Specificity of inhibitory KIRs enables NK cells to detect changes in an altered peptide environment

The activity of natural killer (NK) cells is tightly regulated by inhibitory and activating receptors. Inhibitory killer immunoglobulin-like receptors (iKIRs) survey the surface of target cells by monitoring the expression of human leukocyte antigen (HLA) class I. The binding of iKIRs has been shown to be sensitive to the peptides presented by HLA class I, implying that iKIRs have the ability to detect the changes in the repertoire of peptide-HLA class I complexes (pHLA), a process occurring during viral infection and in tumor cells. To study how the pHLA repertoire changes upon infection, and whether an iKIR is able to detect these changes, we study peptides eluted from cells prior and after infection with measles virus (MV). Remarkably, most changes in the repertoire of potential iKIR ligands are predicted to be caused by the altered expression of self-peptides. We show that an iKIR can detect these changes in the presented peptides only if it is sufficiently specific, e.g., if iKIRs can distinguish between different amino acids in the contact residues (e.g., position 7 and 8). Our analysis further indicates that one single iKIR per host is not sufficient to detect changes in the peptide repertoire, suggesting that a multigene family encoding for different iKIRs is required for successful peptide recognition.