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

被引:95
作者
Colucci, F [1 ]
Schweighoffer, E
Tomasello, E
Turner, M
Ortaldo, JR
Vivier, E
Tybulewicz, VLJ
Di Santo, JP
机构
[1] Inst Pasteur, Lab Cytokines & Lymphoid Dev, Paris, France
[2] Natl Inst Med Res, London NW7 1AA, England
[3] CNRS Marseille Luminy, INSERM, Ctr Immunol, Marseille, France
[4] Babraham Inst, Cambridge CB2 4AT, England
[5] NCI, Frederick, MD 21702 USA
基金
英国医学研究理事会;
关键词
D O I
10.1038/ni764
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:288 / 294
页数:7
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