Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8(+) T cell-mediated insulin-dependent diabetes mellitus

CD8(+) cytotoxic T cells play a critical role in initiating insulin-depende nt diabetes mellitus. The relative contribution of each of the major cytoto xic pathways, perforin/granzyme and Fas/Fas ligand (FasL), in the induction of autoimmune diabetes remains controversial. To evaluate the role of each lytic pathway in beta cell lysis and induction of diabetes, we have used a transgenic mouse model in which beta cells expressing the influenza virus hemagglutinin (HA) are destroyed by IFA-specific CD8(+) T cells from clone- 4 TCR-transgenic mire. Upon adoptive transfer of CD8(+) T cells from perfor in-deficient clone-4 TCR mice, there was a 30-fold increase in the number o f T cells required to induce diabetes. In contrast, elimination of the Fas/ FasL pathway of cytotoxicity had little consequence. When both pathways of cytolysis were eliminated, mice did not become diabetic. Using a model of s pontaneous diabetes, which occurs in double transgenic neonates that expres s both clone-4 TCR and Zns-HA transgenes, mice deficient in either the perf orin or FasL/Fas lytic pathway become diabetic soon after birth. This indic ates that, in the neonate, large numbers of autoreactive CD8+ T cells can l ead to destruction of islet beta cells by either pathway.