J. Exp. Med., Volume 186, Number 12, December 15, 1997 1965-1974

Functional Role for Syk Tyrosine Kinase in Natural Killer Cell-mediated Natural Cytotoxicity

By Kathryn M. Brumbaugh,^* Bryce A. Binstadt,^* Daniel D. Billadeau,^* Renee A. Schoon,^* Christopher J. Dick,^* Rosa M. Ten, and Paul J. Leibson^*

From the ^* Department of Immunology, and the  Division of Allergy, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Natural killer (NK) cells are named based on their natural cytotoxic activity against a variety of target cells. However, the mechanisms by which sensitive targets activate killing have been difficult to study due to the lack of a prototypic NK cell triggering receptor. Pharmacologic evidence has implicated protein tyrosine kinases (PTKs) in natural killing; however, Lck-deficient, Fyn-deficient, and ZAP-70-deficient mice do not exhibit defects in natural killing despite demonstrable defects in T cell function. This discrepancy implies the involvement of other tyrosine kinases. Here, using combined biochemical, pharmacologic, and genetic approaches, we demonstrate a central role for the PTK Syk in natural cytotoxicity. Biochemical analyses indicate that Syk is tyrosine phosphorylated after stimulation with a panel of NK-sensitive target cells. Pharmacologic exposure to piceatannol, a known Syk family kinase inhibitor, inhibits natural cytotoxicity. In addition, gene transfer of dominant-negative forms of Syk to NK cells inhibits natural cytotoxicity. Furthermore, sensitive targets that are rendered NK-resistant by major histocompatibility complex (MHC) class I transfection no longer activate Syk. These data suggest that Syk activation is an early and requisite signaling event in the development of natural cytotoxicity directed against a variety of cellular targets.

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