Paired NK cell receptors controlling NK cytotoxicity

Abstract

a b s t r a c tHuman natural killer (NK) cells possess an arsenal of receptors programmed to regulate the NK cell functions, once encountering a target cell. In general, the activating receptors mediate cytotoxicity when engaged by their tumor specific, stress induced, virally encoded, or rarely, self ligands. Whereas, the inhibitory receptors bind self molecules, mostly MHC class I, presented on all normal and healthy nucleated cells. However, NK cells also possess numerous, highly homologous, pairs of receptors that sometimes even share the same ligands but display divergent functions. In this review we describe the NK cell repertoire of paired receptors and discuss questions regarding their function and mode of action. We focus primarily on the three PVR-binding receptors; the co-stimulatory DNAM1 and CD96 and the inhibitory TIGIT. Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Paired inhibitory and activating NK cell receptorsNK cells, which belong to the innate immune system, are able to quickly kill virally infected and malignant cells. The complicated repertoire of activating and inhibitory receptors that regulate NK activity helps to ensure that NK cells would be able to efficiently kill invading pathogens but not normal self cells [1]. The differences in the function of the inhibitory and activating NK cell receptors are reflected by the different ligands recognized by the various receptors. While the activating NK cell receptors recognize pathogen-derived, stress-induced, tumor specific and surprisingly sometimes even self ligands, the inhibitory receptors, in general, recognize self proteins, mainly MHC class I [2]. The differences in the inhibitory and activating ligands repertoire probably exist to guarantee the discrimination between self and non-self. Therefore, it was surprising to discover the existence of pairs of highly homologous proteins that in some cases even share the same ligands, but display divergent functions (Table 1). In this review we discuss the properties of the various members of the human paired NK receptors and mainly focus on reviewing the activity of the PVR-binding receptors in an attempt to better understand the biological function of the paired receptors. Paired receptors: MHC class I binding proteinsMost of the paired receptors belong to the killer cell immunoglobulin-like receptors (KIR) family. This family includes inhibitory receptors with a long intra cytoplasmic domain containing a variable number of immunoreceptor tyrosine-based inhibitory motifs (ITIM), and activating or co-activating receptors, with a nearly identical extracellular region containing shorter intra cytoplasmic domain which lacks ITIMs (Table 1). These short killer activating receptors (KAR) also display a unique transmembrane sequence, which contains a charged amino acid that interacts with an activating adaptor molecule [3].The ligands of most of the KARs are unknown (Table 1) and most of the known KAR ligands are MHC class I proteins which are...

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