Peptide selectivity of killer cell immunoglobulin-like receptors differs with allotypic variation in HLA class I

Natural killer (NK) cell activation is regulated by killer cell immunoglobulin-like receptors (KIRs) that recognize human leukocyte antigen (HLA) class I molecules. While polymorphism in HLA can directly impact these interactions, the extent to which the HLA-associated peptide repertoire modulates NK cell function is less well understood. Therefore, the peptide requirements for the recognition of 2 ligands, HLA-B*57:01 and HLA-A*24:02, that share similar KIR3DL1 binding residues but differ in their capacity to inhibit human NK cells were assessed. Immunopeptidome and functional analyses of endogenous peptides associated with each allotype showed that both repertoires contained peptides capable of facilitating or impairing KIR3DL1-dependent recognition of target cells. While distinct sequence features at positions 7 and 8 of the bound peptide similarly impacted recognition of both HLA class I allotypes, HLA-B*57:01 remained a more potent ligand overall. In silico analyses suggested that most peptides presented by HLA-B*57:01 would facilitate KIR3DL1 engagement, whereas the peptide repertoire of HLA-A*24:02 possessed fewer peptides predicted to support strong KIR3DL1 recognition. Nevertheless, the exogenous addition of highly permissive peptides to cells expressing HLA-A*24:02 could bolster KIR3DL1-mediated NK cell inhibition of peptide-competent cells to levels seen with HLA-B*57:01. Together, these data indicate that allotypic differences in peptide repertoire impact KIR recognition of HLA class I and suggest that NK cells have the potential to sense infection- or transformation-induced repertoire perturbations, particularly when the intrinsic KIR/HLA interactions are of modest avidity.