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.
Makedonas
George
G
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Banerjee
Pinaki P
PP
Pandey
Rahul
R
Hersperger
Adam R
AR
Sanborn
Keri B
KB
Hardy
Gareth A D
GA
Orange
Jordan S
JS
Betts
Michael R
MR
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*
D018984:Epitopes, T-Lymphocyte; D054353:Perforin