Innate receptors with high specificity for HLA class I-peptide complexes

Genetic studies associate killer-cell immunoglobulin-like receptors (KIR) and their HLA class I ligands with a variety of human diseases. The basis for these associations, and the relative contribution of inhibitory and activating KIR to NK cell responses are unclear. As KIR binding to HLA-I is peptide-dependent, we performed systematic screens totaling over 3,500 specific interactions to determine the specificity of five KIR for peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence agnostic, binding approximately 60% of hundreds of HLA-peptide complexes tested. Inhibitory KIR2DL2, KIR2DL3, and activating KIR2DS1 and KIR2DS4 bound only 10%, down to 1% of HLA-peptide complexes tested, respectively. Activating KIR2DS1, previously described as weak, had high binding affinity for HLA-C with high peptide sequence specificity. Our data revealed MHC-restricted peptide recognition by germ-line encoded NK receptors and imply that NK cell responses can be shaped by HLA-I bound immunopeptidomes in the context of disease or infection.