title: Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity.
abstract: Co-repressor histone deacetylase 9 (HDAC9) plays a key role in the development and differentiation of many types of cells, including regulatory T cells. However, the biological function of HDAC9 in T effector cells is unknown. Systemic autoimmune diseases like lupus, diabetes, and rheumatoid arthritis have dysfunctional effector T cells. To determine the role of HDAC9 in systemic autoimmunity, we created MRL/lpr mice with HDAC9 deficiency that have aberrant effector T cell function. HDAC9 deficiency led to decreased lympho-proliferation, inflammation, autoantibody production, and increased survival in MRL/lpr mice. HDAC9-deficient mice manifested Th2 polarization, decreased T effector follicular cells positive for inducible co-stimulator, and activated T cells in vivo compared with HDAC9-intact MRL/lpr mice. HDAC9 deficiency also resulted in increased GATA3 and roquin and decreased BCL6 gene expression. HDAC9 deficiency was associated with increased site-specific lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) globally that was localized to IL-4, roquin, and peroxisome proliferator-activated receptor-γ promoters with increased gene expression, respectively. In kidney and spleen, HDAC9 deficiency decreased inflammation and cytokine and chemokine production due to peroxisome proliferator-activated receptor γ overexpression. These findings suggest that HDAC9 acts as an epigenetic switch in effector T cell-mediated systemic autoimmunity.
authors.affiliation: Sections on Rheumatology and Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yan
authors.affiliation: Sections on Rheumatology and Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University and the Edward Via College of Osteopathic Medicine, Blacksburg, Virginia 24060, and.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544.
authors.forename: Nicolas L
authors.initials: NL
authors.lastname: Young
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Sections on Rheumatology and Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157,. Electronic address: nmishra@wfubmc.edu.
authors.forename: Nilamadhab
authors.initials: N
authors.lastname: Mishra
mesh_terms: D000107:Acetylation; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; D006657:Histones; C508598:IL4 protein, human; D047495:PPAR gamma; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D015847:Interleukin-4; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C486544:HDAC9 protein, human; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases