Critical role for IFN-gamma in natural killer cell-mediated protection from diabetes

Autoimmune diabetes in nonobese diabetic (NOD) mice can be prevented by a single injection of complete Freund's adjuvant (CFA), but the mechanisms mediating protection remains unclear. We previously showed that NOD mice immunized with CIA have a markedly reduced incidence of diabetes that is associated with a significant decrease in the number of P-cell-specific, autoreactive cytotoxic T lymphocytes and, furthermore, that the effect of CFA is mediated by natural killer (NK) cells. In this study, we report one mechanism by which NK cells regulate the onset of diabetes. Administration of CIA produced a rapid increase in NK cell frequency and function, including cytotoxicity and IFN-gamma secretion. By co-transferring NK cells from IFN-gamma-deficient (or wild-type) NOD mice and spleen cells from diabetic NOD mice to NOD/SCID recipients, we show that IFN-gamma secretion by NK cells significantly influences the effect of CIA protection. In contrast, NK cytotoxicity does not appear to participate in CFA-mediated protection from diabetes. Our findings demonstrate that NK cells mediate the protective effects of CIA through secretion of IFN-gamma.