J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/02/673/12 $2.00
Volume 185, Number 4, February 17, 1997 673-684

Mouse Ly-49A Interrupts Early Signaling Events in Natural Killer Cell Cytotoxicity and Functionally Associates with the SHP-1 Tyrosine Phosphatase

By Mary C. Nakamura,^* Eréne C. Niemi,^* Mark J. Fisher,^* Leonard D. Shultz, William E. Seaman,^*§ and James C. Ryan^*

From the ^* Department of Medicine, University of California, San Francisco, California 94143; the Veterans Administration Medical Center, San Francisco, California 94121;  The Jackson Laboratory, Bar Harbor, Maine 04609; and the ^§ Department of Microbiology and Immunology, University of California, San Francisco, California 94143

The lytic activity of natural killer (NK) cells is inhibited by the expression of class I major histocompatibility complex (MHC) antigens on target cells. In murine NK cells, Ly-49A mediates inhibition of cytotoxicity in response to the class I MHC antigen H-2D^d. In this report, we studied the function of mouse Ly-49A in both the rat NK cell tumor line, RNK-16, transfected with Ly-49A cDNA, and in primary NK cells. We show that ligation of Ly-49A by H-2D^d inhibits early signaling events during target cell stimulation, including polyphosphoinositide turnover and tyrosine phosphorylation. We also show that Ly-49A directly associates with the cytoplasmic tyrosine phosphatase SHP-1, and that Ly-49A function is impaired in NK cells from SHP-1 mutant viable motheaten mice and from SHP-1-deficient motheaten mice. Finally, we demonstrate that mutational substitution of the tyrosine within the proposed SHP-1 binding motif in Ly-49A completely abrogates inhibition of NK cell cytotoxicity through this receptor. These results demonstrate that Ly-49A interrupts early activating signals in NK cells, and that SHP-1 is an important mediator of Ly-49A function.

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