Peptide-Specific Natural Killer cell Receptors

Natural killer (NK) cells are innate cytotoxic lymphocytes that play critical roles in immunity to cancer and infection. NK cells are also the dominant lymphocyte at the maternal-fetal interface where they directly interact with fetal derived cells and contribute to successful pregnancy. NK cell functions are tightly regulated by an array of activating and inhibitory receptors. Principal among these are receptors that bind class I HLA molecules (HLA-I) and include members of the killer cell immunoglobulin-like receptors (KIR) family. The KIR are a multi-gene family of activating and inhibitory receptors, many of which have HLA-I ligands. Association studies link the KIR with numerous diseases but the mechanistic bases for these associations are poorly understood. 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.