]  J. Bluestone,et al.  Control of TH17 cells occurs in the Small Intestine , 2011, Nature.

[10]  P. D. Smith,et al.  Intestinal macrophages and response to microbial encroachment , 2011, Mucosal Immunology.

[11]  C. Bain,et al.  Macrophages in intestinal homeostasis and inflammation , 2014, Immunological reviews.

[12]  R. Nurieva,et al.  Bcl6 Mediates the Development of T Follicular Helper Cells , 2009, Science.

[13]  A. Shen,et al.  Interferon gamma (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription , 2011, Nucleic acids research.

[14]  S. Fagarasan Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. , 2006, Current topics in microbiology and immunology.

[15]  A. Regev,et al.  Induction and molecular signature of pathogenic TH17 cells , 2012, Nature Immunology.

[16]  D. Leprince,et al.  Deciphering HIC1 control pathways to reveal new avenues in cancer therapeutics , 2013, Expert opinion on therapeutic targets.

[17]  R. Proia,et al.  Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 , 2004, Nature.

[18]  Gisen Kim,et al.  Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. , 2009, Immunity.

[19]  F. Annunziato,et al.  The 3 major types of innate and adaptive cell-mediated effector immunity. , 2015, The Journal of allergy and clinical immunology.

[20]  B. Chassaing,et al.  Dextran Sulfate Sodium (DSS)‐Induced Colitis in Mice , 2014, Current protocols in immunology.

[21]  Xiao Han,et al.  HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer. , 2016, Cancer letters.

[22]  J. Daniel,et al.  POZ for effect--POZ-ZF transcription factors in cancer and development. , 2006, Trends in cell biology.

[23]  J. Herman,et al.  Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors , 2003, Nature Genetics.

[24]  Russell G. Jones,et al.  Enhancing CD8 T-cell memory by modulating fatty acid metabolism , 2009, Nature.

[25]  D. Leprince,et al.  Hypermethylated in Cancer 1 (HIC1) Recruits Polycomb Repressive Complex 2 (PRC2) to a Subset of Its Target Genes through Interaction with Human Polycomb-like (hPCL) Proteins* , 2012, The Journal of Biological Chemistry.

[26]  J. O’Shea,et al.  Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. , 2010, Immunity.

[27]  R. Noelle,et al.  Seeing through the dark: New insights into the immune regulatory functions of vitamin A , 2015, European journal of immunology.

[28]  V. Laudet,et al.  Genome-wide in Silico Identification of New Conserved and Functional Retinoic Acid Receptor Response Elements (Direct Repeats Separated by 5 bp)* , 2011, The Journal of Biological Chemistry.

[29]  T. Mcclanahan,et al.  Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. , 2015, Immunity.

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

[31]  Graham M Lord,et al.  Retinoic Acid Is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program , 2015, Immunity.

[32]  P. Puigserver,et al.  Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α , 2007, The EMBO journal.

[33]  W. Paul,et al.  Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells , 2008, Nature Immunology.

[34]  C. Elson,et al.  Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. , 1994, Gastroenterology.

[35]  Marc Vandemeulebroecke,et al.  Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial , 2012, Gut.

[36]  E. Podack,et al.  Defining the roles of perforin, Fas/FasL, and tumour necrosis factor α in T cell induced mucosal damage in the mouse intestine , 2002, Gut.

[37]  J. Ortonne,et al.  Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. , 2012, The New England journal of medicine.

[38]  S. Targan,et al.  Mo2083 A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 827 in Subjects With Moderate to Severe Crohn's Disease , 2012 .

[39]  G. V. D. Windt,et al.  Metabolic switching and fuel choice during T‐cell differentiation and memory development , 2012, Immunological reviews.

[40]  S. Kang,et al.  Complementary roles of retinoic acid and TGF-β1 in coordinated expression of mucosal integrins by T cells , 2010, Mucosal Immunology.

[41]  T. Mcclanahan,et al.  TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology , 2007, Nature Immunology.

[42]  O. Lantz,et al.  The transcription factor PLZF directs the effector program of the NKT cell lineage. , 2008, Immunity.

[43]  M. Genovese,et al.  LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. , 2010, Arthritis and rheumatism.

[44]  F. Powrie,et al.  Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells , 2010, Immunity.

[45]  C. Elson,et al.  Adaptive immunity in the host–microbiota dialog , 2011, Mucosal Immunology.

[46]  Erin Stevens,et al.  Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. , 2015, Immunity.

[47]  Hiroshi Kawamoto,et al.  Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate , 2008, Nature Immunology.

[48]  D. Leprince,et al.  Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells , 2010, Molecular and Cellular Biology.

[49]  Si-young Song,et al.  Retinoic acid imprints gut-homing specificity on T cells. , 2004, Immunity.

[50]  L. Staudt,et al.  BCL-6 expression during B-cell activation. , 1996, Blood.

[51]  S. Jameson,et al.  Transcriptional downregulation of S1pr1 is required for establishment of resident memory CD8+ T cells , 2013, Nature Immunology.

[52]  R. Caspi,et al.  Faculty Opinions recommendation of Fate mapping of IL-17-producing T cells in inflammatory responses. , 2011 .

[53]  S. Baylin,et al.  p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3 , 1995, Nature Genetics.

[54]  M. Lazar,et al.  Activation of retinoic acid receptor‐α favours regulatory T cell induction at the expense of IL‐17‐secreting T helper cell differentiation , 2007, European journal of immunology.

[55]  Sung-Uk Lee,et al.  POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function , 2012, Immunological reviews.

[56]  D. Beier,et al.  Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. , 1999, Journal of immunology.

[57]  D. Leprince,et al.  Molecular dissection of the interaction between HIC1 and SIRT1. , 2012, Biochemical and biophysical research communications.

[58]  D. Leprince,et al.  HIC1 interacts with and modulates the activity of STAT3 , 2013, Cell cycle.

[59]  R. Coffman,et al.  Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. , 1993, International immunology.

[60]  Dan R. Littman,et al.  Th17 and Regulatory T Cells in Mediating and Restraining Inflammation , 2010, Cell.

[61]  S. Baylin,et al.  Tumor Suppressor HIC1 Directly Regulates SIRT1 to Modulate p53-Dependent DNA-Damage Responses , 2005, Cell.

[62]  Y. Belkaid,et al.  Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. , 2011, Immunity.

[63]  Hilde Cheroutre,et al.  The light and dark sides of intestinal intraepithelial lymphocytes , 2011, Nature Reviews Immunology.