A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (TH17) lineage, was recently described based on developmental and functional features distinct from those of classical TH1 and TH2 lineages1,2. Like TH1 and TH2, TH17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens3, such as extracellular bacteria4. Aberrant TH17 responses have been implicated in a growing list of autoimmune disorders5,6,7. TH17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rβ1, that pairs with unique, inducible components, IL-23R and IL-12Rβ2, to confer receptor responsiveness9. Here we identify transforming growth factor-β (TGF-β) as a cytokine critical for commitment to TH17 development. TGF-β acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-β on naive T cells is antagonized by interferon-γ and IL-4, thus providing a mechanism for divergence of the TH1, TH2 and TH17 lineages.
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The authors thank P. Bucy, D. Chaplin, S. Schoenberger, A. Zajac and members of the Weaver laboratory for their comments and suggestions. We thank J. Oliver, M. Blake and C. Song for animal husbandry and phenotyping, and N. LeLievre for editorial assistance. We also thank R. Kastelein for provision of p19-/- mice. This work was supported by grants from the NIH (to C.T.W., R.D.H. and P.R.M.), Sankyo Co. Ltd (C.T.W.) and a postdoctoral fellowship from the National Multiple Sclerosis Society (L.E.H.).
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
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