The receptors that regulate the activity of NK cells fall into two large families that contain a number of other cell-surface receptors in addition to NK receptors (Fig. 3.40). Members of the killer cell immunoglobulin-like receptor family, or KIRs, have differing numbers of immunoglobulin domains. Some, such as KIR-2D, have two immunoglobulin domains, whereas others, such as KIR-3D, have three. The KIR genes form part of a larger cluster of immunoglobulin-like receptor genes known as the leukocyte receptor complex (LRC). Another family, the killer cell lectin-like receptors, or KLRs, are C-type lectin-like proteins whose genes reside within a gene cluster called the NK receptor complex (NKC). Mice lack KIR genes, and instead predominantly express Ly49 receptors encoded in the NKC on mouse chromosome 6 to control their NK-cell activity. These receptors can be activating or inhibitory, and are highly polymorphic between different strains of mice. By contrast, humans lack functional Ly49 genes and rely on KIRs encoded in the LRC to control their NK-cell activity. An important feature of the NK-cell population is that any given NK cell expresses only a subset of the receptors in its potential repertoire, and so not all NK cells in the individual are identical.
Activating and inhibitory receptors are present within the same structural family. Whether a KIR protein is activating or inhibitory depends on the presence or absence of particular signaling motifs in its cytoplasmic domain. Inhibitory KIRs have long cytoplasmic tails that contain an immunoreceptor tyrosine-based inhibition motif (ITIM). The consensus sequence for the ITIM is V/I/LxYxxL/V, where x stands for any amino acid. For example, the cytoplasmic tails of the inhibitory receptors KIR-2DL and KIR-3DL each contain two ITIMs (Fig. 3.41). When ligands associate with an inhibitory KIR, the tyrosine in its ITIM becomes phosphorylated by the action of Src family protein tyrosine kinases. When phosphorylated, the ITIM can then bind the intracellular protein tyrosine phosphatases SHP-1 (src homology region 2-containing protein tyrosine phosphatase-1) and SHP-2, which become localized near the cell membrane. These phosphatases inhibit signaling induced by other receptors by removing phosphates from tyrosine residues on other intracellular signaling molecules.
Activating KIRs have short cytoplasmic tails, designated, for example, as KIR2DS and KIR-3DS (see Fig. 3.41). These receptors lack an ITIM and instead have a charged residue in their transmembrane regions that associates with an accessory signaling protein called DAP12. DAP12 is a transmembrane protein that contains an immunoreceptor tyrosine-based activation motif (ITAM, with consensus sequence YXX[L/I]X6–9YXX[L/I]) in its cytoplasmic tail and forms a disulfide-linked homodimer in the membrane. When a ligand binds to an activating KIR, the tyrosine residues in the ITAM of DAP12 become phosphorylated, turning on intracellular signaling pathways that activate the NK cell and lead to release of the cytotoxic granules. The phosphorylated ITAMs bind and activate intracellular tyrosine kinases such as Syk or ZAP-70, leading to further signaling events similar to those described for T cells in Chapter 7.