title: Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
abstract: CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Harrington
authors.forename: Robin D
authors.initials: RD
authors.lastname: Hatton
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mangan
authors.forename: Henrietta
authors.initials: H
authors.lastname: Turner
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D020381:Interleukin-17 / Q000032:analysis / Q000096:biosynthesis*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D020825:T-Box Domain Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D015704:CD4 Antigens; D004268:DNA-Binding Proteins; C508841:Il23a protein, mouse; D007370:Interferon Type I; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma