Lipid antigen presentation in the immune system: lessons learned from CD1dknockout mice

CD1 molecules represent a distinct lineage of antigen-presenting molecules that are evolutionarily related to the classical major histocompatibility c omplex (MHC) class I and class II molecules. Unlike the classical MHC produ cts that bind peptides, CD1 molecules have evolved to bind lipids and glyco lipids. Murine and human CD1d molecules can present glycolipid antigens suc h as alpha-galactosylceramide (alpha-GalCer) to CD1d-restricted natural kil ler (NK) T cells. Using CD1d knockout mice we demonstrated that CD1d expres sion is required for the development of NK T cells. These animals were also deficient in the rapid production of interleukin-4 and interferon-gamma in response to stimulation by anti-CD3 antibodies. Despite these defects, CD1 d knockout animals were able to generate strong T-helper type 1 (T(H)1) and T(H)2 responses. Spleen cells from these animals neither proliferated nor produced cytokines in response to stimulation by alpha-GalCer. Repealed inj ection of alpha-GalCer into wild-type but not CD1d mutant mice was able to clear metastatic tumors. We further showed that alpha-GalCer can inhibit di sease in diabetes-prone non-obese diabetic mice. Collectively, these findin gs with CD1d knockout animals indicate a critical role for CD1d-dependent T cells in various disease conditions, and suggest that alpha-GalCer may be useful for therapeutic intervention in these diseases.