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J. Exp. Med.,
Volume 187, Number 7, April 6, 1998 1057-1067
By
§
From the * Department of Microbiology, Cytolytic T cells use two mechanisms to kill virally infected cells, tumor cells, or other potentially autoreactive T cells in short-term in vitro assays. The perforin/granule exocytosis mechanism uses preformed cytolytic granules that are delivered to the target cell to induce apoptosis
and eventual lysis. FasL/Fas (CD95 ligand/CD95)-mediated cytolysis requires de novo protein synthesis of FasL by the CTL and the presence of the death receptor Fas on the target cell to induce apoptosis. Using a CD8+ CTL clone that kills via both the perforin/granule exocytosis and FasL/Fas mechanisms, and a clone that kills via the FasL/Fas mechanism only, we have examined the requirement of intra- and extracellular Ca2+ in TCR-triggered cytolytic effector
function. These two clones, a panel of Ca2+ antagonists, and agonists were used to determine
that a large biphasic increase in intracellular calcium concentration, characterized by release of
Ca2+ from intracellular stores followed by a sustained influx of extracellular Ca2+, is required
for perforin/granule exocytosis. Only the sustained influx of extracellular Ca2+ is required for
FasL induction and killing. Thapsigargin, at low concentrations, induces this small but sustained
increase in [Ca2+]i and selectively induces FasL/Fas-mediated cytolysis but not granule exocytosis. 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.
Beirne B. Carter Center for Immunology Research, and
the § Department of Pathology, University of Virginia, Health Sciences Center, Charlottesville, Virginia
22908
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