title: IFNαR signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease.
abstract: Type I IFNs are a family of proinflammatory cytokines that are essential for antiviral immunity but whose overexpression is associated with several autoimmune disorders. In this study, we asked how chronic IFN overexpression regulates the activity of different cell types and how this contributes to immune dysfunction during IFN-associated inflammatory diseases. We show that in mice that chronically overproduce type I IFNs owing to loss of the DNA exonuclease Trex1, inflammatory disease completely depends on IFNαR signaling in T cells. Although IFNs directly inhibited the proliferation and activation of Foxp3(+) regulatory T cells, this was neither required nor sufficient for development of inflammatory disease. Rather, chronic IFN expression directly promoted the expansion and activation of effector T cells, and disease development was completely dependent on IFNαR signaling in these cells. Thus, chronic IFN expression can drive inflammatory disease via its direct effects on effector, but not regulatory, T cells.
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA 98101; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; and.
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA 98101; Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Koch
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA 98101; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; and campbell@benaroyaresearch.org.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D005090:Exodeoxyribonucleases / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007370:Interferon Type I; D010750:Phosphoproteins; D053633:Receptor, Interferon alpha-beta; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1
references.citation: Nat Immunol. 2013 Sep;14(9):959-65
references.pmid: 23852275
references.citation: Immunity. 2012 Jan 27;36(1):120-31
references.pmid: 22284419
references.citation: Science. 2013 Apr 12;340(6129):202-7
references.pmid: 23580528
references.citation: Clin Exp Metastasis. 2012 Oct;29(7):801-5
references.pmid: 22752507
references.citation: J Exp Med. 2014 May 5;211(5):961-74
references.pmid: 24711580
references.citation: Blood. 2006 Feb 1;107(3):987-93
references.pmid: 16210337
references.citation: Immunity. 1994 Oct;1(7):553-62
references.pmid: 7600284
references.citation: J Immunol. 2013 Sep 1;191(5):2771-9
references.pmid: 23913971
references.citation: Immunity. 2014 Jan 16;40(1):78-90
references.pmid: 24439266
references.citation: J Exp Med. 1989 Nov 1;170(5):1569-81
references.pmid: 2572671
references.citation: Cancer Res. 1986 Sep;46(9):4315-29
references.pmid: 2425950
references.citation: J Autoimmun. 2012 Feb;38(1):59-69
references.pmid: 22257939
references.citation: Blood. 2012 Nov 1;120(18):3718-28
references.pmid: 22968462
references.citation: Immunity. 2001 Jun;14(6):661-4
references.pmid: 11420036
references.citation: J Immunol. 2006 Mar 15;176(6):3315-9
references.pmid: 16517698
references.citation: Cell Metab. 2010 Aug 4;12(2):142-53
references.pmid: 20674859
references.citation: J Neuroimmunol. 2010 Jan 25;218(1-2):120-4
references.pmid: 19932513
references.citation: J Exp Med. 2011 Sep 26;208(10):1989-2003
references.pmid: 21930769
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2610-5
references.pmid: 12604793
references.citation: J Exp Med. 1998 Dec 21;188(12):2335-42
references.pmid: 9858519
references.citation: Science. 2013 Apr 12;340(6129):207-11
references.pmid: 23580529
references.citation: Autoimmunity. 2003 Dec;36(8):511-8
references.pmid: 14984028
references.citation: Immunol Rev. 2005 Apr;204:9-26
references.pmid: 15790347
references.citation: Immunology. 2010 Sep;131(1):107-17
references.pmid: 20465564
references.citation: J Immunol. 1998 Aug 15;161(4):1947-53
references.pmid: 9712065
references.citation: Blood. 2011 Aug 25;118(8):2170-3
references.pmid: 21708889
references.citation: Nat Med. 2007 Apr;13(4):423-31
references.pmid: 17384649
references.citation: Arthritis Rheum. 2008 Mar;58(3):801-12
references.pmid: 18311820
references.citation: Nature. 2006 Mar 23;440(7083):540-4
references.pmid: 16525420
references.citation: Annu Rev Immunol. 2005;23:307-36
references.pmid: 15771573
references.citation: Genes Immun. 2009 Jul;10(5):373-9
references.pmid: 19440199
references.citation: J Immunol. 2003 Apr 15;170(8):3939-43
references.pmid: 12682220
references.citation: Am J Hum Genet. 2007 Apr;80(4):811-5
references.pmid: 17357087
references.citation: Mol Cell Biol. 2004 Aug;24(15):6719-27
references.pmid: 15254239
references.citation: J Exp Med. 2009 Jul 6;206(7):1589-602
references.pmid: 19564349
references.citation: J Immunol. 2006 Oct 1;177(7):4376-83
references.pmid: 16982872
references.citation: J Hepatol. 2001 Jun;34(6):964-5
references.pmid: 11451187
references.citation: Cell. 2008 Aug 22;134(4):587-98
references.pmid: 18724932
references.citation: J Exp Med. 1999 Oct 4;190(7):995-1004
references.pmid: 10510089
references.citation: Gastroenterology. 2012 Jul;143(1):145-54
references.pmid: 22475534
references.citation: Cell. 2007 Nov 30;131(5):873-86
references.pmid: 18045533
references.citation: J Immunol. 2010 Jun 1;184(11):5969-79
references.pmid: 20427775
references.citation: Curr Protoc Immunol. 2001 May;Chapter 3:Unit 3.19
references.pmid: 18432783
references.citation: J Immunol. 2008 Feb 1;180(3):1592-7
references.pmid: 18209055
references.citation: J Exp Med. 2003 Mar 17;197(6):711-23
references.pmid: 12642603
references.citation: J Exp Med. 2005 Sep 5;202(5):637-50
references.pmid: 16129706