The Human NK Cell Receptor KIR2DS4 Detects a Conserved Bacterial Epitope Presented by HLA-C

Abstract

Abstract Natural killer (NK) cells are innate immune effector cells regulated by many germline-encoded activating and inhibitory receptors. The DAP12-associated activating receptor KIR2DS4 has been linked with multiple disease processes including cancer, disorders of pregnancy, and resistance to HIV. However, the precise ligands for KIR2DS4 remain poorly defined and the role of this receptor in immune responses is unclear. Here we show that human KIR2DS4 is a highly peptide-specific receptor for the human MHC-I molecule HLA-C*05:01. Of over 60 different peptides tested, only two conferred strong binding to KIR2DS4. Recognition of these peptides presented by HLA-C*05:01 potently activated KIR2DS4+ NK cells to degranulate and produce IFN-gamma and TNF-alpha. A recombinant peptide:HLA-C complex was sufficient to activate KIR2DS4+ NK cells. An alignment search of the KIR2DS4 binding peptides identified an epitope in recombinase A (RecA), a highly conserved bacterial protein. RecA epitopes from Chlamydia, Campylobacter, Brucella and Helicobacter pathogens were presented by HLA-C* 05:01, bound KIR2DS4 and activated KIR2DS4+ NK cells. By sequence alignment we predict that hundreds of species of bacteria contain RecA epitopes that can be presented by HLA-C*05:01 and bind KIR2DS4. These data provide clear evidence that KIR2DS4 is a highly peptide specific activating receptor and suggest that KIR2DS4 evolved to play a role in immune defense to bacteria.