Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

CD4(+) T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity(1–4). Crucial for T helper17 (Th17) 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)-β1 have been argued to be the factors responsible for initiating specification(7–10). Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. 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 naïve 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 and T-bet. T-bet(+) Rorγt(+) Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest 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 have may have therapeutic implications.