The mechanisms that regulate the TH9 subset of helper T cells and diseases mediated by TH9 cells remain poorly defined. Here we found that the costimulatory receptor OX40 was a powerful inducer of T H9 cells in vitro and TH9 cell-dependent airway inflammation in vivo. In polarizing conditions based on transforming growth factor-α (TGF-α), ligation of OX40 inhibited the production of induced regulatory T cells and the TH17 subset of helper T cells and diverted CD4+ Foxp3- T cells to a TH9 phenotype. Mechanistically, OX40 activated the ubiquitin ligase TRAF6, which triggered induction of the kinase NIK in CD4+ T cells and the noncanonical transcription factor NF-κB pathway; this subsequently led to the generation of TH9 cells. Thus, our study identifies a previously unknown mechanism for the induction of TH9 cells and may have important clinical implications in allergic inflammation.
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