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- Title
Generation of pathogenic T<sub>H</sub>17 cells in the absence of TGF-? signalling.
- Authors
Ghoreschi, Kamran; Laurence, Arian; Yang, Xiang-Ping; Tato, Cristina M.; McGeachy, Mandy J.; Konkel, Joanne E.; Ramos, Haydeé L.; Wei, Lai; Davidson, Todd S.; Bouladoux, Nicolas; Grainger, John R.; Qian Chen; Kanno, Yuka; Watford, Wendy T.; Sun, Hong-Wei; Eberl, Gérard; Shevach, Ethan M.; Belkaid, Yasmine; Cua, Daniel J.; Chen, WanJun
- 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)-?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.
- Publication
Nature, 2010, Vol 467, Issue 7318, p967
- ISSN
0028-0836
- Publication type
Academic Journal
- DOI
10.1038/nature09447