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Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic [small beta, Greek] cells by T lymphocytes.It is believed that CD8 (+) cytotoxic T lymphocytes (CTLs) effect the initial [small beta, Greek]-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of [small beta, Greek] cell-reactive CD8+ T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8+ CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2Kd complex on [small beta, Greek] cells, to effect [small beta, Greek]-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide-pulsed non-[small beta, Greek]-cell targets via both perforin and Fas, but they killed NOD [small beta, Greek] cells via Fas exclusively. Perforin-deficient 8.3-TCR-transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8+ CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill [small beta, Greek] cells in a Fas-dependent and perforin-independent manner.J.Clin. Invest. 103:1201-1209 (1999).