title: Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.
abstract: CD4+ regulatory T cells (Tregs) maintain immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses. The core genetic program of Tregs and their ability to suppress pathologic immune responses depends on the transcription factor Foxp3. Despite progress in understanding mechanisms of Foxp3-dependent gene activation, the molecular mechanism of Foxp3-dependent gene repression remains largely unknown. We identified Eos, a zinc-finger transcription factor of the Ikaros family, as a critical mediator of Foxp3-dependent gene silencing in Tregs. Eos interacts directly with Foxp3 and induces chromatin modifications that result in gene silencing in Tregs. Silencing of Eos in Tregs abrogates their ability to suppress immune responses and endows them with partial effector function, thus demonstrating the critical role that Eos plays in Treg programming.
authors.affiliation: Immunology and Hematopoiesis Division, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Pan
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Eric V
authors.initials: EV
authors.lastname: Dang
authors.forename: Joseph
authors.initials: J
authors.lastname: Barbi
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Pan
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grosso
authors.forename: Dinili
authors.initials: D
authors.lastname: Jinasena
authors.forename: Sudarshana M
authors.initials: SM
authors.lastname: Sharma
authors.forename: Erin M
authors.initials: EM
authors.lastname: McCadden
authors.forename: Derese
authors.initials: D
authors.lastname: Getnet
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
mesh_terms: D000107:Acetylation; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000276:immunology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D014161:Transduction, Genetic; D016335:Zinc Fingers
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006657:Histones; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; C118760:Zfpn1a4 protein, mouse; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein
references.citation: Genes Dev. 2002 Jul 15;16(14):1779-91
references.pmid: 12130538
references.citation: Int Immunol. 1993 Nov;5(11):1461-71
references.pmid: 7903159
references.citation: Am J Pathol. 1996 May;148(5):1503-15
references.pmid: 8623920
references.citation: Mol Cell Biol. 2007 Jun;27(11):4018-27
references.pmid: 17403896
references.citation: Immunity. 2004 Oct;21(4):503-13
references.pmid: 15485628
references.citation: Immunol Rev. 2006 Aug;212:256-71
references.pmid: 16903919
references.citation: Cell. 2008 May 30;133(5):775-87
references.pmid: 18510923
references.citation: Nature. 2007 Apr 5;446(7136):685-9
references.pmid: 17377532
references.citation: J Immunol. 2004 May 15;172(10):6136-43
references.pmid: 15128800
references.citation: Nat Immunol. 2001 Sep;2(9):816-22
references.pmid: 11526392
references.citation: J Immunol. 2006 Sep 1;177(5):3133-42
references.pmid: 16920951
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5138-43
references.pmid: 15790681
references.citation: Eur J Biochem. 2002 Dec;269(23):5885-92
references.pmid: 12444977
references.citation: Nat Immunol. 2003 Mar;4(3):235-40
references.pmid: 12548284
references.citation: Nature. 2007 Nov 22;450(7169):566-9
references.pmid: 18033300
references.citation: Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7958-62
references.pmid: 1387709
references.citation: J Biol Chem. 2002 Aug 2;277(31):27697-705
references.pmid: 12015313
references.citation: Nature. 2003 Apr 17;422(6933):735-8
references.pmid: 12700765
references.citation: Cell Cycle. 2007 Jun 15;6(12):1432-6
references.pmid: 17592252
references.citation: J Biol Chem. 2007 May 25;282(21):15476-83
references.pmid: 17403666
references.citation: Nat Immunol. 2007 May;8(5):457-62
references.pmid: 17440451
references.citation: EMBO J. 2006 Mar 8;25(5):1081-92
references.pmid: 16498406
references.citation: Annu Rev Immunol. 2000;18:423-49
references.pmid: 10837065
references.citation: J Biol Chem. 2001 Oct 5;276(40):37672-9
references.pmid: 11483607
references.citation: Immunity. 2007 Nov;27(5):786-800
references.pmid: 18024188
references.citation: Nature. 2007 Feb 22;445(7130):931-5
references.pmid: 17237765
references.citation: J Exp Med. 2003 Sep 1;198(5):737-46
references.pmid: 12939344
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6
references.pmid: 17360565
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14023-7
references.pmid: 18779564