Inhibition of autoimmune diabetes by Fas ligand: The paradox is solved

Previous reports that diabetogenic lymphocytes did not induce diabetes in n onobese diabetic (NOD)-lpr mice suggested the critical role of Fas-Fas liga nd (FasL) interaction in pancreatic beta cell apoptosis, However, recent wo rks demonstrated that Fast is not an effector molecule in islet beta cell d eath, We addressed why diabetes cannot be transferred to NOD-lpr mice despi te the nonessential role of Fas in beta cell apoptosis, Lymphocytes from NO D-lpr mice were constitutively expressing Fast, A decrease in the number of FasL(+) lymphocytes by neonatal thymectomy facilitated the development of insulitis, Cotransfer of FasL(+) lymphocytes from NOD-lpr mice completely a brogated diabetes after adoptive transfer of lymphocytes from diabetic NOD mice. The inhibition of diabetes by cotransferred lymphocytes was reversed by anti-Fast Bb, indicating that Fast on abnormal lymphocytes from NOD-lpr mice was responsible for the inhibition of diabetes transfer. Pretreatment of lymphocytes with soluble Fast (sFasL) also inhibited diabetes transfer, sFasL treatment decreased the number of CD4(+)CD45RB(low) cells and increas ed the number of propidium iodide-stained cells among CD4(+)CD45RB(low) cel ls, suggesting that sFasL induces apoptosis on CD4(+)CD45RB(low) "memory" c ells. These results resolve the paradox between previous findings and sugge st a new role for Fast in the treatment of autoimmune disorders. Our data a lso suggest that sFasL is involved in the deletion of potentially hazardous peripheral "memory" cells, contrary to previous reports that Fas on unmani pulated peripheral lymphocytes is nonfunctional.