* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Human-specific evolution of killer cell immunoglobulin
Survey
Document related concepts
12-Hydroxyeicosatetraenoic acid wikipedia , lookup
Adaptive immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Major histocompatibility complex wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Molecular mimicry wikipedia , lookup
Innate immune system wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
A30-Cw5-B18-DR3-DQ2 (HLA Haplotype) wikipedia , lookup
X-linked severe combined immunodeficiency wikipedia , lookup
Transcript
Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Phil. Trans. R. Soc. B (2012) 367, 800–811 doi:10.1098/rstb.2011.0266 Review Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules Peter Parham1,2,*, Paul J. Norman1,2, Laurent Abi-Rached1,2 and Lisbeth A. Guethlein1,2 1 Department of Structural Biology, and 2Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA 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. Keywords: natural killer cells; major histocompatibility complex; balancing selection 1. INTRODUCTION From their variable cell-surface receptors, that detect infection, cancer and other physiological perturbations, lymphocytes are divided into three broad types. These comprise the B cells and T cells that use gene rearrangement and somatic mutation to diversify their variable antigen receptors (immunoglobulins and T-cell receptors (TCRs) respectively), and the natural killer (NK) cells that do not employ these mechanisms. In their place, NK cells use transcriptional regulation of a variety of receptor genes to form and maintain a diverse repertoire of NK cells with heterogeneous cell-surface phenotype [1]. NK cells exert their functional effects by physically interacting with other types of cell, engagements that can lead to the killing of cells damaged by infection or malignancy, and to the secretion of cytokines that recruit other inflammatory immune system cells [2]. NK cells contribute to innate immunity, the early phase of an immune response, when NK-cell interactions with dendritic cells can help initiate the adaptive immune response mediated by B and T cells, but only if and when it is necessary. Further distinguishing NK cells from B and T cells is their role in placental reproduction [3]. Implantation of an embryo into the uterus and formation of the placenta involves interactions between maternal uterine NK cells and foetal extra-villous trophoblast cells that cause the latter to invade the mother’s spiral arteries and convert them into large vessels capable of supplying the placenta with sufficient blood to nourish the baby to term. NK cells thus make vital contributions to the immune system and the reproductive system, the former being essential for day-to-day survival of human individuals, the latter for the generation-togeneration survival of human populations and the human species. * Author for correspondence ([email protected]). One contribution of 14 to a Discussion Meeting Issue ‘Immunity, infection, migration and human evolution’. 800 This journal is q 2012 The Royal Society Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Review. Coevolution of KIR and HLA class I P. Parham et al. 801 isotype variants HLA complex human chromosome 6 ligands for NK cell receptors highly conserved interaction HLA-A 1243 HLA-B 1737 HLA-C 884 3 HLA-E 4 HLA-F HLA-G 15 HLA-A, -B, -C HLA-E killer cell immunoglobulin CD94:NKG2A -like receptors (KIRs) natural killer complex human chromosome 12 lectin-like NK cell receptors highly diversified interaction leucocyte receptor complex human chromosome 19 antibody-like NK cell receptors 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. In their cell-surface phenotype and function, NK cells are more like T cells than B cells, and more closely resemble the CD8-bearing killer T cells than the CD4-bearing helper T cells [1]. Central to killer T-cell biology are the interactions of ab TCRs with small 8 – 10 amino acid peptides presented by major histocompatibility complex (MHC) class I molecules. In analogous fashion, NK-cell receptors for MHC class I have similar critical influences on NK-cell development and response. In a process known as education for human NK cells [4 – 6] and licensing for mouse NK cells [7], developmental interactions between MHC class I ligands and cognate NK-cell receptors determine how mature NK cells carrying such receptors can respond to unhealthy cells exhibiting perturbed expression of the MHC class I ligand. Likewise, the strength of NK-cell effector functions can be modulated by the strength of the avidity between allelic variants of an NK-cell receptor and its cognate MHC class I ligand [5,8]. Despite the striking parallels, there are many differences in the way that NK-cell and T-cell receptors for MHC class I guide and regulate their respective lymphocyte populations. 2. GENETIC COMPLEXES ENCODING NATURAL KILLER CELL RECEPTORS AND LIGANDS Identified in the 1930s as highly polymorphic antigens that determine the rejection of transplanted tissues and organs, MHC class I molecules were studied for the next four decades in the non-physiological context of clinical transplantation (reviewed by Klein [9]). Although their physiological function of presenting antigens to T cells unfolded in the 1970s and 1980s, it was not until the 1990s that the important influence that MHC class I molecules exert on NK-cell biology was appreciated [10]. The human MHC is Phil. Trans. R. Soc. B (2012) alternatively called the human leucocyte antigen (HLA) complex, a name reflecting its discovery and initial characterization using antibody-based serological assays that distinguish different antigens. The approximately 4.8 Mb HLA complex on chromosome 6 contains many immune system genes and is the most highly polymorphic segment of the human genome [11,12]. Of the six expressed HLA class I genes, HLA-A, -B and -C are extraordinarily polymorphic, whereas HLA-E, -F and -G are conserved (figure 1). All these genes except HLA-F have been shown to encode ligands for NK-cell receptors. For decades, the function of HLA-F has been an enigma, but a recent report raises the possibility that it acts as a kind of chaperone that retrieves other HLA class I molecules that have become unfolded at the plasma membrane and escorts them inside the cell [13]. Complementing the MHC are two further genetic complexes containing families of genes that encode NK-cell receptors: the natural killer complex (NKC) on chromosome 12 [14] and the leucocyte receptor complex (LRC) on chromosome 19 (figure 1) [15,16]. The NKC encodes receptors whose ligand-binding domains have a structure related to that of calcium-dependent carbohydrate-binding proteins called lectins. But instead of binding to carbohydrates, the NK-cell receptors have evolved to bind protein ligands and some of them bind to MHC class I. Critical human NKC-encoded receptors are the heterodimeric receptors CD94:NKG2A (an inhibitory receptor) and CD94:NKG2C (an activating receptor), which both recognize complexes of HLA-E and peptides derived from the leader sequences of other HLA class I (figure 1) [17]. The functional consequence of this composite specificity is that CD94:NKG2 receptors are sensors that monitor the total amount HLA class I made by a cell and how it changes in the context of disease. Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 802 P. Parham et al. Review. Coevolution of KIR and HLA class I KIR locus Y human Y chimpanzee Y orangutan Y Y gibbon rhesus macaque owl monkey Y Y Y mouse lemur galago Y Y pig seal dog mouse 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 [19–25]. 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, C, pseudogene. The LRC encodes receptors whose ligand-binding domains are made up from several modules each of which is an immunoglobulin-like domain. Of particular interest here is the diverse family of human killer cell immunoglobulin-like receptors (KIRs), some of which recognize the polymorphic HLA-A, -B and -C molecules. In a complementary fashion to CD94:NKG2A/ C, these KIRs monitor the presence and level of individual HLA class I allotypes on cell surfaces. Consistent with these complementary functions, HLA-E and CD94:NKG2 are conserved in the human population, whereas KIR and HLA-A, -B and -C are highly diversified (figure 1) [18]. 3. COUNTERPARTS TO THE HUMAN KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR FAMILY ARE PRESENT ONLY IN SIMIAN PRIMATES Comparing a range of mammalian species has shown that most of them do not have a diversified family of KIR genes (figure 2). For example, the KIR locus appears deleted from dog and cat genomes; and in the mouse genome, the two KIR genes are not in the LRC but on the X chromosome [26], with only one of them being expressed by NK cells [27]. Seals have a single, conserved and functional KIR gene [19]; but in prosimians, the single KIR gene is non-functional [20]. To date, diversified families of KIR genes have been found only for simian primates (monkeys, apes and the human species) and cattle, a ruminant [20–22,28–33]. However, the primate and cattle KIR families diverged 135 million years ago, prior to the radiation of placental mammals. At that time an ancestral KIR gene duplicated to form two daughter genes: KIR3DL and KIR3DX [34,35]. Subsequently, Phil. Trans. R. Soc. B (2012) the KIR3DL gene exclusively expanded in the simian primates, whereas the KIR3DX gene degenerated to become a pseudogene. Conversely, the KIR3DX gene expanded in cattle (and probably related ruminant species), whereas KIR3DL remained a single-copy gene. Although cattle and simian primates both have diverse KIR gene families, they are clearly the products of independent expansions [34]. Further emphasizing the restriction of diverse KIR3DL to the simian primates, prosimian primates have expanded and diversified the CD94 and NKG2 families of NKC genes in the context of their non-functional KIR [20]. Particularly extreme in their divergence from the human situation are rodents (for example mouse and rat), who use diverse families of NKC-encoded Ly49 receptors as their variable NK-cell receptors for MHC class I [36,37]. In contrast to the flourishing Ly49 gene families of rodents, the single human Ly49 gene is non-functional [38]. 4. KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTORS RECOGNIZE FOUR MUTUALLY EXCLUSIVE EPITOPES OF HUMAN LEUCOCYTE ANTIGEN CLASS I HLA-E is highly selective in binding peptides derived from HLA class I leader sequences [39]. Consequently, the CD94:NKG2A/C receptors are highly peptidespecific. The interactions of KIR with HLA class I are also sensitive to the sequence of the bound peptides [40–43]. Three-dimensional structures show that the KIR-binding site on the HLA class I molecule overlaps with that of the ab TCR, and involves the face formed by the exposed parts of the a helices of the a1 and a2 domains and of the outstretched peptide gripped between them (figure 3) [44]. Direct contact is possible Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Review. Coevolution of KIR and HLA class I P. Parham et al. 803 C1 Bw4 a1 helix 80 A11 83 HLA-A Bw4 C1 C2 A3 HLA-B HLA-C 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]. a2 helix KIR binding site TCR binding site Figure 3. Killer cell immunoglobulin-like receptor (KIR) and the ab 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 a1 and a2 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. with peptide residues seven and eight, and indirect effects may also arise from other peptide positions that interact with the pockets of the HLA class I binding groove [47]. Although not well studied, the peptide sensitivity of KIR binding to HLA class I appears to vary with the KIR. For example, KIR3DL2 binding to HLA-A3 and HLA-A11 appears to be very peptidedependent, because only one peptide (derived from Epstein–Barr virus (EBV)) has been shown to be permissive for the interaction [43]. Less fastidious are the HLA-C-specific KIRs, for which around 40 per cent of the peptides that bind to HLA-C are compatible with KIR interaction [40,48–50]. That the KIR- and ab TCR-binding sites physically overlap raises the possibility that the individual selection pressures exerted on HLA class I by T-cell and NK-cell immunity can compete with each other (figure 3). In other words, a variant HLA class I selected for its beneficial T-cell response to one infection might have detrimental consequences for a subsequent NK-cell response against another infectious agent, and vice versa. The interaction between KIR and HLA class I is relatively rigid, involving little accommodation through conformational change [44]. Only a fraction of the HLA-A, -B and -C variants interact with KIRs and these all carry one of four mutually exclusive epitopes (A3/11, Bw4, C1 and C2) that are structural variations on a theme (figure 4). These epitopes are alternatively referred to as KIR ligands, particularly in the clinical literature pertaining to bone marrow transplantation and the role of donor-derived NK cells in improving the survival of transplanted patients Phil. Trans. R. Soc. B (2012) [52–55]. That all HLA-C allotypes have either the C1 or C2 epitope, whereas only 45 per cent of HLA-A and 36 per cent of HLA-B allotypes are KIR ligands, is consistent with HLA-C having evolved to be a superior and more specialized ligand for KIR [56,57]. This distribution also shows how a majority of HLA-A and -B allotypes do not function as KIR ligands and are thus free to evolve exclusively under pressure from the T-cell response. HLA-C is of more recent origin than HLA-A and -B and probably evolved from an HLAB-like ancestor that carried the C1 epitope [58]. Studies to compare the HLA class I specificities of mutant human and ape KIRs show that hominoid KIRs are inherently restricted to recognizing HLA class I allotypes carrying the A3/11, Bw4, C1 or C2 epitope, further emphasizing the partition of HLA-A and -B allotypes into those that serve as KIR ligands and those that cannot [56,57]. 5. POPULATION BIOLOGY AND GENETICS OF KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTORS There are 13 expressed human KIR genes and two KIR pseudogenes (figure 5). KIR2DS1, 2, 3, 4 and 5 are dedicated activating receptors, whereas KIR2DL1, 2DL2/3 and 2DL5 are dedicated inhibitory receptors. KIR2DL4 has potential for both activating and inhibitory functions, whereas KIR3DL1/S1 is unusual in having mutually exclusive subsets of allotypes with activating (KIR3DS1) and inhibitory (KIR3DL1) function [59]. Haplotypes of the KIR locus differ in their content of KIR genes [33], an important feature that is illustrated for several common KIR haplotypes in figure 5 [23]. Three conserved genes (KIR3DL3, 2DL4 and 3DL2) form the common framework that defines two regions of gene-content diversity, one in the centromeric part of the locus and the other in the telomeric part [60]. Only five of the 13 human KIRs have been demonstrated to recognize HLA class I: A3/11 by KIR3DL2 [61], Bw4 by KIR3DL1 (but not KIR3DS1) [62,63], C2 by KIR2DL1 and 2DS1 [64], C1 and some C2 by KIR2DL2/3 [46,65], a mix of some C1, some C2 and A11 by KIR2DS4 [66] and HLA-G by KIR2DL4 [67] (table 1). In contrast, KIR2DS2, 2DS3, 2DS5, 2DL5, 3DS1 and 3DL3 remain orphan receptors for which no ligand has yet been identified. In the case of KIR2DS2, it is likely that at one time it did bind to Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 804 P. Parham et al. Review. Coevolution of KIR and HLA class I KIR haplotype B A Cen Tel 3DL3 2DS2 2DL2L3 2DL5C 2DS3S5C 2DP1 2DL1 3DP1 2DL4 3DL1S1 B01 B01 B01 B01 B01 B01 B03 B02 B02 B02 B02 B02 B02 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 B01 B01 B01 A01 A01 A01 A01 B01 B01 B01 A01 A01 A01 B01 B01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 A01 *0030102 *0030103 *00301 *0030104 *0140203 *0040202 par t *0030101 *00801 *0140202 *0040201 *0140201 *036 *0090102 *01001 *00201 *00206 *00802 *0090102 *0090101 *0010102 *0010105 *0010105 *0010112 *0010111 *0010109 2*0010101 2*0010102 2*0010106 2*0010107 2*0010105 2*0010104 3*010 2*0030101 2*0030107 2*0030106 2*0030105 2*0010103 2*0030104 3*0010102 3*0010105 3*0010101 3*0010106 3*0010108 3*0010102 3*0010104 3*0010103 3*0010107 3*0010109 3*00101 10 3*0020102 3*0020103 3*006 *0020103 *0020105 *0020107 *0020107 *0080101 *004 *00601 3*0010301 3*0010301 3*0010301 3*0010302 5*007 5*006 5*010 *0010201 *0010201 *0010202 *0010203 *010 *009 *006 *0040101 *0040101 *0040101 *007 *0040102 *1201 *010 *0030101 *0030102 *0030102 *0030101 *0030402 *0030401 *00902 *002 *0090103 *0090101 *007 *001 *0090102 *0030205 *0030202 *0030201 *00303 *0030202 *0030202 *0030204 *0030202 *008 *010 *0030206 *006 *006 *0030203 *00501 *00501 *00501 *00602 *011 *011 *0080203 *00501 *00501 *00501 *0010201 *00602 *0080105 *0010308 *00501 *0080101 *0010202 *0010201 *0010303 *011 *0010305 *0010307 *011 *0010201 *0010304 *0080204 *0010306 *0130101 *0130101 *0130101 *0070102 *0050102 *0050102 *063 *0130101 *0130103 *0130101 *0290101 *0070101 *0010102 *014 *0130102 *0010101 *0150201 *0150203 *025 *0050101 *008 *01701 *0050102 *0290102 *062 *00401 *0150202 *0090103 *0090101 *012 *048 *00101 *019 *005 *0010101 *0010110 *0010108 *0010107 *0010102 *0010106 *0020107 *0020104 *0020101 *008 *0020106 *0020103 *0020103 *005 *0020105 *0020109 *0020108 *004 *0030102 *007 *025 *0030207 *0030201 *0030208 *0030205 *0030203 *0030206 *0030204 *0030209 *0030210 *0030204 *0020102 *0020103 *00303 2DL5T 2DS3S5T *0010102 5*0020102 *0050101 3*0020101 *0050101 3*0020103 2DS1 2DS4 *0020102 *0020104 *0020104 *0040102 *010 *010 *0060101 *0010101 5*0020101 *0050104 3*0020102 *0010103 5*0020104 *0020101 *0020106 *0020103 *0010109 *0040101 *0030103 typing typing *0050103 3*0020101 par t *0020105 *0030101 *0010101 *0010107 *0010104 *010 *0030104 *0010108 *010 *0010102 *0010106 *0060102 *0010105 3DL2 *0070101 *0070103 *0070103 *008 *010 *010 *00202 *006/007 *0070102 *018 *0020103 *008 *0010102 *056 *0070102 *0010101 *0020104 *0020105 par t *0010302 *00901 *023 *010 *0020106 *00903 *00501 *0020102 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. Table 1. Human leukocyte antigen epitopes recognized by killer cell immunoglobulin-like receptor. HLA class I ligand KIR A3 A11 Bw4 3DL1 3DS1 3DL2 3DL3 2DL1 2DL2/3 2DS1 2DS2 2DS3 2DS4 2DS5 2DL4 2DL5 HLA class I but was then actively selected to lose that function [68,69]. Population studies provide an alternative approach for assessing the functional benefit of the enigmatic orphan KIR. To date, approximately 200 populations have been studied for KIR gene content (http://www. allelefrequencies.net [51]). With the exception of KIR2DS3 and KIR2DL5B, which are absent from some Amerindian tribes [70,71], all populations have significant frequencies for all the KIR genes. Likewise, all populations have both inhibitory KIR3DL1 that binds to Bw4 [62] and activating KIR3DS1 that does not bind Bw4 or other HLA class I [63]. Such Phil. Trans. R. Soc. B (2012) C1 C2 G unknown some some some retention, particularly in the case of Amerindian populations who have experienced successive population bottlenecks and severe epidemics of infectious disease, is unlikely to have occurred by chance and argues that the orphan KIRs serve useful functions, but this need not necessarily involve interaction with HLA class I. A precedent is set by KIR3DL2, which in addition to recognizing the A3/11 epitope of HLA class I [61] also recognizes microbial products and carries them inside cells for possible delivery to Toll-like receptors [72,73]. That loss of KIR2DS3 and KIR2DL5B has been tolerated by some populations could reflect the sequence similarities of these KIRs with KIR2DS5 Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Review. Coevolution of KIR and HLA class I centromeric 3DL3 telomeric 2DS2 2DL2/3 2DL5B 2DS3/5 2DP1 2DL1 3DP1 2DL4 3DL/S1 2DL5A 2DS3/5 B 2DL2 3DS1 A 2DL3 3DL1 0 25 50 P. Parham et al. 805 75 100 125 length (kb) 150 2DS1 haplotype 2DS4 3DL2 2DS5 175 200 length frequency (kb) (%) 157 47 143 46 225 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. and KIR2DL5A, respectively. For KIR2DS3, its poor folding in the endoplasmic reticulum and inability to reach the NK cell surface could also be a factor [74]. On the basis of KIR gene content, two groups of KIR haplotype have been defined. This concept is well illustrated by the Yucpa population of Amerindians who have only two major KIR gene-content haplotypes, one of group A and one of group B, which are present at roughly equal frequencies (figure 6). Differences of gene content are seen in both the centromeric and telomeric regions; and at the allele level, the two haplotypes have no KIR factor in common [75]. The group A haplotype has a content of seven genes of which six encode KIRs that bind HLA class I and the seventh (KIR3DL3) has not been tested. The group B KIR haplotype has nine expressed KIRs, of which three bind HLA class I (KIR2DL2, 2DL4 and 3DL2), four do not bind HLA class I (KIR2DS2, 3DS1, 2DL5A and 2DS5), and KIR3DL3 remains uncertain. Thus, a major difference between the two haplotypes is that the A haplotype is enriched for KIRs that bind HLA class I, whereas the B haplotype is enriched for KIRs that have either lost that function or never had it. This effect is also seen at the allelic level for genes that are common to A and B haplotypes. The Yucpa B haplotype lacks the KIR2DL1 gene, but that is not the case for all B haplotypes. However, the common KIR2DL1 allele of B haplotypes is KIR2DL1*004 which has attenuated signalling function compared with the common KIR2DL1*003 allele of the A haplotype [76]. Such functional difference between allotypes of the A and B KIR haplotypes is particularly extreme for the KIR3DL1/S1 gene, where A haplotype inhibitory KIR3DL1 binds the Bw4 epitope and is polymorphic, whereas B haplotype KIR3DS1 does not bind Bw4 and is practically monomorphic. By some margin, the genetics and functional effects of KIR polymorphism have been more extensively studied for KIR3DL1/S1 than for other KIR genes and are the subject of a recent review [12]. The central region of the KIR locus between 3DP1 and 2DL4 is a major site of reciprocal combination. This mechanism has re-assorted centromeric and telomeric gene-content motifs to form recombinant haplotypes that combine an A haplotype centromeric motif with a B haplotype telomeric motif, and vice Phil. Trans. R. Soc. B (2012) versa [23,77]. The convention has been to describe all such recombinant haplotypes as B haplotypes, reserving the A haplotype designation for haplotypes that have both a centromeric and a telomeric A motif. In disease-association studies, the effects of the B motifs appear dominant as is consistent with them having loss of function [78]. 6. MAJOR DIFFERENCES IN HUMAN AND CHIMPANZEE KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTORS Comparing the KIR locus in different species of simian primate shows an extraordinary degree of species specificity that attests to the rapid and variable evolution of KIR (figure 2). Phylogenetic analysis of the nucleotide sequences encoding simian primate KIR shows they form four discrete lineages that have coevolved with their target epitopes [21]. Presence in Old World monkeys of multiple HLA-A- and -B-like loci is associated with an expansion of lineage II KIR related to the human lineage II KIR3DL1 and 3DL2 that recognize the Bw4 and A3/ 11 epitopes, respectively. Likewise, the emergence of an HLA-C orthologue in orangutans is associated with expansion of lineage III KIR related to the human lineage III KIR2DL1, 2DS1 and 2DL2/3 that recognize HLA-C. As the chimpanzee is the living species most closely related to humans, we have extensively studied the function and population biology of chimpanzee KIR, so as to provide a valid assessment of what features of the human system are shared with other species and what features are unique (figure 7). Although both humans and chimpanzees have 13 KIR genes, only 3DL3, 2DL4, 2DL5 and 2DS4 are orthologous [30]. The framework of the KIR locus in the two species is similar but the distribution of genes within this framework is qualitatively different (figure 8) [24,79]. Whereas the variable gene content in the human KIR locus is evenly distributed between the centromeric and telomeric regions, all 10 chimpanzee KIR genes that contribute to variable gene content are packed together in the centromeric region. This leaves the telomeric region empty except for the 3DL1/2 lineage II framework gene which encodes a receptor having a specificity for MHC-A and MHC-B that combines Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 806 P. Parham et al. Review. Coevolution of KIR and HLA class I KIR divergence time from human (million years) prosimians one pseudogene 58–69 New World monkeys expansion of a novel lineage 40–45 expansion of lineage II 28–30 contraction of KIR locus 19–24 first expansion of lineage III 14–18 MHC class I isotype primate species E G Old World monkeys A B C Bw6 inactive Bw4 Bw6 gibbons Bw4 C1 Bw6 orangutans Bw4 Bw6 gorillas (C1) C2 Bw4 C1 Bw6 chimpanzees C2 Bw4 C1 Bw6 humans cognate receptor in human CD94: NKG2 lineage I KIR lineage II KIR further expansion of lineage III Bw4 C2 lineage II and III KIR lineage III KIR 10–12 7–10 elaboration of group A and B haplotypes 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. chimpanzee FCAR LILR C1 3DL3 C2 C1 3DL1/2 2DL4 C2 C2 C2 C1 C2 3DS2 2DL9 2DS2 C1 C1 3DS6 2DL6 2DL5 2DL8 2DL2 2DL5B 2DS3/5 C2 C2 C2 3DL5 3DL4 2DS4 2DL7 3DS1 2DL5A 2DS3/ 5 2DS1 C2 C1 3DL3 3DL2 3DP1 2DL4 FCAR LILR C1 2DL3 C2 2DP1 2DL1 human 3DL1 2DS4 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. elements of the Bw4 and A3/11 specificities of human lineage II KIR3DL1 and 3DL2, respectively [80]. All nine of the chimpanzee lineage III bind HLA class I, compared with only three of six human lineage III [58,69]. In addition to an orthologue of human 2DS4, the Phil. Trans. R. Soc. B (2012) chimpanzee has a battery of three C1-specific KIRs (one activating and two inhibitory) and five C2-specific KIRs (one activating and four inhibitory) that vary in both signalling and ligand-binding domains, and display more allelic variability than their human counterparts Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Review. Coevolution of KIR and HLA class I P. Parham et al. 807 0.7 (a) (b) HLA-C2 frequency 0.6 0.5 0.4 0.3 0.2 0.1 n = 58, b = –1.3, r2 = 0.6116, p < 0.0001 0 0.3 0.4 0.5 0.6 0.7 KIR A haplotype frequency 0.8 African east southeast Asian Asian southwest Oceanian South Hispanic European Asian Amerindian 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). [79]. Importantly, however, the chimpanzee KIR haplotypes do not divide into two groups as is the case for the human KIR haplotypes. 7. AN EVOLUTIONARY COMPROMISE FOR HUMAN KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTORS THAT WAS NOT MADE BY CHIMPANZEE KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTORS In the context of hominoid evolution, during which HLA-C evolved specifically as a KIR ligand and the C1 epitope preceded the C2 epitope by several million years, the chimpanzee KIR locus has taken this progression to a higher level than the human KIR locus. The majority of chimpanzee KIRs are HLA-C receptors and the C2-specific receptors outweigh the C1-specific receptors in number. In contrast, the human system represents a less robust or compromised system in which the group A KIR haplotypes are more similar to the chimpanzee KIR haplotypes, whereas the group B KIR haplotypes have accumulated genes encoding KIRs with reduced or no binding to HLA class I. Common disorders of reproduction, such as preeclampsia, spontaneous abortion and foetal growth restriction, have been associated with pregnancies in which the mother is homozygous for group A KIR haplotypes and the foetus has HLA-C bearing the C2 epitope [81,82]. This combination implicates interactions between foetal C2 and maternal inhibitory C2-specific KIR2DL1 in the disease-causing mechanism. Consistent with this model, activating C2-specific KIR2DS1 is a protective factor on maternal B KIR haplotypes [83]. Indicating that these pregnancy disorders have been a major selective force on human populations is the observed inverse correlation Phil. Trans. R. Soc. B (2012) between the frequencies of C2 bearing HLA-C and group A KIR haplotypes (figure 9). This correlation strongly argues that pressure from human reproduction drove the evolution of the group B KIR haplotypes. The common disorders of pregnancy are associated with insufficient invasion of the uterus by foetal extravillous trophoblast cells, which enlarge maternal blood vessels called spiral arteries so that they will be capable of supplying the growing baby with sufficient nutrition [3]. This remodelling function of the trophoblast appears to be guided through physical and chemical interactions with specialized uterine NK cells of the mother, which have phenotypic and functional properties that are different from those of the majority of blood NK cells [84]. Extra-villous trophoblast uniquely expresses an abundance of HLA-C but not HLA-A and -B [85]. Thus, the underlying disease-causing mechanism probably involves interaction between C2-bearing HLA-C on the foetal trophoblast and KIR2DL1 on the maternal uterine NK cells. That this type of interaction has been attenuated in humans, by evolution of the group B KIR haplotypes, but not in chimpanzees indicates a selective pressure that demanded an ever-increasing supply of maternal blood to feed the foetus. An important difference that distinguishes human and chimpanzee evolution, since they last shared a common ancestor more than 6 Myr ago, is that the adult human brain is now more than three times the size of an adult chimpanzee brain [86]. The evolution of ever-bigger brains would have been energetically expensive, necessitating continual improvement of the supply of maternal blood to the placenta. This improvement seems to have been accomplished by the evolution of the KIR B haplotypes that have an activating C2-specific KIR that counters the effect of inhibitory KIR2DL1, and a Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 808 P. Parham et al. Review. Coevolution of KIR and HLA class I series of inhibitory KIRs, including allotypes of KIR2DL1 [76], that have been selected for attenuation or loss of function [23]. NK cells have been strongly implicated in providing immunity against viral infections [87]. For example, a person lacking NK cells was susceptible to fulminating herpes virus infection and eventually died of disease caused by EBV [88]. Relatively few studies have been performed to correlate the progress of viral infection with KIR and HLA type [89,90], but the evidence as it stands indicates that the group A KIR haplotype, and by implication all chimpanzee KIR haplotypes, evolved to mount defence against infection. The human immune system appears to have made a compromise between KIRs that are beneficial for fighting infection and those that facilitate reproduction, an evolutionary compromise that the chimpanzee has not had to make. This difference may in part explain why chimpanzees are relatively resistant to a variety of infections that plague the modern human population [91]. This work was supported by NIH grants nos. AI17892 and AI22039 to P.P. REFERENCES 1 Parham, P. 2005 MHC class I molecules and KIRs in human history, health and survival. Nat. Rev. Immunol. 5, 201 –214. (doi:10.1038/nri1570) 2 Vivier, E., Raulet, D. H., Moretta, A., Caligiuri, M. A., Zitvogel, L., Lanier, L. L., Yokoyama, W. M. & Ugolini, S. 2011 Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49. (doi:10.1126/science.1198687) 3 Moffett, A. & Loke, C. 2006 Immunology of placentation in eutherian mammals. Nat. Rev. Immunol. 6, 584–594. (doi:10.1038/nri1897) 4 Anfossi, N. et al. 2006 Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342. (doi:10.1016/j.immuni.2006.06.013) 5 Yawata, M., Yawata, N., Draghi, M., Partheniou, F., Little, A. M. & Parham, P. 2008 MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response. Blood 112, 2369–2380. (doi:10.1182/ blood-2008-03-143727) 6 Andersson, S., Fauriat, C., Malmberg, J. A., Ljunggren, H. G. & Malmberg, K. J. 2009 KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression. Blood 114, 95–104. (doi:10.1182/blood-2008-10-184549) 7 Yokoyama, W. M. & Kim, S. 2006 How do natural killer cells find self to achieve tolerance? Immunity 24, 249–257. (doi:10.1016/j.immuni.2006.03.006) 8 Yawata, M., Yawata, N., Draghi, M., Little, A. M., Partheniou, F. & Parham, P. 2006 Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function. J. Exp. Med. 203, 633–645. (doi:10.1084/jem.20051884) 9 Klein, J. 1975 Biology of the mouse histocompatibility-2 complex: principles of immunogenetics applied to a single system. New York, NY: Springer. 10 Ljunggren, H. G. & Karre, K. 1990 In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol. Today 11, 237–244. (doi:10.1016/0167-5699(90)90097-S) 11 1000 Genomes Project Consortium. 2010 A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073. (doi:10.1038/nature09534) Phil. Trans. R. Soc. B (2012) 12 Parham, P., Norman, P. J., Abi-Rached, L. & Guethlein, L. A. 2011 Variable NK cell receptors exemplified by human KIR3DL1/S1. J. Immunol. 187, 11–19. (doi:10. 4049/jimmunol.0902332) 13 Goodridge, J. P., Burian, A., Lee, N. & Geraghty, D. E. 2010 HLA-F complex without peptide binds to MHC class I protein in the open conformer form. J. Immunol. 184, 6199–6208. (doi:10.4049/jimmunol.1000078) 14 Yokoyama, W. M. & Seaman, W. E. 1993 The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu. Rev. Immunol. 11, 613 –635. (doi:10.1146/annurev.iy.11. 040193.003145) 15 Wilson, M. J., Torkar, M., Haude, A., Milne, S., Jones, T., Sheer, D., Beck, S. & Trowsdale, J. 2000 Plasticity in the organization and sequences of human KIR/ILT gene families. Proc. Natl Acad. Sci. USA 97, 4778–4783. (doi:10.1073/pnas.080588597) 16 Kelley, J., Walter, L. & Trowsdale, J. 2005 Comparative genomics of natural killer cell receptor gene clusters. PLoS Genet. 1, 129– 139. (doi:10.1371/journal.pgen. 0010027) 17 Braud, V. M. et al. 1998 HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795 –799. (doi:10.1038/35869) 18 Shum, B. P., Flodin, L. R., Muir, D. G., Rajalingam, R., Khakoo, S. I., Cleland, S., Guethlein, L. A., Uhrberg, M. & Parham, P. 2002 Conservation and variation in human and common chimpanzee CD94 and NKG2 genes. J. Immunol. 168, 240– 252. 19 Hammond, J. A., Guethlein, L. A., Abi-Rached, L., Moesta, A. K. & Parham, P. 2009 Evolution and survival of marine carnivores did not require a diversity of killer cell Ig-like receptors or Ly49 NK cell receptors. J. Immunol. 182, 3618–3627. (doi:10.4049/jimmunol. 0803026) 20 Averdam, A. et al. 2009 A novel system of polymorphic and diverse NK cell receptors in primates. PLoS Genet. 5, e1000688. (doi:10.1371/journal.pgen.1000688) 21 Abi-Rached, L. et al. 2010 A small, variable, and irregular killer cell Ig-like receptor locus accompanies the absence of MHC-C and MHC-G in gibbons. J. Immunol. 184, 1379–1391. (doi:10.4049/jimmunol.0903016) 22 Cadavid, L. F. & Lun, C. M. 2009 Lineage-specific diversification of killer cell Ig-like receptors in the owl monkey, a New World primate. Immunogenetics 61, 27–41. (doi:10. 1007/s00251-008-0342-y) 23 Pyo, C. W. et al. 2010 Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS ONE 5, e15115. (doi:10.1371/journal. pone.0015115) 24 Sambrook, J. G., Bashirova, A., Palmer, S., Sims, S., Trowsdale, J., Abi-Rached, L., Parham, P., Carrington, M. & Beck, S. 2005 Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates. Genome Res. 15, 25–35. (doi:10. 1101/gr.2381205) 25 Guethlein, L. A., Older Aguilar, A. M., Abi-Rached, L. & Parham, P. 2007 Evolution of killer cell Ig-like receptor (KIR) genes: definition of an orangutan KIR haplotype reveals expansion of lineage III KIR associated with the emergence of MHC-C. J. Immunol. 179, 491–504. 26 Welch, A. Y., Kasahara, M. & Spain, L. M. 2003 Identification of the mouse killer immunoglobulin-like receptor-like (KIRL) gene family mapping to chromosome X. Immunogenetics 54, 782 –790. (doi:10.1007/ s00251-002-0529-6) 27 Dissen, E., Fossum, S., Hoelsbrekken, S. E. & Saether, P. C. 2008 NK cell receptors in rodents and cattle. Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Review. Coevolution of KIR and HLA class I 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Semin. Immunol. 20, 369 –375. (doi:10.1016/j.smim. 2008.09.007) Guethlein, L. A., Flodin, L. R., Adams, E. J. & Parham, P. 2002 NK cell receptors of the orangutan (Pongo pygmaeus): a pivotal species for tracking the coevolution of killer cell Ig-like receptors with MHC-C. J. Immunol. 169, 220–229. Hershberger, K. L., Shyam, R., Miura, A. & Letvin, N. L. 2001 Diversity of the killer cell Ig-like receptors of rhesus monkeys. J. Immunol. 166, 4380–4390. Khakoo, S. I. et al. 2000 Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity 12, 687–698. (doi:10. 1016/S1074-7613(00)80219-8) McQueen, K. L., Wilhelm, B. T., Harden, K. D. & Mager, D. L. 2002 Evolution of NK receptors: a single Ly49 and multiple KIR genes in the cow. Eur. J. Immunol. 32, 810–817. (doi:10.1002/1521-4141(200203)32:3,810:: AID-IMMU810.3.0.CO;2-P) Rajalingam, R., Parham, P. & Abi-Rached, L. 2004 Domain shuffling has been the main mechanism forming new hominoid killer cell Ig-like receptors. J. Immunol. 172, 356 –369. Uhrberg, M., Valiante, N. M., Shum, B. P., Shilling, H. G., Lienert-Weidenbach, K., Corliss, B., Tyan, D., Lanier, L. L. & Parham, P. 1997 Human diversity in killer cell inhibitory receptor genes. Immunity 7, 753 –763. (doi:10.1016/S1074-7613(00)80394-5) Guethlein, L. A., Abi-Rached, L., Hammond, J. A. & Parham, P. 2007 The expanded cattle KIR genes are orthologous to the conserved single-copy KIR3DX1 gene of primates. Immunogenetics 59, 517 –522. (doi:10. 1007/s00251-007-0214-x) Sambrook, J. G., Bashirova, A., Andersen, H., Piatak, M., Vernikos, G. S., Coggill, P., Lifson, J. D., Carrington, M. & Beck, S. 2006 Identification of the ancestral killer immunoglobulin-like receptor gene in primates. BMC Genomics 7, 209. (doi:10.1186/1471-2164-7-209) Carlyle, J. R., Mesci, A., Fine, J. H., Chen, P., Belanger, S., Tai, L. H. & Makrigiannis, A. P. 2008 Evolution of the Ly49 and Nkrp1 recognition systems. Semin. Immunol. 20, 321 –330. (doi:10.1016/j.smim.2008.05.004) Wilhelm, B. T. & Mager, D. L. 2004 Rapid expansion of the Ly49 gene cluster in rat. Genomics 84, 218–221. (doi:10.1016/j.ygeno.2004.01.010) Westgaard, I. H., Berg, S. F., Orstavik, S., Fossum, S. & Dissen, E. 1998 Identification of a human member of the Ly-49 multigene family. Eur. J. Immunol. 28, 1839–1846. (doi:10.1002/(SICI)1521-4141(199806)28: 06,1839::AID-IMMU1839.3.0.CO;2-E) Braud, V., Jones, E. Y. & McMichael, A. 1997 The human major histocompatibility complex class Ib molecule HLAE binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169. (doi:10.1002/eji.1830270517) Fadda, L. et al. 2010 Peptide antagonism as a mechanism for NK cell activation. Proc. Natl Acad. Sci. USA 107, 10 160 –10 165. (doi:10.1073/pnas.0913745107) Sharma, D. et al. 2009 Dimorphic motifs in D0 and D1 þ D2 domains of killer cell Ig-like receptor 3DL1 combine to form receptors with high, moderate, and no avidity for the complex of a peptide derived from HIV and HLA-A*2402. J. Immunol. 183, 4569–4582. (doi:10.4049/jimmunol.0901734) Thananchai, H. et al. 2007 Cutting edge: allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B. J. Immunol. 178, 33–37. Hansasuta, P., Dong, T., Thananchai, H., Weekes, M., Willberg, C., Aldemir, H., Rowland-Jones, S. & Braud, V. M. 2004 Recognition of HLA-A3 and HLA-A11 by Phil. Trans. R. Soc. B (2012) 44 45 46 47 48 49 50 51 52 53 54 55 56 57 P. Parham et al. 809 KIR3DL2 is peptide-specific. Eur. J. Immunol. 34, 1673 –1679. (doi:10.1002/eji.200425089) Boyington, J. C. & Sun, P. D. 2002 A structural perspective on MHC class I recognition by killer cell immunoglobulinlike receptors. Mol. Immunol. 38, 1007–1021. (doi:10. 1016/S0161-5890(02)00030-5) Roomp, K. & Domingues, F. S. 2011 Predicting interactions between T cell receptors and MHC-peptide complexes. Mol. Immunol. 48, 553–562. (doi:10.1016/j. molimm.2010.10.014) Winter, C. C. & Long, E. O. 1997 A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes. J. Immunol. 158, 4026–4028. Sanjanwala, B., Draghi, M., Norman, P. J., Guethlein, L. A. & Parham, P. 2008 Polymorphic sites away from the Bw4 epitope that affect interaction of Bw4þ HLA-B with KIR3DL1. J. Immunol. 181, 6293 –6300. Mandelboim, O., Wilson, S. B., Vales-Gomez, M., Reyburn, H. T. & Strominger, J. L. 1997 Self and viral peptides can initiate lysis by autologous natural killer cells. Proc. Natl Acad. Sci. USA 94, 4604–4609. (doi:10.1073/pnas.94.9.4604) Rajagopalan, S. & Long, E. O. 1997 The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity. J. Exp. Med. 185, 1523–1528. (doi:10.1084/jem.185.8.1523) Zappacosta, F., Borrego, F., Brooks, A. G., Parker, K. C. & Coligan, J. E. 1997 Peptides isolated from HLA-Cw*0304 confer different degrees of protection from natural killer cell-mediated lysis. Proc. Natl Acad. Sci. USA 94, 6313–6318. (doi:10.1073/pnas.94.12.6313) Gonzalez-Galarza, F. F., Christmas, S., Middleton, D. & Jones, A. R. 2011 Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res. 39, D913 –D919. (doi:10.1093/nar/gkq1128) Cooley, S. et al. 2009 Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood 113, 726–732. (doi:10.1182/blood2008-07-171926) Hsu, K. C., Keever-Taylor, C. A., Wilton, A., Pinto, C., Heller, G., Arkun, K., O’Reilly, R. J., Horowitz, M. M. & Dupont, B. 2005 Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 105, 4878– 4884. (doi:10.1182/ blood-2004-12-4825) Pfeiffer, M. M., Feuchtinger, T., Teltschik, H. M., Schumm, M., Muller, I., Handgretinger, R. & Lang, P. 2010 Reconstitution of natural killer cell receptors influences natural killer activity and relapse rate after haploidentical transplantation of T- and B-cell depleted grafts in children. Haematologica 95, 1381–1388. (doi:10.3324/haematol.2009.021121) Ruggeri, L. et al. 2002 Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100. (doi:10.1126/ science.1068440) Older Aguilar, A. M., Guethlein, L. A., Adams, E. J., Abi-Rached, L., Moesta, A. K. & Parham, P. 2010 Coevolution of killer cell Ig-like receptors with HLA-C to become the major variable regulators of human NK cells. J. Immunol. 185, 4238–4251. (doi:10.4049/ jimmunol.1001494) Older Aguilar, A. M., Guethlein, L. A., Hermes, M., Walter, L. & Parham, P. 2011 Rhesus macaque KIR bind human MHC class I with broad specificity and Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 810 58 59 60 61 62 63 64 65 66 67 68 69 70 71 P. Parham et al. Review. Coevolution of KIR and HLA class I recognize HLA-C more effectively than HLA-A and HLAB. Immunogenetics 63, 577–585. (doi:10.1007/s00251011-0535-7) Moesta, A. K., Abi-Rached, L., Norman, P. J. & Parham, P. 2009 Chimpanzees use more varied receptors and ligands than humans for inhibitory killer cell Ig-like receptor recognition of the MHC-C1 and MHC-C2 epitopes. J. Immunol. 182, 3628 –3637. (doi:10.4049/ jimmunol.0803401) Campbell, K. S. & Purdy, A. K. 2011 Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology 132, 315 –325. (doi:10.1111/j.1365-2567.2010.03398.x) Martin, A. M., Kulski, J. K., Gaudieri, S., Witt, C. S., Freitas, E. M., Trowsdale, J. & Christiansen, F. T. 2004 Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B. Gene 335, 121– 131. (doi:10.1016/j.gene.2004.03.018) Dohring, C., Scheidegger, D., Samaridis, J., Cella, M. & Colonna, M. 1996 A human killer inhibitory receptor specific for HLA-A. J. Immunol. 156, 3098–3101. Cella, M., Longo, A., Ferrara, G. B., Strominger, J. L. & Colonna, M. 1994 NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80. J. Exp. Med. 180, 1235– 1242. (doi:10. 1084/jem.180.4.1235) Carr, W. H., Rosen, D. B., Arase, H., Nixon, D. F., Michaelsson, J. & Lanier, L. L. 2007 Cutting edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. J. Immunol. 178, 647 –651. Biassoni, R., Pessino, A., Malaspina, A., Cantoni, C., Bottino, C., Sivori, S., Moretta, L. & Moretta, A. 1997 Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules. Eur. J. Immunol. 27, 3095–3099. (doi:10.1002/eji. 1830271203) Vales-Gomez, M., Reyburn, H. T., Erskine, R. A. & Strominger, J. 1998 Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. Proc. Natl Acad. Sci. USA 95, 14 326–14 331. (doi:10.1073/pnas.95.24.14326) Graef, T. et al. 2009 KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C. J. Exp. Med. 206, 2557–2572. (doi:10.1084/jem.20091010) Rajagopalan, S. & Long, E. O. 1999 A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J. Exp. Med. 189, 1093–1100. (doi:10.1084/jem.189.7.1093) Winter, C. C., Gumperz, J. E., Parham, P., Long, E. O. & Wagtmann, N. 1998 Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J. Immunol. 161, 571–577. Moesta, A. K., Graef, T., Abi-Rached, L., Older Aguilar, A. M., Guethein, L. A. & Parham, P. 2010 Humans differ from other hominids in lacking an activating NK cell receptor that recognizes the C1 epitope of MHC class I. J. Immunol. 185, 4233–4237. (doi:10.4049/ jimmunol.1001951) Gendzekhadze, K., Norman, P. J., Abi-Rached, L., Layrisse, Z. & Parham, P. 2006 High KIR diversity in Amerindians is maintained using few gene-content haplotypes. Immunogenetics 58, 474 –480. (doi:10.1007/ s00251-006-0108-3) Gutierrez-Rodriguez, M. E. et al. 2006 KIR gene in ethnic and Mestizo populations from Mexico. Hum. Immunol. 67, 85–93. (doi:10.1016/j.humimm.2005.11.007) Phil. Trans. R. Soc. B (2012) 72 Sivori, S., Falco, M., Carlomagno, S., Romeo, E., Soldani, C., Bensussan, A., Viola, A., Moretta, L. & Moretta, A. 2010 A novel KIR-associated function: evidence that CpG DNA uptake and shuttling to early endosomes is mediated by KIR3DL2. Blood 116, 1637–1647. (doi:10.1182/blood-2009-12-256586) 73 Sivori, S., Falco, M., Moretta, L. & Moretta, A. 2010 Extending killer Ig-like receptor function: from HLA class I recognition to sensors of microbial products. Trends Immunol. 31, 289 –294. (doi:10.1016/j.it.2010. 05.007) 74 VandenBussche, C. J., Mulrooney, T. J., Frazier, W. R., Dakshanamurthy, S. & Hurley, C. K. 2009 Dramatically reduced surface expression of NK cell receptor KIR2DS3 is attributed to multiple residues throughout the molecule. Genes Immun. 10, 162 –173. (doi:10. 1038/gene.2008.91) 75 Gendzekhadze, K., Norman, P. J., Abi-Rached, L., Graef, T., Moesta, A. K., Layrisse, Z. & Parham, P. 2009 Coevolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands. Proc. Natl Acad. Sci. USA 106, 18 692–18 697. (doi:10.1073/pnas.0906051106) 76 Bari, R., Bell, T., Leung, W. H., Vong, Q. P., Chan, W. K., Das Gupta, N., Holladay, M., Rooney, B. & Leung, W. 2009 Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine 245. Blood 114, 5182–5190. (doi:10.1182/blood-2009-07-231977) 77 Hsu, K. C., Liu, X. R., Selvakumar, A., Mickelson, E., O’Reilly, R. J. & Dupont, B. 2002 Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J. Immunol. 169, 5118–5129. 78 Kulkarni, S., Martin, M. P. & Carrington, M. 2008 The Yin and Yang of HLA and KIR in human disease. Semin. Immunol. 20, 343– 352. (doi:10.1016/j.smim. 2008.06.003) 79 Abi-Rached, L., Moesta, A. K., Rajalingam, R., Guethlein, L. A. & Parham, P. 2010 Human-specific evolution and adaptation led to major qualitative differences in the variable receptors of human and chimpanzee natural killer cells. PLoS Genet. 6, e1001192. (doi:10.1371/ journal.pgen.1001192) 80 Khakoo, S. I., Geller, R., Shin, S., Jenkins, J. A. & Parham, P. 2002 The D0 domain of KIR3D acts as a major histocompatibility complex class I binding enhancer. J. Exp. Med. 196, 911–921. (doi:10.1084/jem.20020304) 81 Hiby, S. E., Regan, L., Lo, W., Farrell, L., Carrington, M. & Moffett, A. 2008 Association of maternal killercell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum. Reprod. 23, 972 –976. (doi:10.1093/humrep/den011) 82 Hiby, S. E., Walker, J. J., O’Shaughnessy, K. M., Redman, C. W., Carrington, M., Trowsdale, J. & Moffett, A. 2004 Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J. Exp. Med. 200, 957–965. (doi:10.1084/jem.20041214) 83 Hiby, S. E. et al. 2010 Maternal activating KIR protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Invest. 120, 4102 –4110. (doi:10. 1172/JCI43998) 84 Lash, G. E., Robson, S. C. & Bulmer, J. N. 2010 Review: functional role of uterine natural killer (uNK) cells in human early pregnancy decidua. Placenta 31, S87– S92. (doi:10.1016/j.placenta.2009.12.022) 85 Redman, C. W., McMichael, A. J., Stirrat, G. M., Sunderland, C. A. & Ting, A. 1984 Class I major histocompatibility complex antigens on human extra-villous trophoblast. Immunology 52, 457 –468. Downloaded from http://rstb.royalsocietypublishing.org/ on August 3, 2017 Review. Coevolution of KIR and HLA class I 86 DeSilva, J. M. 2011 A shift toward birthing relatively large infants early in human evolution. Proc. Natl Acad. Sci. USA 108, 1022–1027. (doi:10.1073/pnas.1003865108) 87 Alter, G. & Altfeld, M. 2011 Mutiny or scrutiny: NK cell modulation of DC function in HIV infection. Trends Immunol. 32, 219–224. (doi:10.1016/j.it.2011.02.003) 88 Biron, C. A., Byron, K. S. & Sullivan, J. L. 1989 Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731 –1735. (doi:10. 1056/NEJM198906293202605) Phil. Trans. R. Soc. B (2012) P. Parham et al. 811 89 Khakoo, S. I. et al. 2004 HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872– 874. (doi:10.1126/science.1097670) 90 Martin, M. P. et al. 2007 Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat. Genet. 39, 733 –740. (doi:10.1038/ng2035) 91 Barreiro, L. B., Marioni, J. C., Blekhman, R., Stephens, M. & Gilad, Y. 2010 Functional comparison of innate immune signaling pathways in primates. PLoS Genet. 6, e1001249. (doi:10.1371/journal.pgen.1001249)