Background and Aims: CD1d is a major histocompatibility complex class I- like molecule that presents glycolipid antigens to a subset of natural killer (NK)1.1+ T cells. These NK T cells exhibit important immunoregulatory functions in several autoimmune disease models. Methods: To investigate whether CD1d and NK T cells have a similar role in intestinal inflammation, the effects of the glycolipid, α-galactosylceramide (α-GalCer), on dextran sodium sulfate (DSS)-induced colitis were examined. Wild-type (WT), CD1d(-/- ), and RAG(-/-) mice were examined for their response to either α-GalCer or the control analogue, α-mannosylceramide (α-ManCer). Results: WT mice, but not CD1d(-/-) and RAG(-/-) mice, receiving α-GalCer had a significant improvement in DSS-induced colitis based on body weight, bleeding, diarrhea, and survival when compared with those receiving α-ManCer. Elimination of NK T cells through antibody-mediated depletion resulted in a reduction of the effect of α-GalCer. Furthermore, adoptive transfer of NK T cells preactivated by α-GalCer, but not α-ManCer, resulted in diminished colitis. Using a fluorescent-labeled analogue of α-GalCer, confocal microscopy localized α-GalCer to the colonic surface epithelium of WT but not CD1d(-/-) mice, indicating α-GalCer binds CD1d in the intestinal epithelium and may be functionally active at this site. Conclusions: These results show an important functional role for NK T cells, activated by α-GalCer in a CD1d- restricted manner, in regulating intestinal inflammation.
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