AbstractTo clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using α‐galactosylceramide (α‐GalCer), a selective ligand for NKT cells. Although continuous administration of α‐GalCer during ovalbumin (OVA) sensitization increased OVA‐specific IgE levels and worsened eosinophil inflammation, a single administration of α‐GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild‐type mice. This inhibitory effect of α‐GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN‐γ, and decreases in IL‐4, IL‐5 and IL‐13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN‐γ increased in NK cells, but not in T or NKT cells, following α‐GalCer administration. Induction of vascular cell adhesion molecule‐1 in the lungs of wild‐type mice was also significantly attenuated by treatment with α‐GalCer. These effects of α‐GalCer were abrogated in Jα281–/– mice, which lack NKT cells, and in wild‐type mice treated with anti‐IFN‐γ Ab. Hence, our data indicate that α‐GalCer suppresses allergen‐induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.See accompanying commentary: http://dx.doi.org/10.1002/eji.200535425