title: Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells.
abstract: Foxp3(+) regulatory T (T(reg)) cells are essential for the maintenance of self-tolerance and immune homeostasis. The majority of T(reg) cells is generated in the thymus as a specific subset of CD4(+) T cells, known as thymus-derived or natural T(reg) (nT(reg)) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nT(reg) cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nT(reg) cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nT(reg) cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nT(reg) generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nT(reg) cells.
authors.affiliation: Department of Immunology and Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lewis Zhichang
authors.initials: LZ
authors.lastname: Shi
authors.forename: Nishan S
authors.initials: NS
authors.lastname: Kalupahana
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Turnis
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Hanno
authors.initials: H
authors.lastname: Hock
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D007376:Interleukin-2; D014157:Transcription Factors
references.citation: Immunity. 2009 Jul 17;31(1):122-30
references.pmid: 19592277
references.citation: Immunity. 2012 Mar 23;36(3):362-73
references.pmid: 22406269
references.citation: J Exp Med. 2001 Sep 17;194(6):823-32
references.pmid: 11560997
references.citation: Immunity. 2008 Jan;28(1):100-11
references.pmid: 18199417
references.citation: Int Immunol. 2009 Jul;21(7):881-9
references.pmid: 19505891
references.citation: Nature. 2006 Jul 20;442(7100):299-302
references.pmid: 16855590
references.citation: J Exp Med. 2003 Dec 15;198(12):1875-86
references.pmid: 14676299
references.citation: Immunity. 2001 Nov;15(5):763-74
references.pmid: 11728338
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13031-6
references.pmid: 12242333
references.citation: Nature. 2002 Feb 21;415(6874):922-6
references.pmid: 11859372
references.citation: Immunity. 2008 Apr;28(4):546-58
references.pmid: 18387831
references.citation: Annu Rev Immunol. 2012;30:531-64
references.pmid: 22224781
references.citation: Immunity. 2009 Oct 16;31(4):576-86
references.pmid: 19818654
references.citation: J Exp Med. 2007 Jun 11;204(6):1257-65
references.pmid: 17502665
references.citation: Nat Rev Immunol. 2012 Feb 10;12(3):157-67
references.pmid: 22322317
references.citation: J Immunol. 1999 Nov 15;163(10):5211-8
references.pmid: 10553041
references.citation: Eur J Immunol. 2003 Feb;33(2):314-25
references.pmid: 12548562
references.citation: Trends Immunol. 2011 Feb;32(2):50-6
references.pmid: 21288770
references.citation: Immunity. 2010 Aug 27;33(2):203-15
references.pmid: 20674402
references.citation: Nature. 2004 Oct 21;431(7011):1002-7
references.pmid: 15457180
references.citation: Immunity. 2010 Aug 27;33(2):153-65
references.pmid: 20732639
references.citation: J Exp Med. 2003 Apr 7;197(7):831-44
references.pmid: 12682108
references.citation: Nat Immunol. 2007 Oct;8(10):1086-94
references.pmid: 17873879
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10278-83
references.pmid: 19515822
references.citation: Immunity. 2008 Jan;28(1):112-21
references.pmid: 18199418
references.citation: Leukemia. 2010 Nov;24(11):1834-43
references.pmid: 20861919
references.citation: Curr Opin Hematol. 2006 Jan;13(1):1-6
references.pmid: 16319680
references.citation: J Exp Med. 2011 Jul 4;208(7):1367-76
references.pmid: 21708926
references.citation: J Exp Med. 2005 Mar 7;201(5):723-35
references.pmid: 15753206
references.citation: J Exp Med. 2009 Feb 16;206(2):329-41
references.pmid: 19188499
references.citation: Nat Genet. 2002 Mar;30(3):295-300
references.pmid: 11810106
references.citation: Annu Rev Immunol. 2012;30:95-114
references.pmid: 22149933
references.citation: Nat Immunol. 2009 Jul;10(7):769-77
references.pmid: 19483717
references.citation: Nat Immunol. 2010 Aug;11(8):709-16
references.pmid: 20601952
references.citation: Eur J Immunol. 2007 Dec;37(12):3551-63
references.pmid: 18034420
references.citation: J Exp Med. 2007 Nov 26;204(12):3003-15
references.pmid: 17998389
references.citation: J Exp Med. 2005 Mar 7;201(5):769-77
references.pmid: 15753210
references.citation: Cancer Res. 2012 Feb 15;72(4):917-27
references.pmid: 22186141
references.citation: Immunity. 2003 Jan;18(1):109-20
references.pmid: 12530980
references.citation: Stem Cells. 2011 Feb;29(2):376-85
references.pmid: 21732494
references.citation: Nat Immunol. 2011 Jul 17;12(9):888-97
references.pmid: 21765414
references.citation: Nat Immunol. 2001 Sep;2(9):882-8
references.pmid: 11526406
references.citation: Nat Immunol. 2009 Nov;10(11):1178-84
references.pmid: 19783988
references.citation: Nat Immunol. 2005 Nov;6(11):1142-51
references.pmid: 16227984
references.citation: Semin Immunol. 2011 Oct;23(5):368-78
references.pmid: 21920773
references.citation: Semin Immunol. 2011 Dec;23(6):401-9
references.pmid: 21733719
references.citation: Nat Immunol. 2008 Jun;9(6):632-40
references.pmid: 18438410
references.citation: J Biol Chem. 2004 Sep 24;279(39):40906-17
references.pmid: 15252036
references.citation: J Exp Med. 2004 Sep 20;200(6):771-82
references.pmid: 15381730
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18214-9
references.pmid: 17116877
references.citation: Immunity. 2002 May;16(5):733-44
references.pmid: 12049724