J. Exp. Med.
Volume 186, Number 3, August 4, 1997 473-478

BRIEF DEFINITIVE REPORT:
Negative Signaling Pathways of the Killer Cell Inhibitory Receptor and FcRIIb1 Require Distinct Phosphatases

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

From the ^* Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852;  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) (FcRIIb1), has been shown to bind SHP-1 when cocross-linked with the antigen receptor on B cells (BCR). However, coligation of FcRIIb1 with BCR and with FcRI 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 FcRIIb1, 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 FcRIIb1. In contrast, a dominant negative mutant of SHIP reverted only the inhibition mediated by the FcRIIb1 tail, providing functional evidence that SHIP plays a role in the FcRIIb1-mediated negative signal. These data demonstrate that inhibition of NK cells by KIR involves primarily the tyrosine phosphatase SHP-1, whereas inhibition mediated by FcRIIb1 requires the inositol phosphatase SHIP.

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