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OX40 signaling favors the induction of TH9 cells and airway inflammation

2012; Nature Portfolio; Volume: 13; Issue: 10 Linguagem: Inglês

10.1038/ni.2390

1529-2916

Xiang Xiao, Savithri Balasubramanian, Wentao Liu, Xiufeng Chu, Haibin Wang, Elizabeth J. Taparowsky, Yang‐Xin Fu, Yongwon Choi, Matthew C. Walsh, Li X,

Pediatric health and respiratory diseases

TH9 cells secrete copious amounts of IL-9, but how their generation is controlled remains poorly defined. Li and colleagues demonstrate that ligation of the costimulatory receptor OX40 potently generates TH9 cells in a manner dependent on noncanonical NF-κB signaling. 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 TH9 cells in vitro and TH9 cell–dependent airway inflammation in vivo. In polarizing conditions based on transforming growth factor-β (TGF-β), 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.