Search

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 CD[8.sup.+] 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 Fas ligation were not protected from diabetes. We next investigated the mechanism of protection provided by over-expression of suppressor of cytokine signaling-1 (SOCS-1) in β-cells of NOD8.3 mice. SOCS-1 islets remained intact when grafted into NOD8.3 mice and were less efficiently killed in vitro. However, addition of exogenous peptide rendered SOCS-1 islets susceptible to 8.3 T-cell-mediated lysis. Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill β-cells and the surprising blockade of NOD8.3 T-cell-mediated β-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition., Type 1 diabetes results from the selective destruction of insulin-secreting β-cells within the pancreas. Autoreactive T-cells play a major role in β-cell death both in humans and in the NOD [...]