Receptor systems controlling natural killer cell function are genetically stratified in Europe

Natural killer (NK) cells are components of the innate immune system that function in identifying and destroying aberrant or pathogen-infected cells. These functions are largely controlled by killer cell immunoglobulin-like receptors (KIRs). KIRs inhibit and activate NK cell functions through interactions with their ligands, epitopes encoded by human leukocyte antigen (HLA) class I genes (HLA-C1, C2 and Bw4). Genes that encode KIR and their HLA ligands vary in frequency across human populations. Here, we characterize two Irish populations for KIR and HLA and determine the spatial distribution of functionally important KIR:HLA systems in Europe, a region known for its considerable underlying genetic stratification. We find that Southern Europe is a region characterized by higher frequencies of activatory KIR and strong inhibitory HLA ligand systems (2DL1:HLA-C2 and 3DL1:Bw4). A lower frequency of activatory KIR and the predominance of a comparatively weaker inhibitory ligand system (2DL3:HLA-C1) are observed northwards. Despite contrasting KIR:HLA systems in Northern and Southern Europe, there is a clear balance between inhibitory and activatory repertoires, and their ligands in both regions. These findings show 'functional stratification' of the epistatic KIR:HLA receptor system in Europe, the presence of which will likely affect NK cell-mediated immunity across different populations.