The Genetic Mechanisms Driving Diversification of the KIR Gene Cluster in Primates

Abstract

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.

Keywords: KIR; Killer cell immunoglobin-like receptor; NK cell; NK cell education; human; macaque; non-human primates.

FIGURE 1

KIR haplotype organizations in different primate species. A schematic overview of the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4 and KIR haplotype organizations in different primate species. A fixed copy of the KIR3DX gene is located within the primate LILR gene cluster, whereas the expanded KIR gene cluster is flanked by the LILR and FcaR genes. The expansion involved four different KIR gene lineages – I, II, III, and V – the members of which are indicated as yellow, blue, red/gray, and pink boxes, respectively. The gray lineage III boxes represent pseudogenes. In most hominoids, KIR haplotype organizations follow a standard framework, in which the centromeric and telomeric regions are bordered by genes from lineages V and III, and lineages I and II, respectively. A relatively large non-coding segment separates the centromeric and telomeric haplotype sections.

FIGURE 2

The genetic mechanisms propelling diversification. The primate KIR cluster diverged as a result of multiple molecular processes, which together modulate the KIR gene content and expression status. (A) The expansion and contraction of KIR haplotypes is mediated by chromosomal recombinations, which can introduce or remove one or multiple KIR genes. Occasionally, a recombination event is accompanied by the generation of a fusion gene, which functionally and structurally expands the gene repertoire. (B) The KIR genes are further diversified by point mutations in coding and non-coding regions, which generate alleles that encode receptors with different structures, localization, function, and expression. (C) Alternative splicing is another mechanism that has a similar impact on the function and structure of receptors. The blue and green boxes indicate exons and introns. The isoforms are generated by different splice events, which involve alternative splice sites and exon skipping. (D) The differential expression of subsets of KIR receptors on different NK cell clones forms another level of variation that is mediated and maintained by sequence variability in the complex promoter regions and epigenetic modifications. A conjunction of the proximal, intermediate, and distal promoters is required to induce KIR expression.

FIGURE 3

Two pathways to educate NK cells in primates. A schematic overview of two strategies to educate NK cells. The leader peptide of MHC class I molecules either contains a methionine (−21M) or threonine (−21T) residue. The -21M peptides strongly bind to MHC-E molecules, and these complexes display an increased cell surface level. Through the conserved CD94:NKG2A receptors, the MHC-E complexes educate and license NK cells. In contrast, -21T leader peptides, which are predominantly present in MHC-B allotypes of humans and chimpanzees, do not interact with MHC-E molecules. Therefore, in the presence of one or more -21T MHC class I allotypes, the cell surface level of MHC-E is decreased. In this case, NK cells are educated by MHC class I molecules that interact with their KIR ligands.

FIGURE 4

The education of NK cells by expanded and contracted KIR haplotypes. The proposed populations of NK cells that are educated (red cells) by self-specific KIR (colored boxes and receptors) on expanded and contracted haplotypes. The gray boxes represent non-self-specific KIR, and are displayed on the uneducated NK cell clones (gray cells). (A) An expanded KIR haplotype provides a broad MHC class I specificity, and might educate some NK cell clones through multiple self-specific receptors, which increases their cytotoxicity (dark red cells). (B) A large KIR repertoire with only a few self-specific KIR might lower the fraction of educated NK cells and thereby provide an insufficient immune response, (C) whereas abundant self-specific receptors increase the educated fraction and their cytotoxicity. (D) A small KIR repertoire might educate large fractions of NK cells with a limited MHC class I specificity, which might provide largely sufficient immune responses.