The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/8/473/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 3, August 4, 1997 473-478

Brief Definitive Reports

Negative Signaling Pathways of the Killer Cell Inhibitory Receptor and Fc{gamma}RIIb1 Require Distinct Phosphatases

Neetu Gupta*, Andrew M. Scharenberg{ddagger}, Deborah N. Burshtyn*, Nicolai Wagtmann*, Mario N. Lioubin§, Larry R. Rohrschneider§, Jean-Pierre Kinet{ddagger}, and Eric O. Long*

From the * Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852; {ddagger} Laboratory of Allergy and Immunology, Department of Pathology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02215; and the § Fred Hutchinson Cancer Research Center, Seattle, Washington 98104

Inhibition of natural killer (NK) cells by the killer cell inhibitory receptor (KIR) involves recruitment of the tyrosine phosphatase SHP-1 by KIR and is prevented by expression of a dominant negative SHP-1 mutant. Another inhibitory receptor, the low affinity Fc receptor for immunoglobulin G (IgG) (Fc{gamma}RIIb1), has been shown to bind SHP-1 when cocross-linked with the antigen receptor on B cells (BCR). However, coligation of Fc{gamma}RIIb1 with BCR and with Fc{varepsilon}RI on mast cells leads to recruitment of the inositol 5' phosphatase SHIP and to inhibition of mast cells from SHP-1–deficient mice. In this study, we evaluated the ability of these two inhibitory receptors to block target cell lysis by NK cells, and the contribution of SHP-1 and SHIP to inhibition. Recombinant vaccinia viruses encoding chimeric receptors and dominant negative mutants of SHP-1 and SHIP were used for expression in mouse and human NK cells. When the KIR cytoplasmic tail was replaced by that of Fc{gamma}RIIb1, recognition of HLA class I on target cells by the extracellular domain resulted in inhibition. A dominant negative mutant of SHP-1 reverted the inhibition mediated by the KIR cytoplasmic tail but not that mediated by Fc{gamma}RIIb1. In contrast, a dominant negative mutant of SHIP reverted only the inhibition mediated by the Fc{gamma}RIIb1 tail, providing functional evidence that SHIP plays a role in the Fc{gamma}RIIb1-mediated negative signal. These data demonstrate that inhibition of NK cells by KIR involves primarily the tyrosine phosphatase SHP-1, whereas inhibition mediated by Fc{gamma}RIIb1 requires the inositol phosphatase SHIP.

Address correspondence to E.O. Long, LIG-NIAID-NIH Twinbrook II, 12441 Parklawn Drive, Rockville, MD 20852-1727. E-mail: elong{at}nih.gov


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