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

F Colucci, E Schweighoffer, E Tomasello, M Turner… - Nature …, 2002 - nature.com
F Colucci, E Schweighoffer, E Tomasello, M Turner, JR Ortaldo, E Vivier, VLJ Tybulewicz
Nature immunology, 2002nature.com
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 …
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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