Exploring the genetic mechanisms driving KIR diversification

Killer cell immunoglobulin-like receptors (KIRs) are key modulators of natural killer cell activity, displaying either activating or inhibitory potential upon recognition of major histocompatibility complex (MHC) class I molecules. The genomic organization of KIR genes is complex, involving copy number variation and allelic polymorphism, which is probably due to their coevolution with highly polymorphic MHC ligands. The KIR diversity is reflected by more than 70 similar region configurations encountered in humans, generated through meiotic recombination events. Rhesus macaques happen to display even more diversity, and over 100 distinct configurations were identified in a relatively small cohort of animals. More than half of these region configurations feature hybrid KIR genes, suggesting a more pronounced mode of diversification in macaques. The molecular mechanism facilitating meiotic rearrangements in the KIR region is poorly understood. Examination of 21 rhesus macaque and 14 human KIR region configurations revealed the presence of long terminal repeats and PRDM9 binding motifs associated with recombination hotspots. The variable DNA recognition patterns of PRDM9 could potentially contribute to the differing recombination activities documented for the KIR region in humans and macaques. The diversification process of the KIR repertoire in natural killer cells is fundamentally distinct from the mechanisms generating T and B cell receptor diversity or MHC polymorphisms. This sophisticated recombination machinery preserves the functional integrity by the frequent generation of in-frame KIR genes. A diverse KIR repertoire contributes to the protection of individuals and populations against pathogen evasion and subversion.