An important role of tumor necrosis factor receptor-2 on natural killer T cells on the development of dsRNA-enhanced Th2 cell response to inhaled allergens

BackgroundRecent evidence indicates that TNF- is a key mediator of the development of dsRNA-enhanced Th2 cell response to inhaled allergens. Natural killer T (NKT) cells may be a candidate source of Th2-polarizing cytokines. ObjectiveThe objective of this study was to evaluate the role of lung NKT cells on the development of TNF--mediated Th2 cell response. MethodsA virus-associated asthma mouse model was generated by the administration of ovalbumin (OVA, 75g) and poly[I:C] (0.1g). Role of NKT and type I NKT cells was evaluated using CD1d- and J18-deficient mice. TNF- receptors (TNFRs) were antagonized by using TNFR blocking peptides. ResultsThe number of infiltrated NKT cells was increased in a virus-associated asthma mouse model. Increase in Th2 and Th17 cytokine levels in wild-type mice were abolished in both CD1d- and J18-deficient mice. In vitro co-culture experiments with alveolar macrophages and NKT cells showed that TNF- produced by macrophages in the presence of poly[I:C] acts on NKT cells, inducing production of Th2-polarizing cytokines. Moreover, the induction of Th2-polarizing cytokines by poly[I:C] or recombinant TNF- was impaired in both CD1d- and J18-deficient mice and that the above effect was reversed by a TNF- receptor-2 (TNFR2) blocking peptide, but not by a TNFR1 blocker. ConclusionsThese findings suggest that NKT cells play a key role in the development of Th2 cell response to inhaled allergens and that TNF- produced by alveolar macrophages induces Th2 cell response, via TNFR2 on NKT cells.