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

• Published in: The Journal of immunology (1950) 2009-05, Vol.182 (9), p.5560-5569
• Main Authors: Makedonas, George, Banerjee, Pinaki P, Pandey, Rahul, Hersperger, Adam R, Sanborn, Keri B, Hardy, Gareth A. D, Orange, Jordan S, Betts, Michael R
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Cell Degranulation - immunology; Cell Line, Transformed; Cytoplasmic Granules - immunology; Cytoplasmic Granules - metabolism; Cytotoxicity Tests, Immunologic - methods; Epitopes, T-Lymphocyte - immunology; Humans; Immunological Synapses - immunology; Lymphocyte Activation - immunology; Perforin - biosynthesis; Perforin - metabolism; Perforin - physiology; Protein Transport - immunology; Signal Transduction - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - virology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.0803945

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.