Missing or altered self: human NK cell receptors that recognize HLA-C

Natural killer (NK) cells are fast-acting and versatile lymphocytes that are critical effectors of innate immunity, adaptive immunity, and placental development. Controlling NK cell function are the interactions between killer-cell immunoglobulin-like receptors (KIRs) and their HLA-A, HLA-B and HLA-C ligands. Due to the extensive polymorphism of both KIR and HLA class I, these interactions are highly diversified and specific combinations correlate with protection or susceptibility to a range of infectious, autoimmune, and reproductive disorders. Evolutionary, genetic, and functional studies are consistent with the interactions between KIR and HLA-C being the dominant control mechanism of human NK cells. In addition to their recognition of the C1 and C2 epitopes, increasing evidence points to KIR having a previously unrecognized selectivity for the peptide presented by HLA-C. This selectivity appears to be a conserved feature of activating KIR and may partly explain the slow progress made in identifying their HLA class I ligands. The peptide selectivity of KIR allows NK cells to respond, not only to changes in the surface expression of HLA-C, but also to the more subtle changes in the HLA-C peptidome, such as occur during viral infection and malignant transformation. Here, we review recent advances in understanding of human-specific KIR evolution and how the inhibitory and activating HLA-C receptors allow NK cells to respond to healthy cells, diseased cells, and the semi-allogeneic cells of the fetus.