CA2-LYMPHOCYTE EFFECTOR FUNCTIONS( SIGNALING MODULATES CYTOLYTIC T)

Cytolytic T cells use two mechanisms to kill virally infected cells, t umor cells, or other potentially autoreactive T cells in short-term in vitro assays. The perform/granule exocytosis mechanism uses performed cytolytic granules that are delivered to the target cell to induce ap optosis and eventual lysis. FasL/Fas (CD95 ligand/CD95)-mediated cytol ysis requires de novo protein synthesis of FasL by the CTL and the pre sence of the death receptor Fas on the target cell to induce apoptosis . Using a CD8(+) CTL clone that kills via both the perforin/granule ex ocytosis and FasL/Fas mechanisms, and a clone that kills via the FasL/ Fas mechanism only, we have examined the requirement of intra- and ext racellular Ca2+ in TCR-triggered cytolytic effector function. These tw o clones, a panel of Ca2+ antagonists, and agonists were used to deter mine that a large biphasic increase in intracellular calcium concentra tion, characterized by release of Ca2+ from intracellular stores follo wed by a sustained influx of extracellular Ca2+, is required for perfo rin/granule exocytosis. Only the sustained influx of extracellular Ca2 + is required for Fast induction and killing. Thapsigargin, at low con centrations, induces this small but sustained increase in [Ca2+](1) an d selectively induces FasL/Fas-mediated cytolysis but not granule exoc ytosis. These results further define the role of Ca2+ in perforin and FasL/Fas killing and demonstrate that differential Ca2+ signaling can modulate T cell effector functions.