title: The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation.
abstract: Regulatory T cells (Treg cells) are required for immune homeostasis. Chromatin remodeling is essential for establishing diverse cellular identities, but how the epigenetic program in Treg cells is maintained throughout the dynamic activation process remains unclear. Here we have shown that CD28 co-stimulation, an extracellular cue intrinsically required for Treg cell maintenance, induced the chromatin-modifying enzyme, Ezh2. Treg-specific ablation of Ezh2 resulted in spontaneous autoimmunity with reduced Foxp3(+) cells in non-lymphoid tissues and impaired resolution of experimental autoimmune encephalomyelitis. Utilizing a model designed to selectively deplete wild-type Treg cells in adult mice co-populated with Ezh2-deficient Treg cells, Ezh2-deficient cells were destabilized and failed to prevent autoimmunity. After activation, the transcriptome of Ezh2-deficient Treg cells was disrupted, with altered expression of Treg cell lineage genes in a pattern similar to Foxp3-deficient Treg cells. These studies reveal a critical role for Ezh2 in the maintenance of Treg cell identity during cellular activation.
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Michel
authors: M
authors: DuPage
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Gaurav
authors: G
authors: Chopra
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Jason
authors: J
authors: Quiros
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Wendy L
authors: WL
authors: Rosenthal
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Malika M
authors: MM
authors: Morar
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Dan
authors: D
authors: Holohan
authors: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors: Ruan
authors: R
authors: Zhang
authors: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors: Laurence
authors: L
authors: Turka
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Innovative Genomics Initiative (IGI), University of California, Berkeley, CA 94720, USA.
authors: Alexander
authors: A
authors: Marson
authors: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeff.bluestone@ucsf.edu.
authors: Jeffrey A
authors: JA
authors: Bluestone
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D042002:Chromatin Assembly and Disassembly; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2