Gastroenterology

Gastroenterology

Volume 119, Issue 1, July 2000, Pages 119-128
Gastroenterology

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

https://doi.org/10.1053/gast.2000.9114Get rights and content

Abstract

Background & 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.

GASTROENTEROLOGY 2000;119:119-128

Section snippets

Mice

Wild-type (WT) and recombinase-activating gene 2 knockout (RAG−/−) C57BL/6x129/Sv mice were purchased from Jackson Laboratories (Bar Harbor, ME). CD1d−/− mice have been generated as previously described22 and were also used as a mixed background of C57BL/6x129/Sv. All animals were maintained under specific pathogen–free conditions on standard laboratory chow and water ad libitum until the desired age (8-10 weeks) and/or weight (20-30 g) were achieved. All mice were treated humanely according to

α-GalCer protects WT mice from colitis associated with DSS administration

To evaluate α-GalCer in the well-characterized DSS model of colitis,26 mice were administered DSS (2.5%) in the drinking water and the glycolipid effects were analyzed after administration of the lipid on day 1 and every other day thereafter for the duration of the study. Preliminary investigations established an optimal dose of α-GalCer at 100 μg/kg body wt (data not shown). At this dose of α-GalCer, there was a significant amelioration in the severity of colitis as observed in WT mice (Figure

Discussion

In this report, we have used a well-established model of colitis associated with administration of DSS to show that NK T cells activated by α-GalCer exhibit an important ameliorative effect on the severity of colitis associated with DSS. DSS is a sulfated polymer that causes a self-limited colitis with acute administration or colitis with chronic features on continuous exposure.26 This model allows for direct testing of cause and effect relationships between specific interventions and colitis.

Acknowledgements

The authors thank Dr. Ramnik Xavier for the donation of some RAG−/− mice; Drs. Xiaoping Zhu, Victor Morales, and Atsushi Nakajima and Dan Brown for helpful advice; and Lili Miao for technical assistance with this project.

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  • Cited by (0)

    Supported by National Institutes of Health grants DK02532 (to L. J. S.), AI33911 (to S. P. B.), DK46906, DK53304, DK43351 (to D.K.P.), and DK44319, DK53056, DK51362 (to R.S.B.).

    ☆☆

    Address requests for reprints to Richard S. Blumberg, M.D., Gastroenterology Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115. e-mail: [email protected]; fax: (617) 264-5185.

    Lawrence J. Saubermann and Paul Beck contributed equally to the work.

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