Two to Tango: Co-evolution of Hominid Natural Killer Cell Receptors and MHC

Abstract

Natural killer (NK) cells have diverse roles in hominid immunity and reproduction. Modulating these functions are the interactions between major histocompatibility complex (MHC) class I molecules that are ligands for two NK cell surface receptor types. Diverse killer cell immunoglobulin-like receptors (KIR) bind specific motifs encoded within the polymorphic MHC class I cell surface glycoproteins, while, in more conserved interactions, CD94:NKG2A receptors recognize MHC-E with bound peptides derived from MHC class I leader sequences. The hominid lineage presents a choreographed co-evolution of KIR with their MHC class I ligands. MHC-A, -B, and -C are present in all great apes with species-specific haplotypic variation in gene content. The Bw4 epitope recognized by lineage II KIR is restricted to MHC-B but also present on some gorilla and human MHC-A. Common to great apes, but rare in humans, are MHC-B possessing a C1 epitope recognized by lineage III KIR. MHC-C arose from duplication of MHC-B and is fixed in all great apes except orangutan, where it exists on approximately 50% of haplotypes and all allotypes are C1-bearing. Recent study showed that gorillas possess yet another intermediate MHC organization compared to humans. Like orangutans, but unlike the Pan-Homo species, duplication of MHC-B occurred. However, MHC-C is fixed, and the MHC-C C2 epitope (absent in orangutans) emerges. The evolution of MHC-C drove expansion of its cognate lineage III KIR. Recently, position -21 of the MHC-B leader sequence has been shown to be critical in determining NK cell educational outcome. In humans, methionine (-21M) results in CD94:NKG2A-focused education whereas threonine (-21T) produces KIR-focused education. This is another dynamic position among hominids. Orangutans have exclusively -21M, consistent with their intermediate stage in lineage III KIR-focused evolution. Gorillas have both -21M and -21T, like humans, but they are unequally encoded by their duplicated B genes. Chimpanzees have near-fixed -21T, indicative of KIR-focused NK education. Harmonious with this observation, chimpanzee KIR exhibit strong binding and, compared to humans, smaller differences between binding levels of activating and inhibitory KIR. Consistent between these MHC-NK cell receptor systems over the course of hominid evolution is the evolution of polymorphism favoring the more novel and dynamic KIR system.

Keywords: CD94; KIR; MHC; NK cells; NKG2; great ape; hominid.

Figure 1

Phylogeny of the great apes. Branch lengths of the tree correspond to divergence time estimates (1, 2). Shown are the scientific name (italics), abbreviation (in parentheses) and common name for the great ape species discussed in this review.

Figure 2

Human KIR lineages, epitopes, and ligands. The four KIR lineages present in great apes are shown on the left with the human members of each lineage given in the second column. There are four haplotype framework genes: KIR2DL4, KIR3DL2, KIR3DL3, and a pseudogene, KIR3DP1 (lineage III, not shown). The third column gives the HLA isotypes having the epitopes recognized by the KIR. Where known, specific binding epitopes are given in the column on the right. Bw4, residues 77–83 with R83 as the key residue recognized by lineage II KIR (–76); A3/11, unknown residues; C1, V76 K80; C2, N80 (77, 78). ^* Binding of 2DS2 to C1 is dependent on binding an appropriate peptide (79). # for these interactions only subsets of molecules with the listed epitope bind (28, 80, 81).

Figure 3

Polymorphism at position −21 of MHC-B and -C. All MHC-B and MHC-C alleles for which sequence information was available in the IMGT and IPD databases (accessed 9 Aug. 2018) (21, 90) were analyzed for polymorphism at position −21 of the full-length immature protein. (A) The number of alleles encoding methionine (M), threonine (T), or other amino acid (Other) is shown for MHC-B and MHC-C. Isoleucine is the alternative residue for all three Patr-B allotypes under “Other.” All orangutan (Pongo) sequences from P. abelii and P. pygmaeus have been grouped together; no sequences are available for P. tapanuliensis. Gogo only includes G. gorilla alleles. For G. beringeri, the one MHC-B sequence has arginine −21 and the one MHC-C sequence has −21M (not shown). The final column shows the predicted bias in NK cell education based on the relative abundance of −21T (34). (B) Phenotypic frequencies for MHC-B position −21 alleles in a panel of 34 Western gorillas (Gogo) (9, 10) are given. Based on the results of Horowitz et al. (34), the predicted dominant mode of NK cell education is indicated. The phenotypic frequencies of human HLA-B position −21 alleles are shown for comparison. The data are from 8,192 individuals representing 51 populations worldwide (34). ^#Gorillas can have more than two Gogo-B variants because all gorillas have one fixed Gogo-B gene, and some gorillas also have an additional related Gogo-B^*07 gene, which is present on some Gogo haplotypes but not on others (9, 10). (C) Association of KIR ligands with position −21M polymorphism in Gogo-B are shown. ^* Indicates that all four B^*07 alleles from the Gogo-B^*07 gene are included in the count.

Figure 4

Distribution of alleles encoding a KIR ligand among great ape MHC class I genes. Alleles included were those for which sequence information was available in the IMGT and IPD databases (Accessed Aug. 9, 2018) (21, 90). (A) The frequency of alleles encoding a KIR ligand for MHC-A, -A-related, -B, and -C genes is shown. Each circle represents a gene and is scaled so that the area of the circle is proportional to the frequency of the gene among MHC haplotypes. Orthologous genes are aligned vertically. KIR ligands are color-coded; gold, A3/11; Bw4, green; C1, red; C2, blue; no ligand, gray. Ψ indicates a pseudogene. *Indicates a non-classical gene. Two Popy-B*03 encode a Bw4-C1 hybrid epitope that are categorized as C1. (B) The table provides the numbers and frequencies used for the pie charts in panel (A).

Figure 5

Number and frequency of KIR in great apes. The table shows the number of KIR genes in each species according to lineage (first column), specificity-determining residue (position 44) of the lineage III KIR (second column) and type of tail, short (S) or long (L) (third column). For each species the number of genes with the characteristics shown in the first three columns is shown along with the combined genotypic frequency. For example, in the cell under Patr, and for the characteristics of lineage III—K—S, there are two KIR genes (3DS6 and 2DS4). The frequency of 0.89 represents the combined frequency of individuals with only 3DS6 (and not 2DS4), those only with 2DS4 (and not 3DS6), and those with both genes. In addition, for cells such as this, where there are several genes with a particular set of characteristics, the genotypic frequency for the individual genes are shown—e.g., for 3DS6, 0.69 is the combined frequency of those individuals with only 3DS6 and those with both 3DS6 and 2DS4. The data for non-human apes come from the study of captive animals (3, 4, 7, 125), and the values for humans represent the range of genotypic values obtained from the website, allelefrequencies.net (126). “0” indicates absence of a gene encoding the characteristics in the first three columns. Colored shading indicates binding specificity as follows: green, Bw4; red, C1; blue, C2; purple, pan C1/C2; orange, A3/11; yellow, complex pattern of 2DS4; gray, unknown specificity.

Figure 6

Gorilla MHC class I isotypes and their KIR-binding epitopes. Summarizes data from a panel of 35 gorillas (9, 10). The first column gives the species, the second gives the individual's name. In each of columns 3–8 the presence of a gene and its encoded KIR ligand are given. Presence of a single entry shows the individual lacked the gene on one haplotype, and no entry indicates absence of the gene. Ligands are color-coded as in Figure 3A: Bw4, green; C1, red; C2, blue. N, no ligand; -, absence of Gogo-B*07 (presence on one or both chromosomes of Gogo-B*07 was determined based on patterns of linkage disequilibrium with Gogo-B*03 alleles); parentheses surrounding the ligand indicate that the sequence encoding the epitope is present but in the context of a non-functional (null) allele of Gogo-Y (9). The final column gives the number of ligand types present in each individual; *indicates that only one type of ligand is present. The lower panel gives the MHC gene frequency and the phenotypic frequency of their encoded ligands.

Figure 7

Chimpanzee and Bonobo MHC class I isotypes and their KIR-binding epitopes. Summarizes the MHC genotype data obtained in several studies (11, 12, 91, 137). Each study population is shown separately, and the summary of frequencies is given below. Chimpanzees are shown on the left (A) and bonobos on the right (B). The color-coding of the KIR ligands is the same as in Figures 3A, 6: Bw4, green; C1, red; C2, blue. U, uncertainty in homozygosity; Phenotypic frequencies are given. * Indicates individuals having a single type of KIR ligand. + Indicates that additional ligands may be present, because of uncertainty in the genotype.

Figure 8

Summary of MHC and KIR gene content in great apes. The cladogram on the left shows relationships among the great apes. Under MHC is a schematic representation of the gene content for the MHC-A, -B, and -C regions. A gene, or genes, enclosed by a dotted rectangle is in a region of variable gene content. A dashed rectangle indicates a pseudogene. Color-coding within the rectangle representing a gene shows the possible KIR ligands encoded by that MHC gene. This color-coding is not proportional to the frequency of the encoded ligand. Numbers beneath MHC-B and -C in gorillas, chimpanzees, and humans give the frequency of −21T in the allotypes of each gene. No number denotes a frequency of 100% for −21M. On the right under KIR is a schematic representation of the KIR locus gene content in each species. The framework genes (3DL3, DP-2DL4, lineage II) are indicated. As for MHC, KIR pseudogenes are indicated by a dashed rectangle and regions of variable gene content are surrounded by a dotted line. The ligand-specificities encoded by each KIR gene are indicated by the same color-coding used for MHC.