OX40 signaling favors the induction of T_H9 cells and airway inflammation

The mechanisms that regulate the T_H9 subset of helper T cells and diseases mediated by T_H9 cells remain poorly defined. Here we found that the costimulatory receptor OX40 was a powerful inducer of T _H9 cells in vitro and T_H9 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 T_H17 subset of helper T cells and diverted CD4⁺ Foxp3^- T cells to a T_H9 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 T_H9 cells. Thus, our study identifies a previously unknown mechanism for the induction of T_H9 cells and may have important clinical implications in allergic inflammation.