Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes

Abstract

Natural killer (NK) cells are lymphocytes of the innate immune system. In humans, NK cell activities are partly controlled by the diverse killer immunoglobulin-like receptor (KIR) gene family. The importance of NK cells in both immunity to infection and reproduction makes KIR strong candidates for genes undergoing dynamic evolution in the human genome. Using highresolution allelic typing, we investigated the potential role of natural selection in the diversification of KIR in the Irish population. Higher diversity than expected is observed at several loci, consistent with a history of balancing selection acting to maintain several allelic variants at high frequency in the population. KIR diversity is enhanced further at the haplotype level with functional polymorphisms at KIR2DL4, KIR3DL1 and KIR2DS4 defining nine 'core' haplotypes. Analysis of these core haplotypes in combination with human leukocyte antigen (HLA) class I ligands revealed several nonrandom associations. In particular, the KIR:HLA association for the core haplotype defined by KIR3DL1*01502 was female specific and a likely consequence of negative selection acting against KIR3DL1*01502 on an HLA-C1/C1 background. Many of the associations between KIR and HLA in the Irish differ from those previously reported, which argues against universal selective pressures for specific KIR:HLA combinations in diverse human populations.

2DL1, 2DL2 and 2DL3 all contribute to KIR phenotype variability on human NK cells

“…Genotyping for the KIR genes and the HLA class I ligands for the KIR was performed using previously described PCR-SSOP methods. 17 KIR genotypes were assigned as follows: donors genotyped as having only the framework KIR genes (3DL3, 3DP1, 2DL4, 3DL2) and the A haplotype KIR genes (2DL1, 2DL3, 3DL1, 2DS4) were deemed to be of the A/A KIR genotype. Donors who had all the A haplotype KIR genes with at least one additional B haplotype (2DL2, 2DS2, 3DS1, 2DL5, 2DS3, 2DS1) were placed in the A/B genotype group, whereas donors lacking at least one of the A haplotype KIR genes were assigned to the B/B genotype group.…”

“…In this current study, phenotypic KIR expression was determined for a large cohort of Irish donors (almost 200 donors), who had previously been typed to the allele level for KIR genes. 17 Recently available antibodies with defined specificity for individual KIR receptors also facilitated characterisation of important receptors which had previously been challenging to assess. In this current study, it was found that the KIR phenotype is influenced by both allelic polymorphism and the presence of HLA ligands for the KIR in the Irish population.…”

NK Cells and Psoriasis

“…In contrast, the inhibitory receptors (termed 2DL or 3DL KIR) have inherent inhibitory signalling capacity through Immuno Tyrosine-based Inhibitory Motifs (ITIMs) in their cytoplasmic tails. KIR haplotypes vary in terms of gene number, gene content, and allelic polymorphism such that there is huge genetic variation even within closely related ethnic groups [55, 62]. Significant progress has been made in terms of molecular typing to the extent that all genes can be identified by relatively straightforward PCR-SSP reactions [63].…”

The frequencies of Killer immunoglobulin-like receptors and their HLA ligands in chronic inflammatory demyelinating polyradiculoneuropathy are similar to those in Guillian Barre syndrome but differ from those of controls, suggesting a role for NK cells in pathogenesis

“…The KIR/HLA system is critical for the function of NK cells (Guinan et al, 2010). No differences were found among the frequency of KIR genes in the 3 groups.…”

“…Studies of NK cells in CIDP are limited to a single study that found reduced numbers of circulating NK (Sanvito et al, 2009). Killer immunoglobulin-like receptors (KIR) are cell surface receptors on NK cells, interact with MHC class I molecules on T cells and are critical for NK cell signalling (Guinan et al, 2010). We recently reported that frequencies of KIR2DL2/HLA-C2 and KIR-3DL1/HLA-B Bw4-T frequencies in GBS are different from those of healthy controls (Blum et al, 2013a).…”