Natural killer cell cytotoxicity and its regulation by inhibitory receptors

Abstract

Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity.

Keywords: activating receptor; cytotoxic synapse; immunoreceptor tyrosine-based inhibitory motif (ITIM); inhibitory receptor; inhibitory synapse; killer-cell Ig-like receptor (KIR); natural killer cell.

Figure 1

Interception of natural killer (NK) cell activation by killer‐cell Ig‐like receptor (KIR). At the inhibitory synapses formed between KIR+ NK cells and HLA‐C+ target cells, KIR clusters rapidly, in actin‐independent manner. The zinc‐dependent polymerization of KIR into filaments could contribute to the rapid and actin‐independent KIR clustering at these synapses. The Src family kinase Lck and Fyn are candidate kinases for immunoreceptor Tyr‐based inhibitory motif (ITIM) phosphorylation. The protein Tyr phosphates SHP‐1, recruited and activated by its interaction with phospho‐ITIMs (pITIMs), dephosphorylates the guanine nucleotide exchange factor Vav‐1. The c‐Abl kinase is recruited to the inhibitory synapses through an unknown mechanism. The c‐Abl kinase phosphorylates the small adaptor protein Crk, and dissociates it from a signalling complex (not shown here) formed during activation. Vav‐1 dephosphorylation and Crk phosphorylation contribute to blockage of actin‐dependent signals for NK cell activation, and thus could contribute to inhibition of proximal actin‐dependent steps, such as LFA‐1 activation (not shown here) and clustering of activating receptors.