The mechanisms regulating T helper 9 (TH9) cells and TH9-mediated diseases remain poorly defined. Here, we demonstrate that the receptor OX40 (Tnfrsf4) is a powerful inducer of TH9 cells in vitro and TH9-dependent airway inflammation in vivo. Under TGF-β based polarizing conditions, OX40 ligation eliminated production of induced regulatory T cells and TH17 cells, and divertedCD4+Foxp3− T cells to a TH9 phenotype. Mechanistically, OX40 activated the ubiquitin ligase TRAF6, which triggered the induction of NF-kB-inducing kinase (NIK) in CD4+ T cells and the non-canonical NF-kB pathway which subsequently lead toTH9 generation. Thus, our study identifies a previously unknown mechanism of TH9 induction and may have important clinical implications in allergic inflammation
