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[CD4.sup.+] T-helper cells that selectively produce interleukin (IL)-17 ([T.sub.H]17), are critical for host defence and autoimmunity (1-4). Although crucial for [T.sub.H]17 cells in vivo (5,6), IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-[β.sub.1] have been proposed to be the factors responsible for initiating specification (7-10). Here we show that [T.sub.H]17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated [T.sub.H]17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. [T-bet.sup.+] RORy[t.sup.+] [T.sub.H]17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred [T.sub.H]17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for [T.sub.H]17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications., TGF-βl is important for murine [T.sub.H]17 differentiation (7,8) and accordingly, transgenic expression of a mutant TGF-β subunit receptor II (CD4dnTGF-βRII) in T cells interferes with the generation of [T.sub.H]17 cells [...]

CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity. Although crucial for TH17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-?1 have been proposed to be the factors responsible for initiating specification. Here we show that TH17 differentiation can occur in the absence of TGF-? signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these cytokines in combination with IL-1? effectively induced IL-17 production in naive precursors, independently of TGF-?. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-?1, allowing the generation of cells that co-expressed ROR?t (encoded by Rorc) and T-bet. T-bet+ROR?t+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-?1 were pathogenic in this disease model. These data indicate an alternative mode for TH17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications. [ABSTRACT FROM AUTHOR]