title: 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.
abstract: 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.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: George
authors.initials: G
authors.lastname: Makedonas
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.forename: Rahul
authors.initials: R
authors.lastname: Pandey
authors.forename: Adam R
authors.initials: AR
authors.lastname: Hersperger
authors.forename: Keri B
authors.initials: KB
authors.lastname: Sanborn
authors.forename: Gareth A D
authors.initials: GA
authors.lastname: Hardy
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015550:Cell Degranulation / Q000276:immunology; D002461:Cell Line, Transformed; D003594:Cytoplasmic Granules / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D054353:Perforin / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D054353:Perforin