The natural killer T-cell ligand α-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice

• Published in: Nature medicine Vol. 7; no. 9; pp. 1052 - 1056
• Main Authors: Van Kaer, Luc, Hong, Seokmann, Wilson, Michael T, Serizawa, Isao, Wu, Lan, Singh, Nagendra, Naidenko, Olga V, Miura, Toru, Haba, Tomoku, Scherer, David C, Wei, Jie, Kronenberg, Mitchell, Koezuka, Yasuhiko
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-09-2001
• Subjects: a-Galactosylceramide; Animals; Antigens, CD1 - genetics; Autoantigens; CD1d antigen; Concanavalin A - pharmacology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Female; Galactosylceramides - pharmacology; Glutamate Decarboxylase - immunology; Immunoglobulin E - blood; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Ligands; Mice; Mice, Inbred NOD; Mice, Inbred Strains; Mice, Mutant Strains; Spleen - drug effects; Spleen - metabolism; Th2 Cells - drug effects; Th2 Cells - physiology
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm0901-1052

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.