Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes.
In this study, we have used a newly generated monoclonal antibody (mAb C1.7) to identify a novel 38-kD signal-transducing surface molecule (p38) expressed by lymphocyte subsets capable of cell-mediated cytotoxicity. Virtually all CD16+/CD56+ natural killer (NK) cells and approximately half of CD8+ (T cell receptor [TCR] alpha/beta+) T cells and TCR-gamma/delta+ T cells express the p38 surface molecule. Stimulation of p38 on NK cells with mAb C1.7 activated cytotoxicity, induced lymphokine production, and initiated polyphosphoinositol turnover and [Ca2+]i increases. Unlike other NK cell surface molecules that activate cytotoxicity, p38 stimulation did not result in the release of the granule enzyme N-carbobenzoxy-L-thiobenzyl ester-esterase even under conditions in which mAb C1.7 induced NK cell-mediated redirected lysis of Fc gamma R+ target cells. Activated (recombinant interleukin 2 [rIL-2], 5 d) CD8+ T cells mediated non-major histocompatibility complex (MHC)-restricted cytotoxicity, and the CD8+/p38+ subset contained the overwhelming majority of this activity. F(ab')2 fragments of mAb C1.7 inhibited non-MHC-restricted cytotoxicity mediated by resting NK cells and rIL-2-cultured T cells but did not affect spontaneous cytotoxicity mediated by activated, cultured NK cells. Taken as a whole, our results suggest that p38 may have a direct role in the recognition, signal transduction, and/or lytic mechanisms of non-MHC-restricted cytotoxicity.
Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104.
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Valiante
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Trinchieri
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D016827:CD8 Antigens; D002455:Cell Division / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004950:Esterases / Q000378:metabolism; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D007140:Immunoglobulin Fab Fragments; D008222:Lymphokines; D004950:Esterases