Abstract
The intracellular signals that trigger natural cytotoxicity have not been clearly determined. The Syk and ZAP-70 tyrosine kinases are essential for cellular activation initiated by B and T cell antigen receptors and may drive natural killer (NK) cell cytotoxicity via receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs). However, we found that, unlike B and T cells, NK cells developed in Syk−/−ZAP-70−/− mice and, despite their nonfunctional ITAMs, lysed various tumor targets in vitro and eliminated tumor cells in vivo, including those without NKG2D ligands. The simultaneous inhibition of phosphotidyl inositol 3 kinase and Src kinases abrogated the cytolytic activity of Syk−/−ZAP-70−/− NK cells and strongly reduced that of wild-type NK cells. This suggests that distinct and redundant signaling pathways act synergistically to trigger natural cytotoxicity.
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Acknowledgements
We thank T. Kadlecek and A. Weiss for the ZAP-70−/− mice; P. Love for the FcRγ−/−CD3ζ−/− mice; E. Corcuff and O. Richard for skillful help; S. Samson, C. Roth, C. Vosshenrich, D. McVicar, A. Diefenbach, D. Raulet and E. Long for constructive discussions; and G. Langsley and O. Acuto for critically reading the manuscript. Supported by grants from The Pasteur Institute, Ligue Nationale Contre le Cancer, Association pour la Recherche sur le Cancer and the Institut National de la Santé et de la Recherche Medicale (to F. C. and J. P. D.); the European Molecular Biology Organization (to E. S.); the Medical Research Council (to V. L .J .T.); the Babraham Institute (to M. T.); and the Fondation pour la Recherche Medicale to (E. T).
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Colucci, F., Schweighoffer, E., Tomasello, E. et al. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nat Immunol 3, 288–294 (2002). https://doi.org/10.1038/ni764
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DOI: https://doi.org/10.1038/ni764
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