title: Type I IFNs regulate effector and regulatory T cell accumulation and anti-inflammatory cytokine production during T cell-mediated colitis.
abstract: We explored the function of endogenous type I IFNs (IFN-1) in the colon using the T cell adoptive transfer model of colitis. Colon mononuclear phagocytes (MPs) constitutively produced IFN-1 in a Toll/IL-1R domain-containing adapter-inducing IFN-β-dependent manner. Transfer of CD4(+)CD45RB(hi) T cells from wild-type (WT) or IFN-α/β receptor subunit 1 knockout (IFNAR1(-/-)) mice into RAG(-/-) hosts resulted in similar onset and severity of colitis. In contrast, RAG(-/-) × IFNAR1(-/-) double knockout (DKO) mice developed accelerated severe colitis compared with RAG(-/-) hosts when transferred with WT CD4(+)CD45RB(hi) T cells. IFNAR signaling on host hematopoietic cells was required to delay colitis development. MPs isolated from the colon lamina propria of IFNAR1(-/-) mice produced less IL-10, IL-1R antagonist, and IL-27 compared with WT MPs. Accelerated colitis development in DKO mice was characterized by early T cell proliferation and accumulation of CD11b(+)CD103(-) dendritic cells in the mesenteric lymph nodes, both of which could be reversed by systemic administration of IL-1R antagonist (anakinra). Cotransfer of CD4(+)CD25(+) regulatory T cells (Tregs) from WT or IFNAR1(-/-) mice prevented disease caused by CD4(+)CD45RB(hi) T cells. However, WT CD4(+)CD25(+)Foxp3(GFP+) Tregs cotransferred with CD4(+)CD45RB(hi) T cells into DKO hosts failed to expand or maintain Foxp3 expression and gained effector functions in the colon. To our knowledge, these data are the first to demonstrate an essential role for IFN-1 in the production of anti-inflammatory cytokines by gut MPs and the indirect maintenance of intestinal T cell homeostasis by both limiting effector T cell expansion and promoting Treg stability.
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Abhisake
authors.initials: A
authors.lastname: Kole
authors.forename: JianPing
authors.initials: J
authors.lastname: He
authors.forename: Aymeric
authors.initials: A
authors.lastname: Rivollier
authors.forename: Danielle D
authors.initials: DD
authors.lastname: Silveira
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Maloy
authors.forename: Brian L
authors.initials: BL
authors.lastname: Kelsall
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D007370:Interferon Type I
references.citation: Nature. 2012 Nov 1;491(7422):119-24
references.pmid: 23128233
references.citation: Immunity. 2011 Feb 25;34(2):213-23
references.pmid: 21349431
references.citation: BMC Gastroenterol. 2009 Mar 20;9:22
references.pmid: 19302707
references.citation: Immunity. 2008 Jul 18;29(1):68-78
references.pmid: 18619869
references.citation: J Exp Med. 2003 Aug 18;198(4):615-21
references.pmid: 12925677
references.citation: Nature. 2006 Mar 23;440(7083):540-4
references.pmid: 16525420
references.citation: J Immunol. 2005 Mar 1;174(5):2974-80
references.pmid: 15728510
references.citation: Immunity. 2012 Dec 14;37(6):1076-90
references.pmid: 23219392
references.citation: Immunity. 2011 Feb 25;34(2):237-46
references.pmid: 21333554
references.citation: Inflamm Bowel Dis. 2007 Mar;13(3):325-30
references.pmid: 17206675
references.citation: J Immunol. 2005 May 15;174(10):6039-44
references.pmid: 15879097
references.citation: J Exp Med. 1984 Jan 1;159(1):126-36
references.pmid: 6607312
references.citation: Gut. 2011 Apr;60(4):449-55
references.pmid: 20971977
references.citation: J Exp Med. 2000 May 15;191(10):1777-88
references.pmid: 10811870
references.citation: J Immunol. 2001 Aug 1;167(3):1179-87
references.pmid: 11466332
references.citation: Int Immunol. 1993 Nov;5(11):1461-71
references.pmid: 7903159
references.citation: Science. 1996 Jun 28;272(5270):1947-50
references.pmid: 8658169
references.citation: J Exp Med. 2002 Feb 18;195(4):517-28
references.pmid: 11854364
references.citation: J Immunol. 1985 Sep;135(3):1857-63
references.pmid: 3926890
references.citation: Blood. 2002 May 1;99(9):3263-71
references.pmid: 11964292
references.citation: Science. 2002 Sep 20;297(5589):2063-6
references.pmid: 12242445
references.citation: Clin Pharmacol Ther. 2012 Apr;91(4):607-20
references.pmid: 22357455
references.citation: J Exp Med. 2012 Jan 16;209(1):139-55
references.pmid: 22231304
references.citation: Immunity. 2011 Mar 25;34(3):422-34
references.pmid: 21435589
references.citation: Immunity. 2008 Dec 19;29(6):848-62
references.pmid: 19100699
references.citation: Gut. 2010 Oct;59(10):1347-54
references.pmid: 20732920
references.citation: Immunity. 2011 Mar 25;34(3):409-21
references.pmid: 21435588
references.citation: J Clin Invest. 2008 May;118(5):1680-90
references.pmid: 18382764
references.citation: Blood. 2000 Sep 15;96(6):2093-9
references.pmid: 10979953
references.citation: Nat Immunol. 2009 Nov;10(11):1200-7
references.pmid: 19801985
references.citation: Curr Opin Immunol. 2008 Feb;20(1):61-7
references.pmid: 18082389
references.citation: J Exp Med. 2010 Jun 7;207(6):1321-32
references.pmid: 20498021
references.citation: J Immunol. 2007 Jun 1;178(11):6705-9
references.pmid: 17513714
references.citation: J Immunol. 2009 Mar 15;182(6):3461-8
references.pmid: 19265124
references.citation: J Immunol. 2009 Oct 15;183(8):5418-27
references.pmid: 19783688
references.citation: Immunity. 2012 Sep 21;37(3):511-23
references.pmid: 22981537
references.citation: J Exp Med. 2005 May 2;201(9):1435-46
references.pmid: 15851485
references.citation: Cell. 2007 Dec 14;131(6):1124-36
references.pmid: 18083102
references.citation: Immunity. 2010 Aug 27;33(2):279-88
references.pmid: 20732640
references.citation: J Immunol. 2012 Feb 15;188(4):2001-13
references.pmid: 22250092
references.citation: Immunity. 2011 Jun 24;34(6):866-78
references.pmid: 21703541
references.citation: Mucosal Immunol. 2013 May;6(3):601-11
references.pmid: 23149660
references.citation: Immunity. 2009 Apr 17;30(4):576-87
references.pmid: 19362022
references.citation: Nat Immunol. 2013 Mar;14(3):246-53
references.pmid: 23314004
references.citation: Expert Rev Vaccines. 2011 Apr;10(4):487-98
references.pmid: 21506646
references.citation: J Immunol. 2010 Dec 1;185(11):6599-607
references.pmid: 21041726
references.citation: J Clin Invest. 2005 Mar;115(3):695-702
references.pmid: 15765149
references.citation: Nat Immunol. 2009 Nov;10(11):1178-84
references.pmid: 19783988
references.citation: Eur J Immunol. 2005 Jun;35(6):1831-40
references.pmid: 16010704
references.citation: Gastroenterology. 2012 Jul;143(1):145-54
references.pmid: 22475534
references.citation: Immunity. 2001 Apr;14(4):461-70
references.pmid: 11336691
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17022-7
references.pmid: 17942668
references.citation: J Exp Med. 2012 Aug 27;209(9):1595-609
references.pmid: 22891275
references.citation: J Exp Med. 1999 Feb 1;189(3):521-30
references.pmid: 9927514