Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus macaques of Indian origin

Abstract

The interaction of killer-cell immunoglobulin-like receptors (KIR) and their respective major histocompatibility complex (MHC) ligands can alter the activation state of the natural killer (NK) cell. In both humans and rhesus macaques, particular types of non-classical MHC class I molecules are predominantly expressed on the trophoblast. In humans, human leukocyte antigen G has been demonstrated to act as a ligand for KIR2DL4, present on all NK cells, whereas Mamu-AG may execute a similar function in rhesus macaques. During primate evolution, orthologues of KIR2DL4 appear to have been highly conserved, suggesting strong purifying selection. A cohort of 112 related and unrelated rhesus macaques of mostly Indian origin were selected to study their KIR2DL4 genes for the occurrence of polymorphism. Comparison of the proximal region provided evidence for strong conservative selection acting on the exons encoding the Ig domains. As is found in humans, in the Indian rhesus macaque population, two different KIR2DL4 entities are encountered, which differ for their intra-cellular signalling motifs. One genotype contains a complex mutation in the distal region of exon 9, which negates a serine/threonine kinase site. Furthermore, both allelic entities are present in a distribution, which suggests that balancing selection is operating on these two distinct forms of KIR2DL4.

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

“…The one exception may be recorded for Mamu-KIR3DL20, which is present on all analyzed genotypes, and therefore cannot be assigned to haplotypes by segregation analysis. In this panel, no KIR2DL04 has been detected on haplotype H-28, which is in accordance with observations that this loci may be absent on certain haplotypes [39].…”

“…The one exception may be recorded for Mamu-KIR3DL20, which is present on all analyzed genotypes, and therefore cannot be assigned to haplotypes by segregation analysis. In this panel, no KIR2DL04 has been detected on haplotype H-28, which is in accordance with observations that this loci may be absent on certain haplotypes [39].Animals of Indian, Chinese, and Burmese origin possess differential KIR gene contentsThe gene content of animals from different populations was compared (Table 2), and significant differences became apparent, especially between Indian-and Chinese-origin animals. Chinese animals, for instance, have on average one additional inhibitory KIR gene present at the genotype level.…”

KIR2DL4Copy Number Variation Is Associated with CD4+T-Cell Depletion and Function of Cytokine-Producing NK Cell Subsets in SIV-InfectedMamu-A*01-Negative Rhesus Macaques

“…KIR2DL4 duplications have, however, been implied in transcriptional analyses in rhesus macaques and humans, with up to three different KIR2DL4 sequences reported in a single subject (16,32,33). In line with these reports, 1 to 3 KIR2DL4 copies per cell were measured in the present study.…”

“…In the present studies, we demonstrate an association between CNV of the other known activating KIR gene family in Indian-origin rhesus macaques, KIR2DL4 (12)(13)(14)(15)(16), and the loss of CD4 ϩ T cells in acutely SIVmac251-infected Mamu-A*01 Ϫ rhesus macaques, with higher KIR2DL4 copy numbers being associated with a less severe CD4 ϩ T-cell depletion. Although KIR2DL4 contains a long cytoplasmic tail that is characteristic for inhibitory KIRs (17)(18)(19), binding through KIR2DL4 stimulates NK cells to produce cytokines and chemokines (20)(21)(22)(23)(24).…”

“…Since the allelic diversity of KIR genes has been shown to affect SIV replication (28,29), we assessed whether particular KIR2DL4 alleles might influence the effect of KIR2DL4 CNV on SIV pathogenesis. In Indian-origin rhesus macaques, two distinct KIR2DL4 forms, KIR2DL4.1 and KIR2DL4.2, differ in their intracellular signaling motifs (16). These structural differences might result in altered NK cell reactivity mediated through these KIR2DL4 allotypes, thereby potentially affecting the association between Ϫ rhesus macaques by quantitative real-time PCR (qPCR) using genomic DNA samples.…”