IL-1 alpha, IL-1 beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes

Cytokines such as IL-1 alpha, IL-1 beta, and IFN-gamma have long been impli cated in the pathogenesis of autoimmune diabetes, but the mechanisms throug h which they promote diabetogenesis remain unclear. Here we show that CD4() T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice exp ressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4. 1-TCR) can kill IL-1 alpha-, IL-1 beta-, and IFN-gamma-treated beta cells f rom NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of i slet cells in vitro was associated with cytokine-induced upregulation of Fa s on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In cont rast, abrogation of perforin expression did not affect beta cell-specific c ytotoxicity or the diabetogenic potential of these T cells. These data demo nstrate a novel mechanism of action of IL-1 alpha, IL-1 beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-de pendent lysis by autoreactive CD4(+) T cells.