Granzyme B-mediated death of pancreatic beta-cells requires the proapoptotic BH3-only molecule bid

Abstract

Perforin-deficient NOD mice are protected from diabetes, suggesting that cytotoxic granule contents of CD8(+) T-cells have a significant role in killing beta-cells. Despite this, cytotoxic granule effects on human or mouse pancreatic islets have not been reported. We tested the susceptibility of human and mouse islet cells to purified recombinant perforin and granzyme B and measured apoptotic death using a number of assays. Perforin and granzyme B impaired insulin secretion from islet cells, and this was accompanied by cytochrome c release, caspase activation, and DNA fragmentation. Granzyme B-mediated apoptotic changes only occurred in the presence of perforin. When compared with hemopoieti..