Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules

Abstract

In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity-combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands-drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species.

Figure 1.

Three genetic complexes encoding cell-surface molecules involved in natural killer (NK) cell responses. Shown is a schematic of interactions between human leucocyte antigen (HLA) class I molecules and NK-cell receptors. The chromosomal locations of the complexes encoding them are given in the orange boxes. The number of protein variants (allotypes) for each of the HLA class I molecules is given in the green box.

Figure 2.

A variable family of KIR3DL genes is specific to the simian primates. Shown is a schematic of the KIR locus in a variety of primate and non-primate species [–25]. A single representative KIR haplotype is shown for each species. Grey colour coding indicates framework genes. Other genes are coloured according to the class of receptor they encode: red, inhibitory KIR; green, activating KIR; purple, leucocyte immunoglobulin-like receptor (LILR); yellow, receptor for the Fc of IgA (CD89); white, Ψ, pseudogene.

Figure 3.

Killer cell immunoglobulin-like receptor (KIR) and the αβ T-cell receptor (TCR) bind to overlapping sites on human leucocyte antigen (HLA) class I. The areas of KIR and TCR binding to MHC class I are given by the red and green lines, respectively. HLA class I residues involved in direct contact [44,45] are shown on the ribbon diagram of the α₁ and α₂ domains in red for KIR binding, green for TCR binding, and yellow for binding to both KIR and TCR. Shown are position 80, the residue that determines the C1 and C2 specificities of lineage III KIR [44,46], and position 83 that is critical for the binding of lineage II KIR to the Bw4 epitopes of HLA-A and HLA-B [41,47]. The HLA structure used to produce the ribbon diagram was PDB ID:1EFX.

Figure 4.

The specificity of KIR recognition of HLA class I. The pie charts show the frequency of HLA class I allotypes carrying the A3/11, orange; Bw4, green; C1, blue; and C2, red, epitopes. Population frequencies were obtained from http://www.allelefrequencies.net [51].

Figure 5.

Killer cell immunoglobulin-like receptor (KIR) haplotypes vary in both gene content and allelic diversity. Shown are the gene and allele content of 27 KIR haplotypes for which complete sequences have been determined [23]. Haplotypes are grouped by gene content (A or B haplotypes) and then further subdivided by their centromeric (Cen) and telomeric (Tel) gene-content motifs. Framework genes are shaded in grey, A haplotype characteristic genes/alleles in red and B haplotype characteristic genes/alleles in blue. Partial sequences are indicated by stippling and ‘part’ indicates where allelic identity was not fully determined. ‘Typing’ indicates that the KIR gene was determined to be present by genotyping.

Figure 6.

Group A and B haplotypes are present at very even frequencies in the Yucpa Amerindians. The structures of the two Yucpa KIR gene-content haplotypes are shown [70,75]. Genes are coloured according to the binding specificity of the encoded receptor. Green denotes KIRs that bind HLA class I. Yellow denotes KIRs that do not bind HLA class I. Grey denotes KIR for which ligands are unknown. White denotes pseudogenes. Dots indicate absence of a gene. The KIR locus is situated at chromosome 19q13.4; its centromeric boundary corresponds to 0 kb in the horizontal scale and its telomeric end to 230 kb.

Figure 7.

Coevolution of KIR with cognate MHC class I ligands. In the columns corresponding to E, A, B, C and G, coloured boxes indicate the presence in other primate species of one or more counterparts to the corresponding human HLA class I isotype. The cognate NK-cell receptor for each HLA class I is shown at the bottom of the column. In the column under ‘KIR’, characteristic features of the KIR in each non-human primate species are given. Bw4 /Bw6 and C1/C2 are pairs of mutually exclusive epitopes at HLA-B and HLA-C, respectively.

Figure 8.

Variation in the chimpanzee KIR locus is restricted to the centromeric interval. This diagram compares the organization and gene-content variability of the chimpanzee and human KIR loci. The branching pathways represent different gene-content motifs and they are combined to produce different KIR haplotypes. Framework genes are coloured grey; chimpanzee-specific lineage III KIR specific for the C1 and C2 epitopes of HLA-C, green; genes characteristic of human A haplotype, red; genes characteristic of human B haplotypes, blue; 2DP1 and 2DL1 in humans have been coloured grey indicating their presence both on A and B haplotypes. Adapted from Abi-Rached et al. [79]. C1 or C2 in a gene box denotes the receptor's epitope specificity.

Figure 9.

Worldwide inverse correlation in human populations between the frequencies of the C2 epitope of HLA-C and the group A KIR haplotype. (a) Compares the frequencies of HLA-C2 and the KIR A haplotype for 58 populations. (b) How the HLA-C2 and KIR A frequencies vary with the geographical origin of populations. (a, b) The populations are colour coded by geographical region. Frequency data for HLA-C2 and KIR A haplotypes were obtained from http://www.allelefrequencies.net (accessed 20 July 2010). KIR A haplotype frequency was calculated from the KIR A/A genotype frequency assuming the Hardy–Weinberg equilibrium in the population. Regression analysis was performed using SAS v. 9.2 and the result is shown in (a).