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Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases

Nature Immunology volume 3, pages 288–294 (2002)Cite this article

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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Figure 1: NK cell development uncoupled from Syk and ZAP-70.
Figure 2: NK cells deficient in Syk and ZAP-70 are heterogeneous in nature.
Figure 3: Natural killing uncoupled from Syk, ZAP-70, FcRγ and CD3ζ.
Figure 4: Natural killing is independent of ITAM-bearing receptors and NKG2D.
Figure 5: Discrimination between Syk- and ZAP-70-dependent and independent receptors on NK cells.
Figure 6: Blocking Syk kinases in wild-type NK cells does not inhibit natural killing.
Figure 7: Additive roles for Syk, Src and PI3K in NK cell signaling.

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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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Authors and Affiliations

  1. Laboratory for Cytokines and Lymphoid Development, The Pasteur Institute, Paris, France

    Francesco Colucci & James P. Di Santo

  2. National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, London, UK

    Edina Schweighoffer & Victor L. J. Tybulewicz

  3. Centre d'Immunologie INSERM-CNRS de Marseille Luminy - Case, 906, France

    Elena Tomasello & Eric Vivier

  4. The Babraham Institute, Babraham, CB2 4AT, Cambridge, UK

    Martin Turner

  5. National Cancer Institute, Frederick, 21702, MD, USA

    John R. Ortaldo

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  1. Francesco Colucci
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Correspondence to Francesco Colucci.

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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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