Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy β-cells via the perforin and Fas pathways

Abstract

Cytotoxic T-cells are the major mediators of β-cell destruction in type 1 diabetes, but the molecular mechanisms are not definitively established. We have examined the contribution of perforin and Fas ligand to β-cell destruction using islet-specific CD8+ T-cells from T-cell receptor transgenic NOD8.3 mice. NOD8.3 T-cells killed Fas-deficient islets in vitro and in vivo. Perforin-deficient NOD8.3 T-cells were able to destroy wild-type but not Fas-deficient islets in vitro. These results imply that NOD8.3 T-cells use both pathways and that Fas is required for β-cell killing only when perforin is missing. Consistent with this theory, transgenic NOD8.3 mice with β-cells that do not respond to F..