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

  1. Author:
    Colucci, F.
    Schweighoffer, E.
    Tomasello, E.
    Turner, M.
    Ortaldo, J. R.
    Vivier, E.
    Tybulewicz, V. L. J.
    Di Santo, J. P.

  2. Author Address

    Inst Pasteur, Lab Cytokines & Lymphoid Dev, Paris, France. Inst Pasteur, Lab Cytokines & Lymphoid Dev, Paris, France. Natl Inst Med Res, London NW7 1AA, England. CNRS Marseille Luminy, INSERM, Ctr Immunol, Marseille, France. Babraham Inst, Cambridge CB2 4AT, England. NCI, Frederick, MD 21702 USA. Colucci F Inst Pasteur, Lab Cytokines & Lymphoid Dev, Paris, France.
    1. Year: 2002
  2. Journal: Nature Immunology
    1. 3
    2. 3
    3. Pages: 288-294
  4. Type of Article: Article
  1. 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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