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The role of natural killer (NK) cells is tightly modulated by interactions of killer cell immunoglobulin-like receptors (KIR) with their ligands of the MHC class I family. Several characteristics of the KIR gene products are conserved in primate evolution, like the receptor structures and the variegated expression pattern. At the genomic level, however, the clusters encoding the KIR family display species-specific diversity, reflected by differential gene expansions and haplotype architecture. The human KIR cluster is extensively studied in large cohorts from various populations, which revealed two KIR haplotype groups, A and B, that represent more inhibitory and more activating functional profiles, respectively. So far, genomic KIR analyses in large outbred populations of non-human primate species are lacking. In this study, we roughly quadrupled the number of rhesus macaques studied for their KIR transcriptome (n = 298). Using segregation analysis, we defined 112 unique KIR region configurations, half of which display a more inhibitory profile, whereas the other half has a more activating potential. The frequencies and functional potential of these profiles might mirror the human KIR haplotype groups. However, whereas the human group A and B KIR haplotypes are confined to largely fixed organizations, the haplotypes in macaques feature highly variable gene content. Moreover, KIR homozygosity was hardly encountered in this panel of macaques. This study exhibits highly diverse haplotype architectures in humans and macaques, which nevertheless might have an equivalent effect on the modulation of NK cell activity. [ABSTRACT FROM AUTHOR]

The activity and function of natural killer (NK) cells are modulated through the interactions of multiple receptor families, of which some recognize MHC class I molecules. The high level of MHC class I polymorphism requires their ligands either to interact with conserved epitopes, as is utilized by the NKG2A receptor family, or to co-evolve with the MHC class I allelic variation, which task is taken up by the killer cell immunoglobulin-like receptor (KIR) family. Multiple molecular mechanisms are responsible for the diversification of the KIR gene system, and include abundant chromosomal recombination, high mutation rates, alternative splicing, and variegated expression. The combination of these genetic mechanisms generates a compound array of diversity as is reflected by the contraction and expansion of KIR haplotypes, frequent birth of fusion genes, allelic polymorphism, structurally distinct isoforms, and variegated expression, which is in contrast to the mainly allelic nature of MHC class I polymorphism in humans. A comparison of the thoroughly studied human and macaque KIR gene repertoires demonstrates a similar evolutionarily conserved toolbox, through which selective forces drove and maintained the diversified nature of the KIR gene cluster. This hypothesis is further supported by the comparative genetics of KIR haplotypes and genes in other primate species. The complex nature of the KIR gene system has an impact upon the education, activity, and function of NK cells in coherence with an individual's MHC class I repertoire and pathogenic encounters. Although selection operates on an individual, the continuous diversification of the KIR gene system in primates might protect populations against evolving pathogens. [ABSTRACT FROM AUTHOR]