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Killer Cell Inhibitory Receptor Recognition of Human Leukocyte Antigen (HLA) Class I Blocks Formation of a pp36/PLC- Signaling Complex in Human Natural Killer (NK) Cells

Nicholas M. Valiante^*, Joseph H. Phillips, Lewis L. Lanier, and Peter Parham^*

From the ^* Departments of Structural Biology and Microbiology & Immunology, Stanford University Medical School, Stanford, California 94305; and the Department of Human Immunology, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto, California 94304

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C- in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.

The authors wish to thank Dr. S. Cooper and Dr. G. Koretzky for their critical reading of the manuscript.

This research was supported by National Institutes of Health grant AI22039 to P. Parham. N.M. Valiante is a fellow of the Cancer Research Institute. DNAX Research Institute for Molecular and Cellular Biology is supported by Schlering Plough Corporation.

¹ Abbreviations used in this paper: GST, glutathione-S-transferase; IP3, inositol 1,4,5-triphosphate; KIR, killer cell inhibitory receptors; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatases.

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