Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ–JAK1/2–STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus–infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.

[1]  B. Vervliet,et al.  The role of short-chain fatty acids in microbiota–gut–brain communication , 2019, Nature Reviews Gastroenterology & Hepatology.

[2]  Ruxolitinib , 2019, Reactions Weekly.

[3]  J. Karrich,et al.  IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine , 2018, Mucosal Immunology.

[4]  W. Ellmeier,et al.  Histone deacetylase function in CD4+ T cells , 2018, Nature Reviews Immunology.

[5]  S. Forman,et al.  Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. , 2018, JCI insight.

[6]  Jishnu Das,et al.  The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes , 2018, eLife.

[7]  Bjoern Peters,et al.  Precursors of human CD4+ cytotoxic T lymphocytes identified by single-cell transcriptome analysis , 2018, Science Immunology.

[8]  Ying Hu,et al.  TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance , 2017, Science Translational Medicine.

[9]  J. O’Shea,et al.  JAK inhibition as a therapeutic strategy for immune and inflammatory diseases , 2017, Nature Reviews Drug Discovery.

[10]  A. Rosato,et al.  Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells , 2017, Front. Immunol..

[11]  Takashi Saito,et al.  CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function , 2017, Front. Immunol..

[12]  S. Kent,et al.  Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection? , 2017, Front. Immunol..

[13]  S. Nutt,et al.  Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus , 2016, Cell reports.

[14]  H. M. Silva,et al.  Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation , 2016, Science.

[15]  M. Kubo,et al.  CRTAM determines the CD4+ cytotoxic T lymphocyte lineage , 2016, The Journal of experimental medicine.

[16]  J. Mesirov,et al.  The Molecular Signatures Database Hallmark Gene Set Collection , 2015 .

[17]  Bjoern Peters,et al.  Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection , 2015, Journal of Virology.

[18]  W. Ellmeier.  Molecular control of CD4(+) T cell lineage plasticity and integrity. , 2015, International immunopharmacology.

[19]  S. Grivennikov,et al.  Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. , 2014, Immunity.

[20]  R. Johnstone,et al.  Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders , 2014, Nature Reviews Drug Discovery.

[21]  Y. Belkaid,et al.  A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells , 2014, Nature Immunology.

[22]  Chunaram Choudhary,et al.  The growing landscape of lysine acetylation links metabolism and cell signalling , 2014, Nature Reviews Molecular Cell Biology.

[23]  K. Bennett,et al.  CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2 , 2014, Nature Immunology.

[24]  H. Lassmann,et al.  A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog , 2014, Development.

[25]  Andreas Krämer,et al.  Causal analysis approaches in Ingenuity Pathway Analysis , 2013, Bioinform..

[26]  P. Matthias,et al.  Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis , 2013, The EMBO journal.

[27]  H. Cheroutre,et al.  CD4 CTL: living up to the challenge. , 2013, Seminars in immunology.

[28]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[29]  L. Wessels,et al.  Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function. , 2013, Blood.

[30]  K. Honda,et al.  Transcriptional Reprogramming of Mature CD4+ T helper Cells generates distinct MHC class II-restricted Cytotoxic T Lymphocytes , 2013, Nature Immunology.

[31]  Aneta Rogoz,et al.  Mutual expression of Runx3 and ThPOK regulates intestinal CD4+ T cell immunity , 2012, Nature Immunology.

[32]  V. Sexl,et al.  Conditional Stat1 Ablation Reveals the Importance of Interferon Signaling for Immunity to Listeria monocytogenes Infection , 2012, PLoS pathogens.

[33]  David R. Kelley,et al.  Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks , 2012, Nature Protocols.

[34]  T. Rülicke,et al.  Generation of mice with a conditional Stat1 null allele , 2012, Transgenic Research.

[35]  John J. O’Shea,et al.  Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550) , 2011, The Journal of Immunology.

[36]  W. Ellmeier,et al.  Conditional Deletion of Histone Deacetylase 1 in T Cells Leads to Enhanced Airway Inflammation and Increased Th2 Cytokine Production , 2010, The Journal of Immunology.

[37]  Min Zhang,et al.  p300-Mediated Acetylation Stabilizes the Th-Inducing POK Factor , 2010, The Journal of Immunology.

[38]  P. Muranski,et al.  Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma , 2010, The Journal of experimental medicine.

[39]  R. Blasberg,et al.  Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts , 2010, The Journal of experimental medicine.

[40]  D. Schrenk,et al.  Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. , 2008, The Journal of nutritional biochemistry.

[41]  A. Oxenius,et al.  The Dynamics of Mouse Cytomegalovirus-Specific CD4 T Cell Responses during Acute and Latent Infection1 , 2008, The Journal of Immunology.

[42]  Bjoern Peters,et al.  Cutting Edge: Murine Cytomegalovirus Induces a Polyfunctional CD4 T Cell Response1 , 2008, The Journal of Immunology.

[43]  M. Grusby,et al.  IL-21 Inhibits IFN-γ Production in Developing Th1 Cells through the Repression of Eomesodermin Expression1 , 2006, The Journal of Immunology.

[44]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  E. Remmerswaal,et al.  Emergence of a CD4+CD28− Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection , 2004, The Journal of Immunology.

[46]  L. Augenlicht,et al.  Requirement of Histone Deacetylase Activity for Signaling by STAT1* , 2004, Journal of Biological Chemistry.

[47]  S. Jonjić,et al.  Gain of Virulence Caused by Loss of a Gene in Murine Cytomegalovirus , 2004, Journal of Virology.

[48]  Wun-Jae Kim,et al.  Transforming Growth Factor-β Stimulates p300-dependent RUNX3 Acetylation, Which Inhibits Ubiquitination-mediated Degradation* , 2004, Journal of Biological Chemistry.

[49]  C. Horvath,et al.  Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  R. Koup,et al.  Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. , 2003, Journal of immunological methods.

[51]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[52]  Anthony D. Kelleher,et al.  Characterization of CD4+ CTLs Ex Vivo1 , 2002, The Journal of Immunology.

[53]  H. Macdonald,et al.  Inactivation of Notch1 in immature thymocytes does not perturb CD4 or CD8 T cell development , 2001, Nature Immunology.

[54]  S. Fujita,et al.  Granule exocytosis, and not the fas/fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4(+) as well as CD8(+) cytotoxic T lymphocytes in humans. , 2000, Blood.

[55]  J. Girdlestone,et al.  Autocrine activation by interferon‐γ of STAT factors following T cell activation , 1996 .

[56]  C. Bock,et al.  A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis. , 2018, Journal of Autoimmunity.

[57]  C. Mackay,et al.  The role of short-chain fatty acids in health and disease. , 2014, Advances in immunology.

[58]  Deborah M. Brown,et al.  IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4+ T cells. , 2009, Cellular immunology.

[59]  E. Olson,et al.  The many roles of histone deacetylases in development and physiology: implications for disease and therapy , 2009, Nature Reviews Genetics.

[60]  H. Macdonald,et al.  Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development. , 2001, Nature immunology.

[61]  J. Girdlestone,et al.  Autocrine activation by interferon-gamma of STAT factors following T cell activation. , 1996, European journal of immunology.