Generation of pathogenic TH17 cells in the absence of TGF-β signalling

K Ghoreschi, A Laurence, XP Yang, CM Tato… - Nature, 2010 - nature.com
K Ghoreschi, A Laurence, XP Yang, CM Tato, MJ McGeachy, JE Konkel, HL Ramos, L Wei…
Nature, 2010nature.com
CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host
defence and autoimmunity,,,. Although crucial for TH17 cells in viv o,, IL-23 has been
thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth
factor (TGF)-β1 have been proposed to be the factors responsible for initiating
specification,,,. Here we show that TH17 differentiation can occur in the absence of TGF-β
signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these …
Abstract
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)-β1 have been proposed to be the factors responsible for initiating specification,,,. Here we show that TH17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 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+RORγt+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-β1 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.
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