title: Antigen-specific CD25- Foxp3- IFN-gamma(high) CD4+ T cells restrain the development of experimental allergic encephalomyelitis by suppressing Th17.
abstract: The current study identifies within the Th1 subtype two distinct CD4(+) populations: those capable of transferring inflammatory autoimmunity and others that regulate its development by suppressing Th17 in an interferon (IFN)-gamma-dependent manner. These CD4(+)IFN-gamma(high)IL-4(low)IL-10(low)TGF-beta(low)FOXp3(-) cells in fact function as antigen-specific regulatory cells that restrain the development of autoimmunity by increasing the threshold of Th17 activation. We show that development of autoimmune conditions within the central nervous system is dependent on the Fas ligand-mediated apoptosis of these regulatory cells at early stages of disease. We also show that not only is the function of these cells IFN-gamma dependent but also that stable over expression of IFN-gamma in encephalitogenic CD4(+) T cells redirects their biological function to become antigen-specific regulatory cells. This may also explain, in part, the pleiotropic role of IFN-gamma in the regulation of autoimmunity, as previously observed by others.
authors.affiliation: Department of Immunology, Bruce Rappaport Faculty of Medicine, Haifa, Israel. nkarin@tx.technion.ac.il.
authors.forename: Gizi
authors.initials: G
authors.lastname: Wildbaum
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Zohar
authors.forename: Nathan
authors.initials: N
authors.lastname: Karin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma
references.citation: J Exp Med. 2008 Oct 27;205(11):2643-55
references.pmid: 18852294
references.citation: J Immunol. 2002 Nov 1;169(9):4712-6
references.pmid: 12391178
references.citation: J Clin Invest. 2000 Jan;105(2):223-31
references.pmid: 10642601
references.citation: Nat Immunol. 2009 Dec;10(12):1252-9
references.pmid: 19838199
references.citation: Am J Pathol. 2009 Sep;175(3):1116-23
references.pmid: 19700760
references.citation: Nat Med. 2007 Feb;13(2):139-45
references.pmid: 17290272
references.citation: Blood. 1994 Mar 1;83(5):1174-8
references.pmid: 7906962
references.citation: J Exp Med. 1995 Apr 1;181(4):1569-74
references.pmid: 7699337
references.citation: J Clin Invest. 2002 Sep;110(5):701-10
references.pmid: 12208871
references.citation: J Immunol. 2005 Apr 1;174(7):4307-15
references.pmid: 15778395
references.citation: J Immunol. 2009 Sep 15;183(6):3672-81
references.pmid: 19710457
references.citation: J Exp Med. 2002 Oct 7;196(7):999-1005
references.pmid: 12370261
references.citation: J Clin Invest. 2000 Sep;106(5):671-9
references.pmid: 10974020
references.citation: J Exp Med. 1999 Jan 18;189(2):219-30
references.pmid: 9892605
references.citation: Nat Med. 2008 Mar;14(3):337-42
references.pmid: 18278054
references.citation: Nat Rev Immunol. 2002 Jun;2(6):389-400
references.pmid: 12093005
references.citation: J Exp Med. 2005 Jan 17;201(2):233-40
references.pmid: 15657292
references.citation: J Immunol. 2008 Sep 15;181(6):3750-4
references.pmid: 18768826
references.citation: Nature. 2003 Feb 13;421(6924):744-8
references.pmid: 12610626
references.citation: Semin Immunol. 2007 Dec;19(6):409-17
references.pmid: 18053739
references.citation: Microbiol Immunol. 2007;51(12):1139-47
references.pmid: 18094532
references.citation: J Immunol. 1997 Oct 1;159(7):3100-3
references.pmid: 9317104
references.citation: J Exp Med. 2008 Jul 7;205(7):1517-22
references.pmid: 18591407
references.citation: Nature. 1997 Oct 16;389(6652):737-42
references.pmid: 9338786
references.citation: J Exp Med. 2008 Jul 7;205(7):1535-41
references.pmid: 18573909
references.citation: Curr Opin Pharmacol. 2007 Jun;7(3):272-8
references.pmid: 17418639
references.citation: Science. 1994 Aug 26;265(5176):1237-40
references.pmid: 7520605
references.citation: J Clin Invest. 2009 Dec;119(12):3678-91
references.pmid: 19884657
references.citation: J Immunol. 2002 Apr 15;168(8):4173-83
references.pmid: 11937578
references.citation: Nat Med. 1999 Jul;5(7):843-7
references.pmid: 10395334
references.citation: Immunol Rev. 2008 Jun;223:87-113
references.pmid: 18613831
references.citation: Immunity. 2001 May;14(5):547-60
references.pmid: 11371357
references.citation: J Exp Med. 2008 Apr 14;205(4):799-810
references.pmid: 18391061
references.citation: J Immunol. 2008 Apr 1;180(7):4451-7
references.pmid: 18354166
references.citation: Infect Immun. 2008 Sep;76(9):4206-13
references.pmid: 18591228
references.citation: J Exp Med. 1999 Apr 19;189(8):1195-205
references.pmid: 10209037
references.citation: Nature. 2007 Jul 26;448(7152):480-3
references.pmid: 17581589
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070