Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C

Significance Natural killer (NK) cells are known for their role in defense against viruses and cancer. Their activity is regulated, in part, by killer cell immunoglobulin-like receptors (KIRs) that bind to polymorphic human leukocyte antigen (HLA) class I molecules. The KIR family includes an activation receptor of unknown function, KIR2DS4. Here, we show that KIR2DS4 binding to HLA-C*05:01 is dependent on specific peptides that include a Trp at position 8 of 9-mer peptides associated with HLA-C*05:01. Through sequence homology, we identified a highly conserved peptide sequence in bacterial recombinase A that binds to HLA-C*05:01 and stimulates KIR2DS4 + NK cells. We predict that over 1,000 bacterial species contain this epitope and propose that NK cells contribute also to immune defense against bacteria.