The natural killer T-cell ligand α-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. Vα14-Jα15 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 Vα14 NKT cells by α-galactosylceramide (α-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that α-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of αGalCer to suppress interferon-γ 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 α-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that α-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.