Summary: CD I molecules represent a distinct lineage of antigen-presenting molecules chat are evolutionarily related to the classical major histocompatility complex (MHC) dass I and class II molecules, Unlike the classical MHC products that bind peptides, GDI molecules have evolved Co bind lipids and glycolipids, Murine and human CD Id molecules can present glycolipid antigens such as α-galactosylceramide (α-GalCer) to CD 1d-restricced natural killer (NK) T cells. Using CD 1d knockout mice we demonstrated chat CDI d expression is required for the development of NK T cells. These animals were also deficient in the rapid production of inter-leukin-4 and intcrferon-γ in response to stimulation by anti-CD3 antibodies. Despite these defects, CD Id knockout animals were able to generate strong T-helper type 1 (TH1) and TH2 responses. Spleen cells from these animals neither proliferated nor produced cytokines in response to stimulation by α-GalCer, Repeated injection of α-GalCer into wild-type but not CD 1 d mutant mice was able to clear metastatic tumors. We further showed that α-GalCer can inhibit disease in diabetes-prone non-obese diabetic mice. Collectively, these findings with CD ld knockout animals indicate a critical role for CD 1 d-dependent T cells in various disease conditions, and suggest that α-GalCer may be useful for therapeutic intervention in these diseases.