Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice.
OBJECTIVE
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, alpha-galactosylceramide (alpha-GalCer), on dextran sodium sulfate (DSS)-induced colitis were examined. Wild-type (WT), CD1d(-/-), and RAG(-/-) mice were examined for their response to either alpha-GalCer or the control analogue, alpha-mannosylceramide (alpha-ManCer).


RESULTS
WT mice, but not CD1d(-/-) and RAG(-/-) mice, receiving alpha-GalCer had a significant improvement in DSS-induced colitis based on body weight, bleeding, diarrhea, and survival when compared with those receiving alpha-ManCer. Elimination of NK T cells through antibody-mediated depletion resulted in a reduction of the effect of alpha-GalCer. Furthermore, adoptive transfer of NK T cells preactivated by alpha-GalCer, but not alpha-ManCer, resulted in diminished colitis. Using a fluorescent-labeled analogue of alpha-GalCer, confocal microscopy localized alpha-GalCer to the colonic surface epithelium of WT but not CD1d(-/-) mice, indicating alpha-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 alpha-GalCer in a CD1d-restricted manner, in regulating intestinal inflammation.
Saubermann
L J
LJ
Division of Gastroenterology and the Harvard Digestive Diseases Center, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Beck
P
P
De Jong
Y P
YP
Pitman
R S
RS
Ryan
M S
MS
Kim
H S
HS
Exley
M
M
Snapper
S
S
Balk
S P
SP
Hagen
S J
SJ
Kanauchi
O
O
Motoki
K
K
Sakai
T
T
Terhorst
C
C
Koezuka
Y
Y
Podolsky
D K
DK
Blumberg
R S
RS
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000494:pharmacology*; D055610:Antigens, CD1d; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D016264:Dextran Sulfate; D005699:Galactosylceramides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016654:Genes, RAG-1 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D020033:Protein Isoforms / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D020033:Protein Isoforms; D016264:Dextran Sulfate