OX40 signaling favors the induction of T(H)9 cells and airway inflammation

Nat Immunol. 2012 Oct;13(10):981-90. doi: 10.1038/ni.2390. Epub 2012 Jul 29.

Abstract

The mechanisms that regulate the T(H)9 subset of helper T cells and diseases mediated by T(H)9 cells remain poorly defined. Here we found that the costimulatory receptor OX40 was a powerful inducer of T(H)9 cells in vitro and T(H)9 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 T(H)17 subset of helper T cells and diverted CD4(+)Foxp3(-) T cells to a T(H)9 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(H)9 cells. Thus, our study identifies a previously unknown mechanism for the induction of T(H)9 cells and may have important clinical implications in allergic inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / biosynthesis
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-9 / biosynthesis
  • Interleukin-9 / metabolism
  • Mice
  • NF-kappa B / metabolism
  • OX40 Ligand / immunology
  • OX40 Ligand / metabolism*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins / metabolism
  • Receptors, OX40 / immunology
  • Receptors, OX40 / metabolism*
  • Respiratory System / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • TNF Receptor-Associated Factor 6 / biosynthesis
  • TNF Receptor-Associated Factor 6 / metabolism
  • Trans-Activators / immunology
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism

Substances

  • CD4 Antigens
  • Interleukin-9
  • NF-kappa B
  • OX40 Ligand
  • Proto-Oncogene Proteins
  • Receptors, OX40
  • TNF Receptor-Associated Factor 6
  • Trans-Activators
  • Transforming Growth Factor beta
  • proto-oncogene protein Spi-1
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase