Diverse killer-cell Ig-like receptors (KIRs) of rhesus and sabaeus monkeys: Evidence for recombination events in the evolution of KIRs

The recognition of pathogen-infected cells by human natural killer cells is mediated, in part, by killer-cell immunoglobulin-like receptors (KIRs) that interact directly with MHC class I molecules on target cells. In order to examine the KIR molecules in primate animal models, complementary DNA sequences encoding the KIR forms of the Indian-origin rhesus monkey (Macaca mulatta) and the West African sabaeus monkey (Chlorocebus sabaeus) were identified using a PCR-based approach. Five forms of monkey KIR molecules were identified: KIR3DL, KIR2DL4, KIR2DL5, KIR3DH, and KIR1D. Two forms, KIR3DH and KIR1D, are unique to these monkey species. With a transmembrane domain that contains an arginine and a short cytoplasmic domain, the KIR3DH form resembles the activating KIR forms of humans. The KIR1D molecule has a frame-shift in the second immunoglobulin-like (Ig-like) domain that is conserved in both monkey species, leading to early termination of the molecule. Multiple splice variants of KIR1D were detected, which encode at least one Ig-like domain, as well as transmembrane and cytoplasmic domains. A novel hybrid form consisting of features found in both KIR2DL5 and KIR3DH was also identified in the sabaeus monkey.; Although human and ape KIR forms with three Ig-like domains are limited in their polymorphism, the KIR3DL and KIR3DH forms in both monkey species were highly polymorphic. The polymorphic residues of the three Ig-like domains were frequently located in structural loops, suggesting that point mutations have occurred in regions that may contribute to ligand binding. The diversity of the monkey KIR3DL and KIR3DH forms and the detection of novel KIR molecules illustrate the extensive evolution of the KIR family of molecules that has occurred in primates.; To elucidate further the molecular evolution of the primate KIR, phylogenetic analysis of each of the three Ig-like domains of the KIR3D forms from six primate species was performed. This analysis revealed different patterns of clustering of the Ig-like domain sequences in the phylogenetic trees, indicating that repeated recombination events have occurred between the Ig-like domains during the evolution of the KIR genes in primates. These recombination events have been a mechanism for generating diversity of the KIR genes.