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
-
NF-kappaB-Inducing Kinase
-
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