Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution

Abstract

Natural killer (NK) cells have roles in immunity and reproduction that are controlled by variable receptors that recognize MHC class I molecules. The variable NK cell receptors found in humans are specific to simian primates, in which they have progressively co-evolved with MHC class I molecules. The emergence of the MHC-C gene in hominids drove the evolution of a system of NK cell receptors for MHC-C molecules that is most elaborate in chimpanzees. By contrast, the human system of MHC-C receptors seems to have been subject to different selection pressures that have acted in competition on the immunological and reproductive functions of MHC class I molecules. We suggest that this compromise facilitated the development of the bigger brains that enabled archaic and modern humans to migrate out of Africa and populate other continents.

Figure 1. Convergent evolution of variable NK-cell receptors for MHC class I

Panel A shows how human KIRs and mouse Ly49 lectin-like receptors bind to different and non-overlapping sites on the surface of the MHC class I molecule. KIRs interact with the upward face of the MHC class I molecule formed by the helices of the α₁ and α₂ domains and the peptide bound in the groove between them. By contrast, Ly49 binds underneath the peptide-binding groove, where it interacts with all four domains of the MHC class I molecule: α₁, α₂, α₃, and β₂-microglobulin (β₂-m). Panel B shows how human KIRs and the human lectin-like receptor CD94:NKG2A bind to overlapping sites on the surface of the MHC class I molecule. The ribbon diagram shows the upward face of the MHC class I molecule with the space-filling image of the peptide between the helices of the α₁ and α₂ domains. The dashed ellipses and coloring of the ribbon diagram denote the areas to which the KIRs (red) and CD94:NKG2A (green) bind. The overlap of the binding sites is colored yellow. Being a lectin-like receptor, CD94:NKG2A is structurally more similar to mouse Ly49 than to human KIRs, but it binds to a different site on MHC class I than does Ly49^, . The overlap in the binding sites for KIRs and CD94:NKG2A on HLA class I molecules does not cause competition between the two receptors, because CD94:NKG2A is restricted to interaction with HLA-E, whereas KIRs are restricted to interactions with HLA-A, -B, -C and -G. On the contrary, CD94:NKG2A and KIRs have complementary roles in NK cell biology because the interaction of HLA-E with CD94:NKG2A is highly conserved, whereas the interactions between KIRs and HLA-A, -B, and -C are highly diverse.

Figure 1. Convergent evolution of variable NK-cell receptors for MHC class I

Panel A shows how human KIRs and mouse Ly49 lectin-like receptors bind to different and non-overlapping sites on the surface of the MHC class I molecule. KIRs interact with the upward face of the MHC class I molecule formed by the helices of the α₁ and α₂ domains and the peptide bound in the groove between them. By contrast, Ly49 binds underneath the peptide-binding groove, where it interacts with all four domains of the MHC class I molecule: α₁, α₂, α₃, and β₂-microglobulin (β₂-m). Panel B shows how human KIRs and the human lectin-like receptor CD94:NKG2A bind to overlapping sites on the surface of the MHC class I molecule. The ribbon diagram shows the upward face of the MHC class I molecule with the space-filling image of the peptide between the helices of the α₁ and α₂ domains. The dashed ellipses and coloring of the ribbon diagram denote the areas to which the KIRs (red) and CD94:NKG2A (green) bind. The overlap of the binding sites is colored yellow. Being a lectin-like receptor, CD94:NKG2A is structurally more similar to mouse Ly49 than to human KIRs, but it binds to a different site on MHC class I than does Ly49^, . The overlap in the binding sites for KIRs and CD94:NKG2A on HLA class I molecules does not cause competition between the two receptors, because CD94:NKG2A is restricted to interaction with HLA-E, whereas KIRs are restricted to interactions with HLA-A, -B, -C and -G. On the contrary, CD94:NKG2A and KIRs have complementary roles in NK cell biology because the interaction of HLA-E with CD94:NKG2A is highly conserved, whereas the interactions between KIRs and HLA-A, -B, and -C are highly diverse.

Figure 2. Humans KIRs recognize four epitopes of HLA-A, -B and –C

a | The pie charts show the distribution of the four target epitopes (green, yellow, blue and red) in five human population groups. These four epitopes are mutually exclusive, so that each HLA-A, -B and -C allotype can either have one of these epitopes or is not a ligand for KIR (grey). The C1 epitope (colored blue) is carried by HLA-C allotypes with asparagine at position 80 and certain Asian HLA-B alleles that have asparagine at position 80 and valine at position 76. The C2 epitope (colored red) is carried by HLA-C allotypes that have lysine at position 80. The Bw4 epitope (colored green) is carried by HLA-A and –B allotypes that have arginine at position 83. The A3/11 epitope (colored yellow) is carried by two HLA-A allotypes, HLA-A*03 and HLA-A*11, and seems to be as peptide-dependent as the αβ T-cell receptor. Data are pooled from a minimum of eight populations in a group up to a maximum of fifty five. b | The upper linear diagram shows the order of the 15 human KIR genes in the KIR locus on human chromosome 19 and the phylogenetic lineages to which they belong (I, II, III or V). Beneath the gene boxes are shown the HLA class I specificities of the encoded receptors. The smaller point size denotes a receptor that only recognizes some of the allotypes carrying the epitope. The boxes for genes encoding inhibitory receptors are coloured orange, the boxes for genes encoding activating receptors are coloured light green and boxes corresponding to pseudogenes are shaded gray. The lower linear diagram shows the framework genes and the centromeric and telomeric regions of gene-content variability that they flank and define.

Figure 3. Co-evolution of HLA-C and KIR lineage III in hominids

a | The organization and KIR-gene content of orangutan, chimpanzee and human KIR haplotypes are compared. Boxes representing the framework genes, which are common to all haplotypes, are shaded dark gray; boxes representing variable lineage I and II KIR genes are shaded light gray, and variable lineage III genes are shaded according to species: orange (orangutan), green (chimpanzee) and purple (human). For those lineage III KIRs that recognize MHC class I, the epitope specificities are given in the gene box, with white script for activating KIRs and black script for inhibitory KIRs. With the exception of KIR2DS4 (the boxes labeled A,C) , which is present in humans and chimpanzees, all of the variable lineage III KIR genes are species-specific. b | The pie charts compare the distribution of the four MHC class I epitopes recognized by KIRs in chimpanzees and humans. The Bw4 (colored green) epitope originated at MHC-B. In chimpanzees Bw4 is only carried by MHC-B allotypes, whereas in humans it was also transferred to MHC-A. The C1 epitope (colored blue) also originated at MHC-B and was directly inherited by MHC-C. Whereas chimpanzees retain C1 at both MHC-B and MHC-C, in humans the C1 epitope has been largely eliminated from HLA-B. The C2 epitope (colored red) originated with MHC-C and remains exclusively an epitope of MHC-C in chimpanzees and humans. The A3/11 epitope (colored yellow) is specific to the human HLA-A*03 and HLA-A*11 allotypes, has not been correlated with polymorphisms in the HLA-A sequence, and seems to be highly peptide dependent.

Figure 3. Co-evolution of HLA-C and KIR lineage III in hominids

a | The organization and KIR-gene content of orangutan, chimpanzee and human KIR haplotypes are compared. Boxes representing the framework genes, which are common to all haplotypes, are shaded dark gray; boxes representing variable lineage I and II KIR genes are shaded light gray, and variable lineage III genes are shaded according to species: orange (orangutan), green (chimpanzee) and purple (human). For those lineage III KIRs that recognize MHC class I, the epitope specificities are given in the gene box, with white script for activating KIRs and black script for inhibitory KIRs. With the exception of KIR2DS4 (the boxes labeled A,C) , which is present in humans and chimpanzees, all of the variable lineage III KIR genes are species-specific. b | The pie charts compare the distribution of the four MHC class I epitopes recognized by KIRs in chimpanzees and humans. The Bw4 (colored green) epitope originated at MHC-B. In chimpanzees Bw4 is only carried by MHC-B allotypes, whereas in humans it was also transferred to MHC-A. The C1 epitope (colored blue) also originated at MHC-B and was directly inherited by MHC-C. Whereas chimpanzees retain C1 at both MHC-B and MHC-C, in humans the C1 epitope has been largely eliminated from HLA-B. The C2 epitope (colored red) originated with MHC-C and remains exclusively an epitope of MHC-C in chimpanzees and humans. The A3/11 epitope (colored yellow) is specific to the human HLA-A*03 and HLA-A*11 allotypes, has not been correlated with polymorphisms in the HLA-A sequence, and seems to be highly peptide dependent.

Figure 4. Increased invasion of the uterus in primates is associated with the presence of NK cells

Panel A shows implantation of the blastocyst, an early stage in embryo development, into the uterine epithelium. Co-operative interactions between fetal trophoblast and maternal cells then form the placenta. In prosimians, such as the lemur shown in panel B, the trophoblast cells abut the surface epithelium of the uterus but do not invade. Neither are NK cells present. Nutrients are transferred to the fetus from maternal blood vessels close to the uterine epithelium and in glandular secretions. This arrangement is called an epitheliochorial placenta. The endometrium does not transform into decidua and NK cells are absent. In Old World monkeys, such as the rhesus macaque, trophoblast cells penetrate through the epithelium and invade maternal arteries where the trophoblast cells replace the vascular endothelial cells. This transformation increases the blood supply to the placenta, where nutrients are transferred directly from maternal blood to the fetal capillaries. Accompanying these changes is the presence of NK cells in the decidua, the name given to the endometrium that has differentiated under the influence of progesterone. This type of placenta, which is also seen in human pregnancy, is called a haemochorial placenta. In human placentation, panel D, trophoblast cells invade the blood vessels as in rhesus macaque, but replace the vascular endothelium to a greater degree that extends into the myometrium. In addition, trophoblast cells invade the decidua, replacing the medial smooth muscle with fibrinoid material. Accompanying these changes is the presence of numerous NK cells.

Figure 5. Model for the maintenance KIR A and KIR B haplotypes and HLA-C1 and HLA-C2 epitopes in human populations

a | A hypothetical cycle in which the size of a population changes over time and circumstance. With the onset of an epidemic of an acute and lethal viral infection the population size will progressively decrease, disproportionately so for infants and the younger generation. If the combination of KIR A haplotypes and HLA-C1 epitopes provides resistance to infection, then the surviving population, which will be largely immune to further infection, will have increased frequencies of KIR A and HLA-C1, compared with the starting population, and decreased frequencies of KIR B and HLA-C2. With the end of the infectious cycle the challenge becomes one of reproduction, as the population can only survive if the next generation is sufficiently viable and numerous. In this situation, where there is a strong element of competition among the survivors, there will be selection for the combination of KIR B haplotypes and HLA-C2, the most recently evolved elements of the system of interactions between KIRs and HLA class I. Pregnancies in which the mother has KIR B and the fetus has C2 are predicted to favor larger and more robust progeny. Thus in this part of the cycle, the frequencies of KIR B haplotypes and HLA-C2 will increase while those of KIR A haplotypes and HLA-C1 will decrease. b | All human populations retain KIR A (red) and KIR B (green) haplotypes, but their relative frequencies vary.

Figure 6. Maintaining HLA diversity during migrations that increased the geographical range of human species

a | Humans first entered the Americas at Alaska after migration from Asia ~17,000 years ago. North, Central and South America were then colonized by southward migration. For present-day Native American populations of North America, the HLA-B alleles largely remain identical to the ones that came with the migrants from Asia. Starting in the southwestern part of the USA and increasing with distance southwards, the Amerindian populations have ‘new’ recombinant HLA-B alleles in which a short sequence segment in one Asian founder allele was replaced by the orthologous segment from another founder allele. This phenomenon is illustrated for the HLA-B*35:01 Asian allele. Shown are fourteen recombinants of HLA-B*35:01, the amino-acid positions that were affected by the recombinations, and the various founder alleles that could have been the donor for the recombinations. All such recombinations involve one or more amino-acid substitutions in the α₁ and α₂ domains that alter the interactions of HLA-B with antigenic peptides (p) and T-cell receptors (t). For each recombination the potential donor alleles are indicated by the coloured boxes on the right and the donated sequences by the coloured residue boxes on the left. For the six recombinations with more than one possible donor, the residues are only shaded with the colour of one of them (the one furthest to the left). b | The ‘heat map’ shows the geographical distribution of the archaic allele HLA-B*73. The colour spectrum denotes increasing frequency from 0% (dark blue) to 4.5% (bright red). Gray shading indicates regions for which high-resolution HLA typing data from ethnically well-defined indigenous populations were not available. The table below the heat map shows the 41 amino-acid differences that distinguish HLA-B*35:01 and HLA-B*73:01. Of these 16 are at functionally important positions that make contact with peptide (p), T-cell receptor (t), KIR (k) or leukocyte immunoglobulin-like receptor (l).

Figure 6. Maintaining HLA diversity during migrations that increased the geographical range of human species

a | Humans first entered the Americas at Alaska after migration from Asia ~17,000 years ago. North, Central and South America were then colonized by southward migration. For present-day Native American populations of North America, the HLA-B alleles largely remain identical to the ones that came with the migrants from Asia. Starting in the southwestern part of the USA and increasing with distance southwards, the Amerindian populations have ‘new’ recombinant HLA-B alleles in which a short sequence segment in one Asian founder allele was replaced by the orthologous segment from another founder allele. This phenomenon is illustrated for the HLA-B*35:01 Asian allele. Shown are fourteen recombinants of HLA-B*35:01, the amino-acid positions that were affected by the recombinations, and the various founder alleles that could have been the donor for the recombinations. All such recombinations involve one or more amino-acid substitutions in the α₁ and α₂ domains that alter the interactions of HLA-B with antigenic peptides (p) and T-cell receptors (t). For each recombination the potential donor alleles are indicated by the coloured boxes on the right and the donated sequences by the coloured residue boxes on the left. For the six recombinations with more than one possible donor, the residues are only shaded with the colour of one of them (the one furthest to the left). b | The ‘heat map’ shows the geographical distribution of the archaic allele HLA-B*73. The colour spectrum denotes increasing frequency from 0% (dark blue) to 4.5% (bright red). Gray shading indicates regions for which high-resolution HLA typing data from ethnically well-defined indigenous populations were not available. The table below the heat map shows the 41 amino-acid differences that distinguish HLA-B*35:01 and HLA-B*73:01. Of these 16 are at functionally important positions that make contact with peptide (p), T-cell receptor (t), KIR (k) or leukocyte immunoglobulin-like receptor (l).