title: FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3.
abstract: Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs.
authors: Liqing
authors: L
authors: Wang
authors: Yujie
authors: Y
authors: Liu
authors: Rongxiang
authors: R
authors: Han
authors: Ulf H
authors: UH
authors: Beier
authors: Tricia R
authors: TR
authors: Bhatti
authors: Tatiana
authors: T
authors: Akimova
authors: Mark I
authors: MI
authors: Greene
authors: Scott W
authors: SW
authors: Hiebert
authors: Wayne W
authors: WW
authors: Hancock
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D051858:Forkhead Transcription Factors; D006655:Histone Deacetylases; D007376:Interleukin-2; D000099186:Histone Deacetylase 3; C498833:Foxp3 protein, mouse
references: Nature. 2007 Feb 22;445(7130):936-40
references: 17237761
references: Gastroenterology. 2010 Feb;138(2):583-94
references: 19879272
references: Annu Rev Immunol. 2012;30:69-94
references: 22149932
references: Nat Immunol. 2012 Oct;13(10):1010-9
references: 22922362
references: J Biol Chem. 2011 Sep 23;286(38):33301-9
references: 21808063
references: J Biol Chem. 2001 Sep 21;276(38):35826-35
references: 11466315
references: PLoS One. 2010;5(7):e11492
references: 20628553
references: Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2865-74
references: 22802645
references: J Clin Invest. 2013 Jul;123(7):3112-23
references: 23921131
references: J Immunol. 2010 Apr 15;184(8):4295-306
references: 20304828
references: Sci Signal. 2012 Jun 19;5(229):ra45
references: 22715468
references: EMBO J. 2008 Apr 9;27(7):1017-28
references: 18354499
references: Cell. 2009 Mar 20;136(6):1056-72
references: 19303849
references: Nature. 2010 Feb 11;463(7282):808-12
references: 20072126
references: Immunity. 2001 Nov;15(5):763-74
references: 11728338
references: J Clin Invest. 2008 Nov;118(11):3588-97
references: 18830415
references: Nat Med. 2013 Sep;19(9):1173-7
references: 23955711
references: Immunity. 2009 May;30(5):656-65
references: 19464988
references: Handb Exp Pharmacol. 2011;206:225-40
references: 21879452
references: J Immunol. 1997 Apr 1;158(7):3464-73
references: 9120308
references: Adv Immunol. 2011;112:137-76
references: 22118408
references: J Neurosci. 2011 Jan 12;31(2):764-74
references: 21228185
references: Nat Med. 2007 Nov;13(11):1299-307
references: 17922010
references: Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17335-40
references: 17956988
references: EMBO J. 2000 Aug 15;19(16):4342-50
references: 10944117
references: Immunity. 2013 Mar 21;38(3):414-23
references: 23521883
references: Diabetes Care. 2012 Sep;35(9):1817-20
references: 22723342
references: Mol Cell. 2013 Dec 26;52(6):769-82
references: 24268577
references: Nat Rev Drug Discov. 2009 Dec;8(12):969-81
references: 19855427
references: Int Immunol. 2014 Feb;26(2):61-9
references: 24324208
references: Cell Transplant. 2011;20(11-12):1747-58
references: 21457615
references: Genes Dev. 2000 May 1;14(9):1048-57
references: 10809664
references: Cold Spring Harb Symp Quant Biol. 2011;76:49-55
references: 21900149
references: Mol Cell Biol. 2001 Sep;21(18):6091-101
references: 11509652
references: Nat Chem Biol. 2010 Mar;6(3):238-243
references: 20139990
references: BMC Bioinformatics. 2010;11:121
references: 20214778
references: J Biol Chem. 2008 Apr 25;283(17):11355-63
references: 18285338
references: J Biol Chem. 2003 Jan 24;278(4):2758-66
references: 12419806
references: Cell. 2011 May 13;145(4):607-21
references: 21565617
references: Mol Cell Biol. 2007 Feb;27(4):1280-95
references: 17158926
references: J Immunol. 2006 Jul 15;177(2):1062-9
references: 16818762
references: Nat Commun. 2013;4:1582
references: 23481390
references: Mol Cell. 2008 Apr 11;30(1):61-72
references: 18406327
references: Clin Immunol. 2009 Oct;133(1):22-6
references: 19559653
references: Nat Struct Mol Biol. 2013 Feb;20(2):182-7
references: 23292142
references: Mol Cell. 2002 Jan;9(1):45-57
references: 11804585
references: Eur J Immunol. 2014 May;44(5):1320-9
references: 24500801
references: Science. 2001 Aug 31;293(5535):1653-7
references: 11533489
references: Nature. 2012 Jan 19;481(7381):335-40
references: 22230954
references: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6
references: 17360565
references: Eur J Immunol. 2007 Oct;37(10):2983-90
references: 17899549
references: Protein Sci. 2013 Jan;22(1):83-92
references: 23139175
references: Immunity. 2008 Apr;28(4):546-58
references: 18387831
references: J Immunol. 2010 Jul 15;185(2):842-55
references: 20548029
references: J Biol Chem. 2010 Dec 10;285(50):39329-38
references: 20947501
references: Nat Rev Immunol. 2013 Jun;13(6):461-7
references: 23681097
references: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7202-7
references: 10860984
references: Blood. 2013 May 2;121(18):3631-9
references: 23444399
references: Cell. 2012 Sep 28;151(1):153-66
references: 23021222