The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice.
Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.
Hong
S
S
Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Wilson
M T
MT
Serizawa
I
I
Wu
L
L
Singh
N
N
Naidenko
O V
OV
Miura
T
T
Haba
T
T
Scherer
D C
DC
Wei
J
J
Kronenberg
M
M
Koezuka
Y
Y
Van Kaer
L
L
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics; D001324:Autoantigens; D003208:Concanavalin A / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000502:physiology
D018949:Antigens, CD1; D001324:Autoantigens; D005699:Galactosylceramides; D008024:Ligands; D003208:Concanavalin A; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase