Nature Immunology
3, 288 - 294 (2002)
Published online: 11 February 2002; | doi:10.1038/ni764
Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinasesFrancesco Colucci1, Edina Schweighoffer2, Elena Tomasello3, Martin Turner4, John R. Ortaldo5, Eric Vivier3, Victor L. J. Tybulewicz2
& James P. Di Santo11
Laboratory for Cytokines and Lymphoid Development, The Pasteur Institute, Paris, France. 2
National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK. 3
Centre d'Immunologie INSERM-CNRS de Marseille Luminy - Case 906, France. 4
The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK. 5
National Cancer Institute, Frederick, MD 21702, USA.
Correspondence should be addressed to Francesco Colucci cecco@pasteur.frThe 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.
|
