The Adaptor Protein Crk Controls Activation and Inhibition of Natural Killer Cells

SummaryNatural killer (NK) cell inhibitory receptors recruit tyrosine phosphatases to prevent activation, induce phosphorylation and dissociation of the small adaptor Crk from cytoskeleton scaffold complexes, and maintain NK cells in a state of responsiveness to subsequent activation events. How Crk contributes to inhibition is unknown. We imaged primary NK cells over lipid bilayers carrying IgG1 Fc to stimulate CD16 and human leukocyte antigen (HLA)-E to inhibit through receptor CD94-NKG2A. HLA-E alone induced Crk phosphorylation in NKG2A+ NK cells. At activating synapses with Fc alone, Crk was required for the movement of Fc microclusters and their ability to trigger activation signals. At inhibitory synapses, HLA-E promoted central accumulation of both Fc and phosphorylated Crk and blocked the Fc-induced buildup of F-actin. We propose a unified model for inhibitory receptor function: Crk phosphorylation prevents essential Crk-dependent activation signals and blocks F-actin network formation, thereby reducing constraints on subsequent engagement of activation receptors.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (292 K)Download as PowerPoint slideHighlights► Inhibitory receptor NKG2A binding to HLA-E induces phosphorylation of adaptor Crk ► Crk is required for activation signals and for movement of receptor microclusters ► Activation receptors and phospho-Crk accumulate at the center of inhibitory synapses ► Crk is required for the HLA-E-mediated inhibition of F-actin accumulation