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Comparing the Relative Role of Perforin/Granzyme Versus Fas/Fas Ligand Cytotoxic Pathways in CD8⁺ T Cell-Mediated Insulin-Dependent Diabetes Mellitus¹

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

CD8⁺ cytotoxic T cells play a critical role in initiating insulin-dependent diabetes mellitus. The relative contribution of each of the major cytotoxic 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 ß cell lysis and induction of diabetes, we have used a transgenic mouse model in which ß cells expressing the influenza virus hemagglutinin (HA) are destroyed by HA-specific CD8⁺ T cells from clone-4 TCR-transgenic mice. Upon adoptive transfer of CD8⁺ T cells from perforin-deficient clone-4 TCR mice, there was a 30-fold increase in the number of 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 spontaneous diabetes, which occurs in double transgenic neonates that express both clone-4 TCR and Ins-HA transgenes, mice deficient in either the perforin or FasL/Fas lytic pathway become diabetic soon after birth. This indicates that, in the neonate, large numbers of autoreactive CD8⁺ T cells can lead to destruction of islet ß cells by either pathway.

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