The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 productionby dendritic cells and IL-12 receptor expression on NKT cells

The natural killer T (NKT) cell ligand alpha-galactosylceramide (alpha-GalC er) exhibits profound antitumor activities in vivo that resemble interleuki n (IL)-12-mediated antitumor activities. Because of these similarities betw een the activities of alpha-GalCer and IL-12, we investigated the involveme nt of IL-12 in the activation of NKT cells by alpha-GalCer. We first establ ished, using purified subsets of various lymphocyte populations, that a-Gal Cer selectively activates NKT cells for production of interferon (IFN)-gamm a. Production of IFN-gamma by NKT cells in response to alpha-GalCer require d IL-12 produced by dendritic cells (DCs) and direct contact between NKT ce lls and DCs through CD40/CD40 ligand interactions. Moreover, alpha-GalCer s trongly induced the expression of IL-12 receptor on NKT cells fi-om wild-ty pe but not CD1(-/-) or V alpha 14(-/-) mice. This effect of alpha-GalCer re quired the production of IFN-gamma by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of alp ha-GalCer together with suboptimal doses of IL-12 resulted in strongly enha nced natural killing activity and IFN-gamma production. Collectively, these findings indicate an important role for DC-produced IL-12 ill the activati on of NKT cells by alpha-GalCer and suggest that NKT cells may be able to c ondition DCs for subsequent immune responses. Our results also suggest a no vel approach For immunotherapy of cancer.