Up on the tightrope: natural killer cell activation and inhibition

Abstract

Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell-driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system.

Figure 1

ITAM-containing NK receptors. Schematic representation of NK receptors of the immunoglobulin superfamily or C-type lectin—like family that pair with the ITAM-bearing DAP12, FcεRI-γ and CD3-ζ signaling subunits. For a comprehensive list of ITAM-signaling NK cell receptors, see Supplementary Table 1. Note that human CD16 can pair with homodimers of FcεRI-γ or CD3-ζ or with heterodimers of FcεRI-γ and CD3-ζ, whereas mouse CD16 signals efficiently only with homodimers of FcεRI-γ. ITAM-bearing signaling subunits contain aspartate residues (D) within their transmembrane segments that associate noncovalently with oppositely charged lysine or arginine residues within the transmembrane of the receptors, an exception being CD16, which also has an aspartate residue within its transmembrane. Y, tyrosine residues within ITAM domains.

Figure 2

ITAM-mediated signaling in NK cells. ITAM-bearing signaling subunits are phosphorylated, probably by Src family kinases, after receptor engagement. Syk and/or ZAP-70 (both of which are expressed by human and mouse NK cells) are recruited to the phosphorylated ITAMs, initiating a cascade of downstream signaling as depicted. The signaling pathways depicted are hypothetical and were deduced by synthesizing results from many studies investigating ITAM-coupled receptor signaling in human and mouse NK cells. DAG, diacylglycerol; IP₃, inositol-3,4,5-trisphosphate; PIP₂, phosphatidylinositol-3,4-bisphosphate; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; pY, phosphotyrosine; ITK, tyrosine kinase; GADS and 3BP2, adaptor proteins; NFATp and NF-κB, transcription factors; PDK, phosphoinositide-dependent protein kinase; PKC-θ, protein kinase C-θ; RAF, mitogen-activated protein (MAP) kinase kinase kinase; RAS, GTPase.

Figure 3

DAP10-mediated signaling in NK cells. Cross-linking NKG2D causes NK cell activation that involves the recruitment of the p85 subunit of PI(3)K and recruitment of the Grb2-Vav1-Sos1 complex to the phosphorylated YINM motif in the cytoplasmic domain of DAP10. These events trigger distal signaling cascades as depicted.

Figure 4

CD244 receptor complexes in NK cells. Phosphorylation of the tyrosines in the TIYXX(V/I) motifs in the cytoplasmic domain of CD244 can recruit the adaptor proteins SAP, EAT2 or ERT (ERT exists in mice, but not humans). SAP binds to Fyn to mediate signal transduction. It has been proposed that the CD244-SAP–Fyn complex is responsible for NK cell activation when NK cells encounter target cells expressing CD48, a ligand of CD244. Alternatively, evidence suggests that CD244-EAT2 and CD244-ERT complexes deliver inhibitory signals into NK cells, although this remains controversial,,,.