Abstract
CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity1,2,3,4. Although crucial for TH17 cells in vivo5,6, 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 specification7,8,9,10. 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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Acknowledgements
We thank J. Simone, J. Lay (Flow Cytometry Section, NIAMS) and the NIAMS LACU staff for technical support. This work has been supported by the Intramural Research Programs of NIAMS, NIDCR and NIAID.
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K.G. designed, performed, analysed and interpreted all the experiments and wrote the manuscript. A.L., X.-P.Y., M.J.G. and C.M.T. planned and performed experiments and helped to write the manuscript; L.W. and H.-W.S. interpreted the microarray experiments and ChIP-seq data; H.L.R., W.T.W. and Y.K. performed and interpreted the ChIP-seq data; J.E.K., N.B. and J.R.G. helped to analyse gut lymphocytes; T.S.D. and Q.C. helped to analyse CNS lymphocytes. G.E. provided the Rorc(γt)-GfpTG mice and made helpful suggestions; W.C. provided the Tgfbr1f/fCD4-Cre+ mice, contributed to the experimental design and data interpretation; Y.B., E.M.S. and D.J.C. contributed to the experimental design, data interpretation and made helpful suggestions. J.J.O'S. contributed to the experimental design, analysed and interpreted all acquired data and helped to write the manuscript.
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Ghoreschi, K., Laurence, A., Yang, XP. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010). https://doi.org/10.1038/nature09447
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DOI: https://doi.org/10.1038/nature09447
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