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Mark T. Esser^*,, Doris M. Haverstick^,, Claudette L. Fuller^*,, Charles A. Gullo^*,, and Vivian Lam Braciale^*,

From the ^* Department of Microbiology, Beirne B. Carter Center for Immunology Research, and the Department of Pathology, University of Virginia, Health Sciences Center, Charlottesville, Virginia 22908

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.

¹Abbreviations used in this paper: BLT, N--benzyloxycarbonyl-L-lysine thiobenzyl; [Ca²⁺]_i, intracellular Ca²⁺ concentration; CsA, cyclosporin A; CTL, cytolytic T cell; ER, endoplasmic reticulum; FasL, fas ligand; FD, factor dependent; HA, hemagglutinin; NBCS, newborn calf serum; NDGA, nordihydroguaiaretic acid; NFAT, nuclear factor of activated T cells.

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This article has been cited by other articles:

• Melzer, N., Meuth, S. G., Wiendl, H. (2009). CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. FASEB J. 23: 3659-3673 [Abstract] [Full Text]  

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