The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/2/673/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 4, February 17, 1997 673-684

Articles

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

Mary C. Nakamura*, Eréne C. Niemi*, Mark J. Fisher*, Leonard D. Shultz{ddagger}, 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; {ddagger} 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-2Dd. 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-2Dd 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.

Address correspondence to Dr. Mary Nakamura, Immunology/Arthritis Section 111-R, Veterans Administration Medical Center, 4150 Clement Street, San Francisco, California 94121.

1Abbreviations used in this paper: APT, phosphotyrosine; InsP3, inositol triphosphates; ITIM, immunoreceptor tyrosine-based inhibitory motif; KIRs, killer inhibitory receptors; LAK, IL-2-activated NK cells.


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