title: Cutting edge: the pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet.
abstract: During the development of experimental autoimmune encephalomyelitis (EAE), the proportion of pathogenic and myelin-specific cells within CNS-infiltrating cytokine-producing Th cells is unknown. Using an IL-17A/IFN-γ double reporter mouse and I-A(b)/myelin oligodendrocyte glycoprotein 38-49 tetramer, we show in this study that IL-17(+)IFN-γ(+) Th cells, which are expanded in the CNS during EAE, are highly enriched in myelin oligodendrocyte glycoprotein-specific T cells. We further demonstrate that IL-23 is essential for the generation and expansion of IFN-γ-producing Th17 cells independently of the Th1-associated transcription factors T-bet, STAT1, and STAT4. Furthermore, Th17 and IL-17(+)IFN-γ(+) Th cells can induce CNS autoimmunity independently of T-bet. Whereas T-bet is crucial for Th1-mediated EAE, it is dispensable for Th17 cell-mediated autoimmunity. Our results suggest the existence of different epigenetic programs that regulate IFN-γ expression in Th1 and Th17 cells.
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA 98101, USA.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Duhen
authors.forename: Simon
authors.initials: S
authors.lastname: Glatigny
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Arbelaez
authors.forename: Tiffany C
authors.initials: TC
authors.lastname: Blair
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.forename: Estelle
authors.initials: E
authors.lastname: Bettelli
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D063308:Myelin-Oligodendrocyte Glycoprotein; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
references.citation: Nat Immunol. 2011 Jun 20;12(7):597-606
references.pmid: 21685955
references.citation: Nat Immunol. 2011 Mar;12(3):255-63
references.pmid: 21278737
references.citation: Immunity. 2009 Jan 16;30(1):92-107
references.pmid: 19119024
references.citation: Science. 2010 Feb 26;327(5969):1098-102
references.pmid: 20185720
references.citation: Nature. 2003 Feb 13;421(6924):744-8
references.pmid: 12610626
references.citation: J Immunol. 2006 Jul 1;177(1):566-73
references.pmid: 16785554
references.citation: Nat Immunol. 2011 Jun;12(6):568-75
references.pmid: 21516111
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: J Exp Med. 2004 Jul 5;200(1):79-87
references.pmid: 15238607
references.citation: J Exp Med. 2009 Jul 6;206(7):1549-64
references.pmid: 19546248
references.citation: Nat Immunol. 2009 Mar;10(3):314-24
references.pmid: 19182808
references.citation: Nat Immunol. 2012 May 06;13(6):604-11
references.pmid: 22561605
references.citation: J Immunol. 2009 May 15;182(10):5904-8
references.pmid: 19414740
references.citation: J Immunol. 2009 Dec 1;183(11):7169-77
references.pmid: 19890056
references.citation: Ann Neurol. 2009 Sep;66(3):390-402
references.pmid: 19810097
references.citation: J Immunol. 2010 Jul 1;185(1):679-87
references.pmid: 20511558
references.citation: Immunity. 2004 Nov;21(5):719-31
references.pmid: 15539157
references.citation: J Exp Med. 2008 May 12;205(5):1063-75
references.pmid: 18411338
references.citation: J Exp Med. 2008 Jul 7;205(7):1535-41
references.pmid: 18573909
references.citation: Nat Immunol. 2011 Jan;12(1):96-104
references.pmid: 21151104
references.citation: Immunology. 2006 Jul;118(3):384-91
references.pmid: 16827899
references.citation: J Immunol. 2010 Feb 1;184(3):1552-9
references.pmid: 20028652
references.citation: Nat Immunol. 2011 Jun;12(6):560-7
references.pmid: 21516112