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OX40 signaling favors the induction of TH9 cells and airway inflammation

Abstract

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.

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Figure 1: Role of OX40 signaling in the polarization of naive CD4+ T cells in vitro.
Figure 2: Role of the ligation of OX40 in the polarization of OT-II T cell subsets in vitro.
Figure 3: Role of PU.1 and cytokine signaling in the OX40-mediated induction of TH9 cells.
Figure 4: Role of the ligation of OX40 in the activation of both the canonical and noncanonical NF-κB pathways.
Figure 5: Role of the canonical NF-κB pathway in the OX40-mediated induction of TH9 cells.
Figure 6: Role of the noncanonical NF-κB pathway in the OX40-mediated induction of TH9 cells.
Figure 7: Analysis of TRAF6 in the OX40-triggered activation of the noncanonical NF-κB pathway.
Figure 8: Conditional deletion of Traf6 in CD4+ T cells prevents the induction of TH9 cells by OX40.
Figure 9: The in vivo effect of OX40 on the induction of TH9 cells and airway inflammation.

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Acknowledgements

We thank N. Ishii (Tohoku University) for OX40L-transgenic mice; A. McKenzie (MRC Laboratory of Molecular Biology) for IL-9-deficient mice; M. Alegre (University of Chicago) for IκBαΔN-transgenic mice; and D. Tenen (Harvard Medical School) for Sfp1f/f mice. Supported by the US National Institutes of Health and the Juvenile Diabetes Research Foundation International.

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X.X., S.B., W.L., X.C. and H.W. designed and did various experiments, E.J.T., Y.-X.F., Y.C. and M.C.W. provided reagents and animal models; and X.C.L. initiated the project, supervised the study and wrote the manuscript.

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Correspondence to Xian Chang Li.

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The authors declare no competing financial interests.

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Xiao, X., Balasubramanian, S., Liu, W. et al. OX40 signaling favors the induction of TH9 cells and airway inflammation. Nat Immunol 13, 981–990 (2012). https://doi.org/10.1038/ni.2390

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