title: Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases.
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 phosphatidyl 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.
authors.affiliation: Laboratory for Cytokines and Lymphoid Development, The Pasteur Institute, Paris, France. cecco@pasteur.fr
authors.forename: Francesco
authors.initials: F
authors.lastname: Colucci
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.forename: Elena
authors.initials: E
authors.lastname: Tomasello
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D004792:Enzyme Precursors / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D055607:Receptors, Natural Killer Cell; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse