2 DISTINCT PATHWAYS OF SPECIFIC KILLING REVEALED BY PERFORIN MUTANT CYTOTOXIC T-LYMPHOCYTES

To study the contribution of putative perforin-independent mechanism i n the antigen-specific target destruction by cytotoxic T lymphocytes, CD8(+) CTL lines were established from spleen cells of chimeric mice p roduced by injecting perforin (-/-) embryonic stem cells into blastocy sts of RAG-2(-/-) mice. When tested on normal concanavalin A blasts, t hese perforin-deficient cytotoxic T lymphocyte lines were found to be capable of inducing antigen-specific target cell lysis accompanied by DNA degradation. In contrast, with target cells carrying a mutation in Fas molecule, perforin-independent cytotoxicity was not detectable. T hese data not only confirmed the primary role of perforin but simultan eously revealed a major contribution of a perforin-independent Fas-med iated pathway in antigen-specific cytolysis.