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

Abstract

Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+cells that expressed the peptide epitope triggered KIR2DS4+NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functionalKIR2DS4with that ofHLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01–restricted activation of human KIR2DS4+NK cells in bacterial recombinase A (RecA). KIR2DS4+NK cells were stimulated by RecA epitopes from multiple human pathogens, includingHelicobacter,Chlamydia,Brucella, andCampylobacter.We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01.

A natural killer cell receptor takes sharp aim at the world of bacteria

“…Sim et al (1) purified and denatured HLA-C*05:01 to release the bound peptides, which were then separated and sequenced. As the peptides, mostly nonamers, arise from intracellular degradation of human proteins, they are called "self" peptides to distinguish them from peptides derived from microbial pathogens.…”

“…None of the 46 complexes bound to KIR2DS4. However, by mutating residues 7 and 8 of IIDKSGSTV, a self peptide isolated from HLA-C*05:01, Sim et al (1) obtained strong binding of KIR2DS4-Fc to the P2-AY mutant peptide, in which alanine 7 and tyrosine 8 replace serine 7 and threonine 8 of the natural peptide. Extending the analysis to a total of 61 peptides, the only other peptides to bind HLA-C*05:01 and engage KIR2DS4 were variants of P2-AY in which tyrosine 8 was replaced by another aromatic residue: tryptophan in mutant P2-AW and phenylalanine in mutant P2-AF.…”

“…Degranulation was observed for the subset of NK cells that express KIR2DS4, but not for the many NK cell subsets that lack KIR2DS4. Other measures of NK cell activation, such as cytokine production, correlate with the extent of degranulation (1). A most unexpected observation is that interaction between peptide-loaded HLA-C*05:01 and KIR2DS4 is, by itself, sufficient to activate NK cells and trigger degranulation.…”

Report from the Eleventh Killer Immunoglobulin‐like Receptor (KIR) Workshop: Novel insights on KIR polymorphism, ligand recognition, expression and function

“…Alignment search of KIR2DS4 binding peptides allowed the identification of an epitope in recombinase A, a highly conserved bacterial protein. Thus, KIR2DS4 appears as a highly peptide specific activating receptor playing a role in immune defense against bacteria …”

Peptide:MHC dependent activation of natural killer cells through KIR2DS2 generates anti-tumor responses

“…However the ligand specificities of the activating KIR have been much harder to identify. Recent work has shown that activating KIR can have an MHC class I-restricted peptide specificity (13)(14)(15)(16). Whilst T cell receptors have a tight restriction on the peptide:MHC complexes that they bind, the KIR recognize families of peptide:MHC complexes with the inhibitory KIR recognizing HLA molecules in a broad motifbased manner allowing recognition of multiple HLA class I allotypes (17,18).…”