Activation of natural killer T cells by α-galactosylceramide in the presence of CD1d provides protection against colitis in mice

Lawrence J. Saubermann, Paul Beck, Ype P. De Jong, Richard S. Pitman, Mark S. Ryan, Hyun S. Kim, Mark Exley, Scott Snapper, Steven P. Balk, Susan J. Hagen, Osamu Kanauchi, Kazuhiro Motoki, Teruyuki Sakai, Cox Terhorst, Yasuhiko Koezuka, Daniel K. Podolsky, Richard S. Blumberg

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)119-128
Number of pages10
JournalGastroenterology
Volume119
Issue number1
DOIs
StatePublished - Jul 2000

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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