Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases, but the underlying mechanisms remain unclear. The effect of this diversity on the nanoscale organization of killer cell immunoglobulin (Ig)-like receptors (KIRs) has yet to be tested. Here, using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primary
human NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance there was a greater proportion of KIRs in clusters. Upon receptor triggering, a structured interface called an immune synapse assembles, which facilitates signal integration and controls the NK cell response. Here, low-abundance receptors exhibited less phosphorylation of downstream hosphatase SHP-1 but more phosphorylation of adaptor protein Crk than did high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated the NK cell spreading response during activation. Thus, genetic variation modulates both the abundance and nanoscale
organization of inhibitory KIRs. In other words, as well as the number of receptors at the cell surface varying with genotype, the way in which these receptors are organized in the membrane also varies. Essentially, a change in the average surface abundance of a protein at the cell surface is a coarse descriptor entwined with changes in local nanoscale clustering. Altogether, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and surprisingly, the formation of activating immune synapses.