Rapid Up-Regulation and Granule-Independent Transport of Perforin to the Immunological Synapse Define a Novel Mechanism of Antigen-Specific CD8+ T Cell Cytotoxic Activity

CTL are endowed with the ability to eliminate pathogens through perforin-mediated cytotoxic activity. The mechanism for perforin-mediated Ag-specific killing has been solely attributed to cytotoxic granule exocytosis from activated CD8(+) T cells. In this study, we redefine this mechanism, demonstrating that virus-specific CD8(+) T cells rapidly up-regulate perforin in response to stimulation temporally with IFN-gamma and CD107a expression. Following Ag-specific activation, newly synthesized perforin rapidly appears at the immunological synapse, both in association with and independent of cytotoxic granules, where it functions to promote cytotoxicity. Our work suggests a novel mechanism of CTL cytotoxicity and identifies a novel correlate of CD8(+) T cell-mediated immunity. The Journal of Immunology, 2009, 182: 5560-5569.