Human KIR3DL1/S1 Variable NK Cell Receptors Exemplified By

Variable NK Cell Receptors Exemplified by Human KIR3DL1/S1 Peter Parham, Paul J. Norman, Laurent Abi-Rached and Lisbeth A. Guethlein This information is current as of September 24, 2021. J Immunol 2011; 187:11-19; ; doi: 10.4049/jimmunol.0902332 http://www.jimmunol.org/content/187/1/11 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Variable NK Cell Receptors Exemplified by Human KIR3DL1/S1 Peter Parham, Paul J. Norman, Laurent Abi-Rached, and Lisbeth A. Guethlein Variegated expression of variable NK cell receptors for Species-specific evolution of variable NK cell receptors polymorphic MHC class I broadens the range of an Some NK cell receptors for MHC class I evolve rapidly, which individual’s NK cell response and the capacity for pop- became apparent from species comparison (13) (Fig. 1). The ulations and species to survive disease epidemics and rodent NKC encodes variable Ly49 receptors that diversify population bottlenecks. On evolutionary time scales, NK cell function in rats (14) and mice (15), while the LRC this component of immunity is exceptionally dynamic, family of killer cell Ig-like receptors (KIR) provides a com- unstable, and short-lived, being dependent on coevolu- parable system for humans and other simian primates (16). tion of ligands and receptors subject to varying, com- Mammalian species having only single-copy Ly49 and KIR Downloaded from peting selection pressures. Consequently these systems genes can survive and flourish (17), but no species has yet of variable NK cell receptors are largely species specific been found to have both variable Ly49 and KIR (Fig. 1A). In and have recruited different classes of glycoprotein, the context of variable KIR, human Ly49 is a single-copy even within the primate order of mammals. Such dis- pseudogene (18); in the context of variable Ly49, the mouse parity helps to explain substantial differences in NK KIR locus left the LRC for the X chromosome (19), where it http://www.jimmunol.org/ cell biology between humans and animal models, for comprises two genes: one expressed by NK cells and T cells which the population genetics is largely ignored. (20), the other by brain cells (21). Such contrasting situations KIR3DL1/S1, which recognizes the Bw4 epitope of point to past crises in mammalian evolution when species- HLA-A and -B and is the most extensively studied of specific expansion of a new type of NK cell receptor accom- the variable NK cell receptors, exemplifies how varia- panied extinction of an older form. tion in all possible parameters of function is recruited Further evidence for independent evolution of MHC class I receptors is seen within the LRC. Flanking the KIR locus is the to diversify the human NK cell response. The Journal gene family encoding the leukocyte Ig-like receptors (LILR) of Immunology, 2011, 187: 11–19. (22). Of these, LILRB1 is an NK cell receptor that binds to by guest on September 24, 2021 a b the more conserved domains (Ig-like 3 and 2-m) of MHC a a class I (12), whereas the variable 1 and 2 domains of MHC nvestigation of NK cell function began in the 1970s, class I are the target for KIR (11). Embedded within the LILR with its major emphasis on anti-tumor immunity (1, 2). locus is a KIR pseudogene (23), KIR3DX, which diverged I During the following decade, the capacity of NK cells to from genes of the functional KIR locus ∼135 million years kill cellular targets was discovered to be inversely correlated ago, before the radiation of placental mammals (24). Cattle, with the amount of MHC class I on the target cell surface (3). even toed ungulates, are the only nonprimates known to have This seminal observation led to the formulation of the variable KIR (20), but in cattle it was KIR3DX that became missing-self hypothesis and the search for NK cell receptors the variable gene family, whereas KIR3DL, the ancestral that recognize MHC class I (4). The 1990s first saw cellular, founder of the variable primate KIR, remained a single-copy then molecular, definition of such receptors (5, 6) and char- gene (24) (Fig. 1A). acterization of the genomic regions that encode them: the NK Common to mice (25) and humans (26) are NKC-encoded complex (NKC) (7) and the leukocyte receptor complex (LRC) MHC class I receptors comprising heterodimers of CD94 and (8, 9). Whereas the binding domains of NKC receptors re- an NKG2 family member. These CD94:NKG2 receptors semble those of C-type lectins (10), their LRC counterparts recognize complexes of a conserved nonclassical class I mol- are Ig-like (11, 12), a qualitative difference revealing that NK ecule (mouse Qa1 or human HLA-E) and peptides derived cell receptors for MHC class I evolved independently in the from the leader sequences of other MHC class I molecules two genetic complexes. (10). Like KIR (11), the CD94:NKG2 receptors interact with

Department of Structural Biology, Stanford University School of Medicine, Stanford, Abbreviations used in this article: LILR, leukocyte Ig-like receptor; LRC, leukocyte CA 94305; and Department of Microbiology and Immunology, Stanford University receptor complex; NKC, NK complex. School of Medicine, Stanford, CA 94305 Ó Received for publication February 9, 2011. Accepted for publication March 21, 2011. Copyright 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 This work was supported by Grants AI017892, AI022039, AI024258, and AI031168 from the National Institutes of Health (to P.P.). Address correspondence and reprint requests to Dr. Peter Parham, Department of Structural Biology, Stanford University, Fairchild D-157, 299 Campus Drive West, Stanford, CA 94305. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902332 12 BRIEF REVIEWS: NK CELL IMMUNOGENETICS

FIGURE 1. Evolution and variability of KIR and Ly49 NK cell receptors in mammalian species. A, On the right is shown the number of KIR and Ly49 genes in modern species. Emerging by gene duplication in an ancestral placental mammal, KIR3DL expanded in primates (red arrow) and KIR3DX expanded in cattle (blue arrow). The tree is adapted from that of Murphy et al. (111), with the primate branches colored yellow. B, KIR diversification in primates. The primate KIR3DL progenitor (black) became a pseudogene in prosimians (empty box), but flourished in simian primates to form five hominoid lineages: IA (dark blue), IB (light blue), II (red), III (green), V (yellow), and a unique New World monkey Downloaded from lineage (brown). Modern KIR haplotypes evolved through species-specific gene duplications (lineage II in Old World monkeys and lineage III in hominids) and deletions (lineages I–III in gibbons). C, pseudogene; MYA, million years ago. http://www.jimmunol.org/

a a the upward face of the 1 and 2 domains and are sensitive B (38, 39) correlates with increased numbers of lineage II KIR to residues of the bound peptide (27, 28). Although CD94, genes (40–42). Associated with the emergence of MHC-C in by guest on September 24, 2021 NKG2, and HLA-E are conserved in humans (29), analysis of hominids is a multiplicity of lineage III KIR genes (34). While the gray mouse lemur showed the potential of CD94:NKG2 KIR evolution in Old World monkeys and hominids is to be a variable NK cell receptor (30). This prosimian primate marked by gene expansions, the lesser apes took a different has single Ly49 and KIR genes, but three CD94 genes and road (43). Although having orthologs of most human class I eight (five expressed, three pseudogenes) NKG2 genes. genes and pseudogenes, gibbon MHC haplotypes lack an Equally distinctive are the lemur’s MHC class I genes; while ortholog of HLA-G that provides the ligand for KIR2DL4 four class I pseudogenes remained part of the MHC, the (44). Correlating with this absence, KIR2DL4 has been either cluster of six functional class I genes left the MHC for a dif- deleted from gibbon KIR haplotypes or disabled. Gibbon ferent chromosome (30). MHC haplotypes also lack an HLA-C ortholog, and corre- spondingly gibbon KIR haplotypes lack the multiplicity of Coevolution of MHC class I and KIR in simian primates lineage III KIR genes characterizing species with MHC-C That prosimians and most nonprimates have just one KIR (43). The only gene spared from the deletions and muta- gene shows that the diverse family of human KIR genes orig- tions that diminished and disordered the gibbon KIR locus inated during simian primate evolution, following their sep- is that of lineage V encoding KIR3DL3, for which ligands and aration from prosimians ∼58–69 million years ago (31) (Fig. function are not known (45, 46). As a potential clue, the in- 1B). Simian primates comprise New World monkeys, Old hibitory signaling motifs of gibbon KIR3DL3 appear stronger World monkeys, lesser apes (gibbons), and hominids (great than their human counterparts (43). apes and humans). Distinctive lineages of human KIR rec- Although first studied in the context of tumor immunity ognize epitopes carried by different HLA class I molecules. (1, 2), 40 y of research have firmly placed NK cells in the Notably, lineage II KIR recognize some HLA-A and B allo- response to infection (47), where they cooperate with dendritic types, and lineage III KIR recognize HLA-C and some HLA- cells (48). NK cells also have a seminal role in reproduction B allotypes (32–34). These functional interactions are the through cooperation with extravillous trophoblast to enlarge result of the coevolution of ligands with receptors during maternal blood vessels that supply the placenta and nourish the simian primate diversification (35). fetus (49). All such cellular interactions of NK cells can be Lacking counterparts to HLA-A, -B, and -C, New World influenced by KIR engagement of MHC class I. Whereas most monkeys have distinctive MHC class I and KIR, showing that cell types express HLA-A, -B, and -C, only HLA-C is expressed they took a different evolutionary tack from that followed by by extravillous trophoblast (50). It is also the only normal other simian primates (36, 37). The abundance of Old World tissue to express HLA-G, which binds avidly to LILRB1 (51) monkey MHC class I genes resembling either HLA-A or HLA- and interacts with lineage I KIR2DL4 in endosomes (44). The Journal of Immunology 13

The tissue distributions of HLA-C and -G, and the fate Bw4/Bw6 difference are polymorphic sequence motifs at a of the gibbon KIR locus in their absence (43) suggest that residues 77–83 in the helix of the HLA class I 1 domain selective pressures from reproduction induced MHC-C to (56), and the capacity for Bw4+ HLA-A and -B allotypes to be evolve away from its MHC-B–like ancestor: to be expressed ligands for the inhibitory KIR3DL1 NK cell receptor (57, on trophoblast and recognized by the lineage III KIR pref- 58), formerly known as NKB1 (59). erentially expressed on uterine NK cells (52). In this model, Of the five residues that distinguish Bw4 and Bw6 motifs HLA-C interactions with lineage III KIR are subject to se- (77 and 80–83) only arginine 83 is essential for binding lection pressures from both immunity and reproduction, KIR3DL1 (60); this contrasts with the position 80 dimor- whereas the interactions of lineage II KIR with HLA-A and phism specifying the C1 and C2 epitopes recognized by lin- HLA-B evolve principally under selection by infection. As a eage III KIR (61). As an additional important structural consequence HLA-A and HLA-B evolved to be exceptionally difference, lineage III KIR interaction with HLA-C is ac- variable, as has lineage II KIR3DL1/S1 that recognizes a complished with two Ig-like domains (D1 and D2), whereas broad range of HLA-A and -B allotypes. In contrast, lineage II an additional domain (D0) is necessary for 3DL1 to bind KIR3DL2, which is specific for the A3/11 epitope, recognizes Bw4 (62, 63). Although a crystallographic structure for a narrow range of HLA-A allotypes and has variability that KIR3D has yet to be achieved, the combination of muta- does not stand out from the mass of human genes (Fig. 2). genesis and homology modeling, based on the three- Because of these features, the genetic and functional proper- dimensional structures of KIR2D bound to HLA-C (11), ties of KIR3DL1/S1 have been most extensively studied, predicts that the D0, D1, and D2 domains contribute equally Downloaded from making it an exemplary variable NK cell receptor. to the HLA-binding surface in which a central pocket grasps arginine 83 (64). That all human lineage III KIR genes con- KIR3DL1 recognizes the Bw4 epitope of HLA-A and HLA-B tain an exon encoding D0, but which is no longer used, Sequences for .1600 HLA-B allotypes are now known (53), indicates the more recent evolution of the interaction between but when first described in the 1960s, HLA-B was a simple HLA-C and lineage III KIR (65). serologic dimorphism comprising the 4a and 4b Ags (54), Some 25–42% of HLA-B and 15–43% of HLA-A allotypes http://www.jimmunol.org/ later renamed the Bw4 and Bw6 epitopes, respectively (55). carry the Bw4 epitope (Fig. 3). The Bw4 and Bw6 sequence Every HLA-B allotype carries either Bw4 or Bw6, while a motifs are frequent targets for short interallelic conversion . subset of HLA-A allotypes carries Bw4. Correlating with the events. Thus, 51 pairs of HLA-B allotypes differ only in the presence or absence of Bw4. Gene conversion similarly in- by guest on September 24, 2021

FIGURE 2. KIR3DL1/S1, like HLA-A,-B,-C and HLA-DRB1, is one of the most highly polymorphic human genes. Compared in this figure is coding-sequence diversity in the genomes of two Asian individuals. For the FIGURE 3. Distribution of HLA-A and -B epitopes recognized by KIR in four alleles of each gene, the number of single nucleotide polymorphisms human populations. Each pie chart represents the HLA-A or -B allotypes in (SNPs) is normalized to the number of codons in the gene. These values are a population. Subdivisions within each pie chart are colored according to the presented in a histogram (yellow bars) and a continuous distribution (blue epitope recognized by KIR, or shaded gray if they do not engage KIR. The line). The genes form a normal distribution, with KIR3DL1/S1, HLA-A,-B, A3/11 epitope is subdivided into A3 and A11, and the Bw4 epitope is sub- and -C, and HLA-DRB1 being outliers. For the named genes, the number of divided according to the combination of residues at positions 80 (within the allotypes described worldwide is in parentheses (112, 53). Although KIR3DL2 Bw4 motif) and 152, both of which influence the avidity of Bw4 for KIR and KIR3DL3 have many alleles, they differ by one or a few substitutions. (115). HLA frequencies for representative Asian (n = 24), African (n = 13) and Summary statistics are from Wang et al. (113) and Kim et al. (114), and were European (n = 10) populations were obtained from http://www.allele- analyzed using Statistica software version 8 (StatSoft, Tulsa, OK). frequencies.net (116). 14 BRIEF REVIEWS: NK CELL IMMUNOGENETICS troduced Bw4 into HLA-A, where it spread by interallelic Balanced polymorphism between three lineages of KIR3DL1/S1 alleles conversion to the HLA-A*23, A*24, A*25, A*26, and A*32 KIR3DL1/S1 alleles represent three phylogenetic lineages: allotypes. Although individual allotype frequencies vary be- 3DS1, 005, and 015, that have existed for .3 million years tween populations, the Bw4 and Bw6 frequencies remain ∼ and are present in all modern human populations. remarkably constant (66), with 50% of HLA haplotypes KIR3DS1*01301, 3DL1*005, and 3DL1*01502 are consid- providing the Bw4 epitope. This even balance indicates 2 ered the prototypical alleles of the 3DS1, 005, and 015 lin- complementary functions for Bw4 allotypes more focused + eages, respectively, because they are the only alleles present on T cell immunity and Bw4 allotypes contributing to both in all human populations (Fig. 4). Simulations point to their NK cell and T cell immunity. maintenance by balancing selection, indicating that each re- KIR3DL1 and KIR3DS1 segregate as functionally divergent alleles of ceptor lineage makes distinctive, complementary contributions the KIR3DL1/S1 gene to NK cell biology. The 015 lineage is uniquely diversified in African populations (Fig. 4, green shading) with commensu- KIR3DL1 and KIR3DS1 are, respectively, inhibitory and rate reduction of the 005 and 3DS1 lineages, whereas the activating receptors that diverge in the domains mediating 3DS1 lineage is highly represented in Amerindians, and the signal transduction, but have similar ligand-binding Ig-like 005 lineage in Caucasians (66). domains. On the basis of their opposing signaling func- NK cell killing assays show that the interaction of KIR3DL1 tions, 3DL1 and 3DS1 were initially considered to be the with Bw4+ HLA class I is sensitive to polymorphisms in the Downloaded from products of different genes (67), but with segregation studies Bw4 motif, notably position 80 (57), to polymorphism at their allelic relationship was recognized (68) and signified by positions away from the Bw4 motif that affect peptide naming the gene KIR3DL1/S1 and numbering the 3DS1 and binding (60) and to the sequence of the bound peptide (86– 3DL1 variants as a single series of alleles (69). Further com- 88). KIR3DL1 polymorphism also affects specificity for HLA plicating the situation, unequal crossing over has produced class I, as seen in both cellular (78, 89) and direct-binding several KIR haplotypes that either lack 3DL1/S1 (70), have

assays (90), as well as inferred by disease-associations (91). For http://www.jimmunol.org/ both 3DS1 and 3DL1 (66, 71, 72), or have a fusion of 3DL1/ example, measurement of binding for five complexes of de- S1 with 3DL2 (73). fined viral peptide and Bw4+ HLA class I to four common Functional difference between 3DL1 and 3DS1 is not re- KIR3DL1 allotypes gave three patterns of reaction and only stricted to signaling. Whereas KIR3DL1 recognition of Bw4 eight of the 20 possible reactions (Table I) (90), a proportion can be readily detected in assays of binding and NK cell identical to that seen in an earlier study using cytotoxicity function (57, 58, 64), 3DS1 has no demonstrable interaction with Bw4, or any other HLA class I epitope (74–76). Despite assays (88). 3DL1*015 and 3DL1*007 have identical Ig-like this apparent lack of function, 3DS1 is present at significant domains and the same narrow reaction pattern, whereas 3DL1*005 has a broader specificity. 3DL1*001 combines the frequency in every human population (66, 77). Another dif- by guest on September 24, 2021 ference is in the subtypic variation: 3DL1 being highly poly- D0 domain of 3DL1*005 with the D1 and D2 domains of morphic and 3DS1 conserved. All human populations have 3DL1*015 and also has a broad but distinctive specificity, a balance between several 3DL1 alleles, even genetically less illustrating the importance of the D0 domain in ligand- variable populations such as the Japanese (five alleles) (78) binding specificity. and Yucpa Amerindians (three alleles) (79), whereas 3DS1* KIR polymorphism was originally observed through its 013 dominates all populations, except Sub-Saharan Africans, influence on the proportion of NK cells expressing 3DL1 and and is the most abundant 3DL1/S1 allele worldwide (66). the amount of 3DL1 on their surfaces (92). For example, of When the six residues distinguishing the extracellular domains five common 3DL1 allotypes in the Japanese population, of 3DS1 from 3DL1 were individually introduced into 3DL1, 3DL1*005 and 3DL1*007 are expressed at low levels, three abrogated interaction with Bw4 while having only mi- 3DL1*001 at an intermediate level, and 3DL1*020 and nor affects on conformation and cell-surface expression, which 3DL1*01502 at high levels—a hierarchy reflected also in the is consistent with 3DS1 having been subjected to strong proportion of NK cells expressing each allele (78). The rela- positive selection for losing its avidity for Bw4 (64). tive level of 3DS1 expression remains uncertain because it is Human KIR haplotypes form two groups, A and B, that detected only by weak cross-reactivity with anti-KIR3DL1 Ab differ in gene content, allele content, variability, and disease (74, 75). Although KIR3DL1 allotypes differ in their capacity association (80–82). Both haplotype groups are present in all to educate NK cells and inhibit NK cell effector function, human populations, often at even frequency, and are main- these differences do not correlate in a simple way with the tained by balancing selection (79). KIR3DL1 is characteristic level of cell-surface expression. Common in Caucasians, of A haplotypes, which mainly have polymorphic genes en- Africans, and South Asians (Fig. 4), 3DL1*004 represents an coding inhibitory receptors, whereas 3DS1 is a characteristic B extreme case with a low level of cell-surface expression (93). haplotype gene. B haplotypes are enriched for less polymor- Inefficient folding causes most of the protein to be retained phic genes encoding activating receptors with either reduced within the cell, but the small amount reaching the surface can (2DS1) or undetectable (2DS2 and 3DS1) avidity for HLA deliver inhibitory signals (94) and may even educate NK cells class I, compared to their inhibitory counterparts (83, 84). (95). Substitution at position 86 in the D0 domain is largely Differential KIR and HLA associations with infectious and responsible for poor folding of 3DL1*004, but also includes reproductive disease suggest that the balance between A and B a minor contribution from position 182 in D1. Mutagenesis haplotypes might derive from the former favoring resolution of 3DL1*015 at 40 sites of natural 3DL1/S1 variation showed of infection and the latter favoring successful reproduction that the great majority of substitutions had no affect or caused (79, 85). modest decrease in cell-surface abundance (as detected by The Journal of Immunology 15

FIGURE 4. Three divergent 3DL1/S1 allelic lineages are maintained in all human populations. The minimum-spanning network shows the phylogenetic relationships and geographic distribution of 3DL1/S1 alleles. The distance between two nodes corresponds to one nucleotide change in the coding region. Gray half-circle denotes substitutions altering surface abun-

dance; ► denotes substitutions in the ligand binding Downloaded from site (66). Nodes with colored circles are the alleles present in the modern human population, the area representing the frequency worldwide and the different colors the distribution between major population groups. Allelic lineages are denoted by the background shading: 015, magenta; 005, cyan; and

3DS1, green. 3DL1*001, a recombinant of the 015 http://www.jimmunol.org/ and 005 lineages, has a purple background. Dashed lines indicate four other recombination events: R1, acquisition of activating signaling function to form 3DS1 from 3DL1 (the 22 unique substitutions in the 3DS1 signaling domain are not shown as nodes, because they were acquired en bloc); R2, causing 3DL1*007 and 3DL1*004-like alleles to have the same cytoplasmic tail; R3, forming a chimera of 3DL1 and 3DL2; and R4, representing two independent events when 3DL1 acquired the D0 do- by guest on September 24, 2021 main of 3DS1 to give the 3DL1*009 and 3DL1*042 alleles. The network was generated using the program TCS 1.21 (117) set to 99% conﬁdence (by parsi- mony) that alleles formed by mutation not recombination.

Abs), suggesting that protein stability is not the only variable for the 13.4-kb region of unique sequence between 3DP1 and causing allele-speciﬁc differences in cell-surface expression 2DL4 (81). (64)—another likely source being transcriptional variation. In hematopoietic stem cells, the KIR locus is inaccessible with transcription prevented by dense methylation, particularly Organization and variegated expression of KIR genes of CpG islands in the promoter region (96, 97). The KIR locus Transcription is controlled at the level of the entire KIR locus, opens up for transcription at a late stage in NK cell develo- which has a conserved organizing framework comprising pment, when it generates a repertoire of NK cells expressing 3DL3 at the centromeric end, 2DL4 and the 3DP1 pseudo- diverse combinations of KIR. The expressed KIR genes have gene in the center, and 3DL2 at the telomeric end. Regions of hypomethylated promoters, whereas the promoters of the si- variable gene content lie between 3DL3 and 3DP1, and be- lenced genes are hypermethylated. The characteristic varie- tween 2DL4 and 3DL2. The intergenic regions containing the gated expression of KIR by mature NK cells is thus determined promoters are small (∼2 kb) and highly homologous, except by diverse patterns of promoter methylation (98, 99). 16 BRIEF REVIEWS: NK CELL IMMUNOGENETICS

Table I. KIR3DL1 polymorphism affects speciﬁcity for HLA class I

HLA Class I Ligand KIR3DL1 Allotype

Epitope Allotype Peptide *005 *001 *015 *007

( )

( ) Downloaded from

( )

A summary of the binding interactions of four KIR3DL1 allotypes with nine complexes of HLA class I and a viral peptide, as

determined by Thananchai et al. (90). Boxes shaded green denote signiﬁcant binding. Under peptide, the amino acid sequence of the http://www.jimmunol.org/ peptide is given and below it, in parentheses, the viral pathogen from which it derives; HIV, CMV, EBV, or Dengue virus. The relationship of the D0, D1, and D2 domains for each 3DL1 allotype is shown; cyan domain designations denote identity with 3DL1*005, magenta domain designations denote identity with 3DL1*015.

NK cells express each KIR gene in one of three ways (100), transcription at the proximal promoter. In this case, stronger exemplified by the three functional framework genes. All forward transcription would favor NK cell commitment to NK cells express 2DL4, a subset of NK cells expresses 3DL2, making the receptor, whereas backward transcription would and few NK cells express 3DL3. These differences correlate favor commitment to not making the receptor. The 3DL1/S1 by guest on September 24, 2021 with promoter sequence variation that affects the binding of alleles expressed at high frequency by NK cells are those also transcription factors, for which there are many potential sites expressed at high level on the cell surface (78), raising the (101). In studying the variegated expression of KIR genes, intriguing possibility that competing dual activities of the KIR3DL1/S1 has been the major subject for research (100, bidirectional promoter also influence the amount of sense 102, 103). mRNA and protein made in mature NK cells. The ∼2-kb intergenic region upstream of 3DL1/S1 contains Three substitutions in the 3DL1/S1 proximal promoter two separate promoters. The proximal promoter (102), be- distinguish four different promoters: associated with 3DS1, tween nucleotides -1 and -255, has two nonoverlapping sites, the 015 lineage, 3DL1*005 and the combination of 3DL1* one promoting synthesis of sense mRNA, the other anti-sense 001 and 3DL1*004. In a cell-free system, measurement of the mRNA (104, 105). The distal promoter (106), in the middle ratio of sense to antisense transcription distinguished the four of the intergenic region .1 kb from exon 1, promotes only promoters, but the values only partially correlated with the sense mRNA. As transcription of a 3DL1/S1 allele begins, 3DL1/S1 phenotypes (105). Notably discordant was 3DS1, the distal promoter makes sense mRNA while the proximal which gave the second-lowest transcription ratio, but is ex- promoter can favor either sense or antisense mRNA. If both pressed by up to ∼40% of NK cells in heterozygotes and promoters make sense mRNA the cell commits to long-term ∼80% in homozygotes (76, 110). Also unexplained by these expression of the 3DL1/S1 allele. In contrast, if antisense promoter polymorphisms are the characteristic low cell-surface mRNA is made from the proximal promoter, it hybridizes to expression and cellular expression of 3DL1*007, which has sense mRNA made from the distal promoter, which prevents the same promoter as high expressing 3DL1*015. In this, as in transcription and leads to silencing of the 3DL1/S1 allele. The other features of KIR3DL1/SI variation, there are important hybrid mRNAs give rise to a 28-bp PIWI-like RNA detect- questions of mechanism still to be answered. 2 able only in the subset of 3DL1/S1 NK cells (107). In mature 3DL1/S1-expressing NK cells, most transcripts arise Conclusions from the proximal promoter, but the distal promoter also VariableNKcellreceptorsbindtothesamecomplexesofpeptide contributes (108). Consistent with the distal promoter play- and MHC class I as the ab TCR of CD8 T cells, and with ing a decisive role in NK cell development is its activation sensitivity to the structural nuances of both peptide and MHC by IL-15, a cytokine inducing NK cell differentiation (109). class I allotype. These interactions contribute to the education That KIR3DL1/S1 alleles differ in their frequencies of ex- of NK cells during development and their effector functions pression in the NK cell population could arise from differ- when responding to cells compromised by infection or malig- ences in the relative strengths of forward and backward nancy, or cells from somebody else, as occurs in pregnancy and The Journal of Immunology 17 transplantation. Within the individual, sets of inherited genes 17. Hammond, J. A., L. A. Guethlein, L. Abi-Rached, A. K. Moesta, and P. Parham. 2009. Evolution and survival of marine carnivores did not require a diversity of killer encoding polymorphic MHC class I and variable NK cell re- cell Ig-like receptors or Ly49 NK cell receptors. J. Immunol. 182: 3618–3627. ceptor cooperate to produce a diverse repertoire of functional 18. Westgaard, I. H., S. F. Berg, S. Orstavik, S. Fossum, and E. Dissen. 1998. Identification of a human member of the Ly-49 multigene family. Eur. J. Immunol. NK cells, which gives versatility and specificity to the NK cell 28: 1839–1846. response. This individual variability is compounded at the 19. Hoelsbrekken, S. E., O. Nylenna, P. C. Saether, I. O. Slettedal, J. C. Ryan, population level, where the number of possible KIR-HLA class I S. Fossum, and E. Dissen. 2003. Cutting edge: molecular cloning of a killer cell Ig- like receptor in the mouse and rat. J. Immunol. 170: 2259–2263. genotypes can exceed the size of the population. 20. Dissen, E., S. Fossum, S. E. Hoelsbrekken, and P. C. Saether. 2008. NK cell Despite this diversity and versatility, comparative studies receptors in rodents and cattle. Semin. Immunol. 20: 369–375. 21. Bryceson, Y. T., J. A. Foster, S. P. Kuppusamy, M. Herkenham, and E. O. Long. have uncovered an unprecedented degree of species specificity 2005. Expression of a killer cell receptor-like gene in plastic regions of the central showing that individual receptors and entire systems of variable nervous system. J. Neuroimmunol. 161: 177–182. 22. Brown, D., J. Trowsdale, and R. Allen. 2004. The LILR family: modulators of NK cell receptors have limited life spans. Thus Ly49, KIR3DL, innate and adaptive immune pathways in health and disease. Tissue Antigens 64: KIR3DX, and CD94:NKG2 are all seen as highly variable NK 215–225. 23. Sambrook, J. G., A. Bashirova, H. Andersen, M. Piatak, G. S. Vernikos, P. Coggill, cell receptors, but in different species of placental mammals. J. D. Lifson, M. Carrington, and S. Beck. 2006. Identification of the ancestral killer Such evolutionary transience in NK cell receptors could arise immunoglobulin-like receptor gene in primates. BMC Genomics 7: 209. from the competing demands of immunity and reproduction, 24. Guethlein, L. A., L. Abi-Rached, J. A. Hammond, and P. Parham. 2007. The expanded cattle KIR genes are orthologous to the conserved single-copy KIR3DX1 botched compromise between the need for MHC class I to gene of primates. Immunogenetics 59: 517–522. serve both NK-cell and TCRs, or from obsolescence, being 25. Gunturi, A., R. E. Berg, and J. Forman. 2004. The role of CD94/NKG2 in innate and adaptive immunity. Immunol. Res. 30: 29–34. too specialized at fighting past infection, and being unable 26. Borrego, F., M. Masilamani, A. I. Marusina, X. Tang, and J. E. Coligan. 2006. Downloaded from to adapt to current threats. Counterparts to the human KIR The CD94/NKG2 family of receptors: from molecules and cells to clinical relevance. Immunol. Res. 35: 263–278. system of variable NK cell receptors exist only in simian 27. Sullivan, L. C., C. S. Clements, T. Beddoe, D. Johnson, H. L. Hoare, J. Lin, primates, species in which the coevolution of KIR with MHC T. Huyton, E. J. Hopkins, H. H. Reid, M. C. Wilce, et al. 2007. The hetero- class I can be reconstructed. The effects of balancing selection dimeric assembly of the CD94-NKG2 receptor family and implications for human leukocyte antigen-E recognition. Immunity 27: 900–911. are evident everywhere, particularly in humans with their 28. Kaiser, B. K., J. C. Pizarro, J. Kerns, and R. K. Strong. 2008. Structural basis for distinctive A and B KIR haplotypes and functionally disparate NKG2A/CD94 recognition of HLA-E. Proc. Natl. Acad. Sci. USA 105: 6696– http://www.jimmunol.org/ 6701. KIR3DL1 and KIR3DS1 alleles. Such striking qualitative 29. Shum, B. P., L. R. Flodin, D. G. Muir, R. Rajalingam, S. I. Khakoo, S. Cleland, differences are consistent with KIR-HLA class I interactions L. A. Guethlein, M. Uhrberg, and P. Parham. 2002. Conservation and variation in human and common chimpanzee CD94 and NKG2 genes. J. Immunol. 168: 240– contributing to two essential but very different functions in 252. human biology: immune defense and reproduction. 30. Averdam, A., B. Petersen, C. Rosner, J. Neff, C. Roos, M. Eberle, F. Aujard, C. Mu¨nch, W. Schempp, M. Carrington, et al. 2009. A novel system of polymorphic and diverse NK cell receptors in primates. PLoS Genet. 5: e1000688. 31. Chatterjee, H. J., S. Y. Ho, I. Barnes, and C. Groves. 2009. Estimating the Disclosures phylogeny and divergence times of primates using a supermatrix approach. BMC Evol. Biol. 9: 259. The authors have no financial conflicts of interest. 32. Guethlein, L. A., L. R. Flodin, E. J. Adams, and P. Parham. 2002. NK cell receptors by guest on September 24, 2021 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. References 33. Rajalingam, R., P. Parham, and L. Abi-Rached. 2004. Domain shuffling has been 1. Herberman, R. B., and H. T. Holden. 1978. Natural cell-mediated immunity. the main mechanism forming new hominoid killer cell Ig-like receptors. J. Adv. Cancer Res. 27: 305–377. Immunol. 172: 356–369. 2. Kiessling, R., and H. Wigzell. 1979. An analysis of the murine NK cell as to 34. Guethlein, L. A., A. M. Older Aguilar, L. Abi-Rached, and P. Parham. 2007. structure, function and biological relevance. Immunol. Rev. 44: 165–208. Evolution of killer cell Ig-like receptor (KIR) genes: definition of an orangutan 3. Ka¨rre, K., H. G. Ljunggren, G. Piontek, and R. Kiessling. 1986. Selective rejection KIR haplotype reveals expansion of lineage III KIR associated with the emergence of H-2-deficient lymphoma variants suggests alternative immune defence strategy. of MHC-C. J. Immunol. 179: 491–504. Nature 319: 675–678. 35. Parham, P., L. Abi-Rached, L. Matevosyan, A. K. Moesta, P. J. Norman, 4. Ljunggren, H. G., and K. Ka¨rre. 1990. In search of the ‘missing self’: MHC A. M. Older Aguilar, and L. A. Guethlein. 2010. Primate-specific regulation of molecules and NK cell recognition. Immunol. Today 11: 237–244. natural killer cells. J. Med. Primatol. 39: 194–212. 5. Moretta, A., C. Bottino, M. Vitale, D. Pende, R. Biassoni, M. C. Mingari, and 36. Adams, E. J., and P. Parham. 2001. Species-specific evolution of MHC class I L. Moretta. 1996. Receptors for HLA class-I molecules in human natural killer genes in the higher primates. Immunol. Rev. 183: 41–64. cells. Annu. Rev. Immunol. 14: 619–648. 37. Cadavid, L. F., and C. M. Lun. 2009. Lineage-specific diversification of killer cell 6. Lanier, L. L. 1998. NK cell receptors. Annu. Rev. Immunol. 16: 359–393. Ig-like receptors in the owl monkey, a New World primate. Immunogenetics 61: 7. Yokoyama, W. M., and W. E. Seaman. 1993. The Ly-49 and NKR-P1 gene 27–41. families encoding lectin-like receptors on natural killer cells: the NK gene complex. 38. Daza-Vamenta, R., G. Glusman, L. Rowen, B. Guthrie, and D. E. Geraghty. Annu. Rev. Immunol. 11: 613–635. 2004. Genetic divergence of the rhesus macaque major histocompatibility com- 8. Trowsdale, J. 2001. Genetic and functional relationships between MHC and NK plex. Genome Res. 14: 1501–1515. receptor genes. Immunity 15: 363–374. 39. Kulski, J. K., T. Anzai, T. Shiina, and H. Inoko. 2004. Rhesus macaque class I 9. Kelley, J., L. Walter, and J. Trowsdale. 2005. Comparative genomics of natural duplicon structures, organization, and evolution within the alpha block of the killer cell receptor gene clusters. PLoS Genet. 1: 129–139. major histocompatibility complex. Mol. Biol. Evol. 21: 2079–2091. 10. Natarajan, K., N. Dimasi, J. Wang, R. A. Mariuzza, and D. H. Margulies. 2002. 40. Bimber, B. N., A. J. Moreland, R. W. Wiseman, A. L. Hughes, and Structure and function of natural killer cell receptors: multiple molecular solutions D. H. O’Connor. 2008. Complete characterization of killer Ig-like receptor (KIR) to self, nonself discrimination. Annu. Rev. Immunol. 20: 853–885. haplotypes in Mauritian cynomolgus macaques: novel insights into nonhuman 11. Boyington, J. C., and P. D. Sun. 2002. A structural perspective on MHC class I primate KIR gene content and organization. J. Immunol. 181: 6301–6308. recognition by killer cell immunoglobulin-like receptors. Mol. Immunol. 38: 1007– 41. Blokhuis, J. H., M. K. van der Wiel, G. G. Doxiadis, and R. E. Bontrop. 2010. 1021. The mosaic of KIR haplotypes in rhesus macaques. Immunogenetics 62: 295–306. 12. Willcox, B. E., L. M. Thomas, and P. J. Bjorkman. 2003. Crystal structure of 42. Kruse, P. H., C. Rosner, and L. Walter. 2010. Characterization of rhesus macaque HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex re- KIR genotypes and haplotypes. Immunogenetics 62: 281–293. ceptor. Nat. Immunol. 4: 913–919. 43. Abi-Rached, L., H. Kuhl, C. Roos, B. ten Hallers, B. Zhu, L. Carbone, P. J. de 13. Vilches, C., and P. Parham. 2002. KIR: diverse, rapidly evolving receptors of Jong, A. R. Mootnick, F. Knaust, R. Reinhardt, et al. 2010. A small, variable, and innate and adaptive immunity. Annu. Rev. Immunol. 20: 217–251. irregular killer cell Ig-like receptor locus accompanies the absence of MHC-C and 14. Wilhelm, B. T., and D. L. Mager. 2004. Rapid expansion of the Ly49 gene cluster MHC-G in gibbons. J. Immunol. 184: 1379–1391. in rat. Genomics 84: 218–221. 44. Rajagopalan, S., Y. T. Bryceson, S. P. Kuppusamy, D. E. Geraghty, A. van der 15. Carlyle, J. R., A. Mesci, J. H. Fine, P. Chen, S. Be´langer, L. H. Tai, and Meer, I. Joosten, and E. O. Long. 2006. Activation of NK cells by an endocytosed A. P. Makrigiannis. 2008. Evolution of the Ly49 and Nkrp1 recognition systems. receptor for soluble HLA-G. PLoS Biol. 4: e9. Semin. Immunol. 20: 321–330. 45. Jones, D. C., S. E. Hiby, A. Moffett, J. Trowsdale, and N. T. Young. 2006. Nature 16. Parham, P. 2008. The genetic and evolutionary balances in human NK cell re- of allelic sequence polymorphism at the KIR3DL3 locus. Immunogenetics 58: 614– ceptor diversity. Semin. Immunol. 20: 311–316. 627. 18 BRIEF REVIEWS: NK CELL IMMUNOGENETICS

46. Trundley, A. E., S. E. Hiby, C. Chang, A. M. Sharkey, S. Santourlidis, 72. Williams, F., L. D. Maxwell, I. A. Halfpenny, A. Meenagh, C. Sleator, M. Uhrberg, J. Trowsdale, and A. Moffett. 2006. Molecular characterization of M. D. Curran, and D. Middleton. 2003. Multiple copies of KIR 3DL/S1 and KIR KIR3DL3. Immunogenetics 57: 904–916. 2DL4 genes identiﬁed in a number of individuals. Hum. Immunol. 64: 729–732. 47. Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens, and T. P. Salazar-Mather. 73. Norman, P. J., L. Abi-Rached, K. Gendzekhadze, J. A. Hammond, A. K. Moesta, 1999. Natural killer cells in antiviral defense: function and regulation by innate D. Sharma, T. Graef, K. L. McQueen, L. A. Guethlein, C. V. Carrington, et al. cytokines. Annu. Rev. Immunol. 17: 189–220. 2009. Meiotic recombination generates rich diversity in NK cell receptor genes, 48. Moretta, L., G. Ferlazzo, C. Bottino, M. Vitale, D. Pende, M. C. Mingari, and alleles, and haplotypes. Genome Res. 19: 757–769. A. Moretta. 2006. Effector and regulatory events during natural killer-dendritic 74. Carr, W. H., D. B. Rosen, H. Arase, D. F. Nixon, J. Michaelsson, and cell interactions. Immunol. Rev. 214: 219–228. L. L. Lanier. 2007. Cutting Edge: KIR3DS1, a gene implicated in resistance to 49. Moffett, A., and C. Loke. 2006. Immunology of placentation in eutherian progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells mammals. Nat. Rev. Immunol. 6: 584–594. that triggers NK cell activation. J. Immunol. 178: 647–651. 50. Apps, R., S. P. Murphy, R. Fernando, L. Gardner, T. Ahad, and A. Moffett. 2009. 75. Gillespie, G. M., A. Bashirova, T. Dong, D. W. McVicar, S. L. Rowland-Jones, Human leucocyte antigen (HLA) expression of primary trophoblast cells and and M. Carrington. 2007. Lack of KIR3DS1 binding to MHC class I Bw4 tet- placental cell lines, determined using single antigen beads to characterize allotype ramers in complex with CD8+ T cell epitopes. AIDS Res. Hum. Retroviruses 23: speciﬁcities of anti-HLA antibodies. Immunology 127: 26–39. 451–455. 51. Shiroishi, M., K. Tsumoto, K. Amano, Y. Shirakihara, M. Colonna, V. M. Braud, 76. O’Connor, G. M., K. J. Guinan, R. T. Cunningham, D. Middleton, P. Parham, D. S. Allan, A. Makadzange, S. Rowland-Jones, B. Willcox, et al. 2003. Human and C. M. Gardiner. 2007. Functional polymorphism of the KIR3DL1/S1 re- inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for ceptor on human NK cells. J. Immunol. 178: 235–241. MHC class I binding and bind preferentially to HLA-G. Proc. Natl. Acad. Sci. USA 77. Single, R. M., M. P. Martin, X. Gao, D. Meyer, M. Yeager, J. R. Kidd, 100: 8856–8861. K. K. Kidd, and M. Carrington. 2007. Global diversity and evidence for co- 52. Sharkey, A. M., L. Gardner, S. Hiby, L. Farrell, R. Apps, L. Masters, J. Goodridge, evolution of KIR and HLA. Nat. Genet. 39: 1114–1119. L. Lathbury, C. A. Stewart, S. Verma, and A. Moffett. 2008. Killer Ig-like receptor 78. Yawata, M., N. Yawata, M. Draghi, A. M. Little, F. Partheniou, and P. Parham. expression in uterine NK cells is biased toward recognition of HLA-C and alters 2006. Roles for HLA and KIR polymorphisms in natural killer cell repertoire with gestational age. J. Immunol. 181: 39–46. selection and modulation of effector function. J. Exp. Med. 203: 633–645. 53. Robinson, J., K. Mistry, H. McWilliam, R. Lopez, P. Parham, and S. G. Marsh. 79. Gendzekhadze, K., P. J. Norman, L. Abi-Rached, T. Graef, A. K. Moesta, 2011. The IMGT/HLA database. Nucleic Acids Res. 39(Database issue): D1171– Z. Layrisse, and P. Parham. 2009. Co-evolution of KIR2DL3 with HLA-C in Downloaded from D1176. a human population retaining minimal essential diversity of KIR and HLA class I 54. Van Rood, J. J., and A. Van Leeuwen. 1963. Leukocyte grouping. A method and ligands. Proc. Natl. Acad. Sci. USA 106: 18692–18697. its application. J. Clin. Invest. 42: 1382–1390. 80. Uhrberg, M., N. M. Valiante, B. P. Shum, H. G. Shilling, K. Lienert-Weidenbach, 55. Albert, E., D. B. Amos, W. F. Bodmer, and R. Ceppellini. 1978. Nomenclature B. Corliss, D. Tyan, L. L. Lanier, and P. Parham. 1997. Human diversity in killer for factors of the HLA system—1977. Tissue Antigens 11: 81–86. cell inhibitory receptor genes. Immunity 7: 753–763. 56. Wan, A. M., P. Ennis, P. Parham, and N. Holmes. 1986. The primary structure of 81. Wilson, M. J., M. Torkar, A. Haude, S. Milne, T. Jones, D. Sheer, S. Beck, and HLA-A32 suggests a region involved in formation of the Bw4/Bw6 epitopes. J. J. Trowsdale. 2000. Plasticity in the organization and sequences of human KIR/

Immunol. 137: 3671–3674. ILT gene families. Proc. Natl. Acad. Sci. USA 97: 4778–4783. http://www.jimmunol.org/ 57. Cella, M., A. Longo, G. B. Ferrara, J. L. Strominger, and M. Colonna. 1994. 82. Pyo, C. W., L. A. Guethlein, Q. Vu, R. Wang, L. Abi-Rached, P. J. Norman, NK3-speciﬁc natural killer cells are selectively inhibited by Bw4-positive HLA S. G. Marsh, J. S. Miller, P. Parham, and D. E. Geraghty. 2010. Different patterns alleles with isoleucine 80. J. Exp. Med. 180: 1235–1242. of evolution in the centromeric and telomeric regions of group A and B haplotypes 58. Gumperz, J. E., V. Litwin, J. H. Phillips, L. L. Lanier, and P. Parham. 1995. The of the human killer cell Ig-like receptor locus. PLoS ONE 5: e15115. Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell 83. Stewart, C. A., F. Laugier-Anfossi, F. Ve´ly, X. Saulquin, J. Riedmuller, A. Tisserant, clones that express NKB1, a putative HLA receptor. J. Exp. Med. 181: 1133–1144. L. Gauthier, F. Romagne´, G. Ferracci, F. A. Arosa, et al. 2005. Recognition of 59. Litwin, V., J. Gumperz, P. Parham, J. H. Phillips, and L. L. Lanier. 1994. NKB1: peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. a natural killer cell receptor involved in the recognition of polymorphic HLA-B Proc. Natl. Acad. Sci. USA 102: 13224–13229. molecules. J. Exp. Med. 180: 537–543. 84. Moesta, A. K., T. Graef, L. Abi-Rached, A. M. Older Aguilar, L. A. Guethlein, and 60. Sanjanwala, B., M. Draghi, P. J. Norman, L. A. Guethlein, and P. Parham. 2008. P. Parham. 2010. Humans differ from other hominids in lacking an activating NK Polymorphic sites away from the Bw4 epitope that affect interaction of Bw4+ cell receptor that recognizes the C1 epitope of MHC class I. J. Immunol. 185:

HLA-B with KIR3DL1. J. Immunol. 181: 6293–6300. 4233–4237. by guest on September 24, 2021 61. Winter, C. C., and E. O. Long. 1997. A single amino acid in the p58 killer cell 85. Parham, P. 2005. MHC class I molecules and KIRs in human history, health and inhibitory receptor controls the ability of natural killer cells to discriminate be- survival. Nat. Rev. Immunol. 5: 201–214. tween the two groups of HLA-C allotypes. J. Immunol. 158: 4026–4028. 86. Malnati, M. S., M. Peruzzi, K. C. Parker, W. E. Biddison, E. Ciccone, A. Moretta, 62. Rojo, S., N. Wagtmann, and E. O. Long. 1997. Binding of a soluble p70 killer cell and E. O. Long. 1995. Peptide specificity in the recognition of MHC class I by inhibitory receptor to HLA-B*5101: requirement for all three p70 immunoglob- natural killer cell clones. Science 267: 1016–1018. ulin domains. Eur. J. Immunol. 27: 568–571. 87. Peruzzi, M., K. C. Parker, E. O. Long, and M. S. Malnati. 1996. Peptide sequence 63. Khakoo, S. I., R. Geller, S. Shin, J. A. Jenkins, and P. Parham. 2002. The D0 requirements for the recognition of HLA-B*2705 by specific natural killer cells. J. domain of KIR3D acts as a major histocompatibility complex class I binding Immunol. 157: 3350–3356. enhancer. J. Exp. Med. 196: 911–921. 88. Peruzzi, M., N. Wagtmann, and E. O. Long. 1996. A p70 killer cell inhibitory 64. Sharma, D., K. Bastard, L. A. Guethlein, P. J. Norman, N. Yawata, M. Yawata, receptor specific for several HLA-B allotypes discriminates among peptides bound M. Pando, H. Thananchai, T. Dong, S. Rowland-Jones, et al. 2009. Dimorphic to HLA-B*2705. J. Exp. Med. 184: 1585–1590. motifs in D0 and D1+D2 domains of killer cell Ig-like receptor 3DL1 combine to 89. Yawata, M., N. Yawata, M. Draghi, F. Partheniou, A. M. Little, and P. Parham. form receptors with high, moderate, and no avidity for the complex of a peptide 2008. MHC class I-specific inhibitory receptors and their ligands structure diverse derived from HIV and HLA-A*2402. J. Immunol. 183: 4569–4582. human NK-cell repertoires toward a balance of missing self-response. Blood 112: 65. Vilches, C., M. J. Pando, and P. Parham. 2000. Genes encoding human killer-cell 2369–2380. Ig-like receptors with D1 and D2 extracellular domains all contain untranslated 90. Thananchai, H., G. Gillespie, M. P. Martin, A. Bashirova, N. Yawata, M. Yawata, pseudoexons encoding a third Ig-like domain. Immunogenetics 51: 639–646. P. Easterbrook, D. W. McVicar, K. Maenaka, P. Parham, et al. 2007. Cutting 66.Norman,P.J.,L.Abi-Rached,K.Gendzekhadze,D.Korbel,M.Gleimer, Edge: Allele-specific and peptide-dependent interactions between KIR3DL1 and D.Rowley,D.Bruno,C.V.Carrington,D.Chandanayingyong,Y.H.Chang, HLA-A and HLA-B. J. Immunol. 178: 33–37. et al. 2007. Unusual selection on the KIR3DL1/S1 natural killer cell receptor in 91. Martin, M. P., Y. Qi, X. Gao, E. Yamada, J. N. Martin, F. Pereyra, S. Colombo, Africans. Nat. Genet. 39: 1092–1099. E. E. Brown, W. L. Shupert, J. Phair, et al. 2007. Innate partnership of HLA-B 67. Valiante, N. M., M. Uhrberg, H. G. Shilling, K. Lienert-Weidenbach, and KIR3DL1 subtypes against HIV-1. Nat. Genet. 39: 733–740. K. L. Arnett, A. D’Andrea, J. H. Phillips, L. L. Lanier, and P. Parham. 1997. 92. Gumperz, J. E., N. M. Valiante, P. Parham, L. L. Lanier, and D. Tyan. 1996. Functionally and structurally distinct NK cell receptor repertoires in the peripheral Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I blood of two human donors. Immunity 7: 739–751. receptor among individuals of different human histocompatibility leukocyte 68. Gardiner, C. M., L. A. Guethlein, H. G. Shilling, M. Pando, W. H. Carr, antigens types appear genetically regulated, but not linked to major histo- R. Rajalingam, C. Vilches, and P. Parham. 2001. Different NK cell surface phe- compatibililty complex haplotype. J. Exp. Med. 183: 1817–1827. notypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J. 93. Pando, M. J., C. M. Gardiner, M. Gleimer, K. L. McQueen, and P. Parham. Immunol. 166: 2992–3001. 2003. The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly 69. Marsh, S. G., P. Parham, B. Dupont, D. E. Geraghty, J. Trowsdale, expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and D. Middleton, C. Vilches, M. Carrington, C. Witt, L. A. Guethlein, et al. 2003. 182 in Ig domain 1. J. Immunol. 171: 6640–6649. Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002. Tissue 94. Taner, S. B., M. J. Pando, A. Roberts, J. Schellekens, S. G. Marsh, Antigens 62: 79–86. K. J. Malmberg, P. Parham, and F. M. Brodsky. 2011. Interactions of NK cell 70. Traherne, J. A., M. Martin, R. Ward, M. Ohashi, F. Pellett, D. Gladman, receptor KIR3DL1*004 with chaperones and conformation-specific antibody re- D. Middleton, M. Carrington, and J. Trowsdale. 2010. Mechanisms of copy veal a functional folded state as well as predominant intracellular retention. J. number variation and hybrid gene formation in the KIR immune gene complex. Immunol. 186: 62–72. Hum. Mol. Genet. 19: 737–751. 95. Parsons, M. S., S. Boulet, R. Song, J. Bruneau, N. H. Shoukry, J. P. Routy, 71. Martin, M. P., A. Bashirova, J. Traherne, J. Trowsdale, and M. Carrington. 2003. C. M. Tsoukas, and N. F. Bernard. 2010. Mind the gap: lack of association be- Cutting edge: expansion of the KIR locus by unequal crossing over. J. Immunol. tween KIR3DL1*004/HLA‐Bw4-induced natural killer cell function and pro- 171: 2192–2195. tection from HIV infection. J. Infect. Dis. 202(Suppl 3): S356–S360. The Journal of Immunology 19

96. Chan, H. W., J. S. Miller, M. B. Moore, and C. T. Lutz. 2005. Epigenetic control of 107. Cichocki, F., T. Lenvik, N. Sharma, G. Yun, S. K. Anderson, and J. S. Miller. highly homologous killer Ig-like receptor gene alleles. J. Immunol. 175: 5966–5974. 2010. Cutting edge: KIR antisense transcripts are processed into a 28-base PIWI- 97. Santourlidis, S., N. Graffmann, J. Christ, and M. Uhrberg. 2008. Lineage-specific like RNA in human NK cells. J. Immunol. 185: 2009–2012. transition of histone signatures in the killer cell Ig-like receptor locus from he- 108. Cichocki, F., R. J. Hanson, T. Lenvik, M. Pitt, V. McCullar, H. Li, matopoietic progenitor to NK cells. J. Immunol. 180: 418–425. S. K. Anderson, and J. S. Miller. 2009. The transcription factor c-Myc enhances 98. Santourlidis, S., H. I. Trompeter, S. Weinhold, B. Eisermann, K. L. Meyer, KIR gene transcription through direct binding to an upstream distal promoter P. Wernet, and M. Uhrberg. 2002. Crucial role of DNA methylation in de- element. Blood 113: 3245–3253. termination of clonally distributed killer cell Ig-like receptor expression patterns in 109. Mro´zek, E., P. Anderson, and M. A. Caligiuri. 1996. Role of interleukin-15 in the NK cells. J. Immunol. 169: 4253–4261. development of human CD56+ natural killer cells from CD34+ hematopoietic 99. Chan, H. W., Z. B. Kurago, C. A. Stewart, M. J. Wilson, M. P. Martin, progenitor cells. Blood 87: 2632–2640. B. E. Mace, M. Carrington, J. Trowsdale, and C. T. Lutz. 2003. DNA methyl- 110. Pascal, V., E. Yamada, M. P. Martin, G. Alter, M. Altfeld, J. A. Metcalf, ation maintains allele-specific KIR gene expression in human natural killer cells. J. M. W. Baseler, J. W. Adelsberger, M. Carrington, S. K. Anderson, and Exp. Med. 197: 245–255. D. W. McVicar. 2007. Detection of KIR3DS1 on the cell surface of peripheral 100. Trompeter, H. I., N. Go´mez-Lozano, S. Santourlidis, B. Eisermann, P. Wernet, blood NK cells facilitates identification of a novel null allele and assessment of C. Vilches, and M. Uhrberg. 2005. Three structurally and functionally divergent KIR3DS1 expression during HIV-1 infection. J. Immunol. 179: 1625–1633. kinds of promoters regulate expression of clonally distributed killer cell Ig-like 111. Murphy, W. J., P. A. Pevzner, and S. J. O’Brien. 2004. Mammalian phyloge- receptors (KIR), of KIR2DL4, and of KIR3DL3. J. Immunol. 174: 4135–4143. nomics comes of age. Trends Genet. 20: 631–639. 101. Presnell, S. R., L. Zhang, C. A. Ramilo, H. W. Chan, and C. T. Lutz. 2006. 112. Robinson, J., M. J. Waller, P. Stoehr, and S. G. Marsh. 2005. IPD—the Immuno Functional redundancy of transcription factor-binding sites in the killer cell Ig-like Polymorphism Database. Nucleic Acids Res. 33(Database issue): D523–D526. receptor (KIR) gene promoter. Int. Immunol. 18: 1221–1232. 113. Wang, J., W. Wang, R. Li, Y. Li, G. Tian, L. Goodman, W. Fan, J. Zhang, J. Li, 102. Stewart, C. A., J. Van Bergen, and J. Trowsdale. 2003. Different and divergent J. Zhang, et al. 2008. The diploid genome sequence of an Asian individual. Nature regulation of the KIR2DL4 and KIR3DL1 promoters. J. Immunol. 170: 6073–6081. 456: 60–65. 103. van Bergen, J., C. A. Stewart, P. J. van den Elsen, and J. Trowsdale. 2005. 114. Kim, J. I., Y. S. Ju, H. Park, S. Kim, S. Lee, J. H. Yi, J. Mudge, N. A. Miller, Structural and functional differences between the promoters of independently D. Hong, C. J. Bell, et al. 2009. A highly annotated whole-genome sequence of expressed killer cell Ig-like receptors. Eur. J. Immunol. 35: 2191–2199. a Korean individual. Nature 460: 1011–1015. 104. Davies, G. E., S. M. Locke, P. W. Wright, H. Li, R. J. Hanson, J. S. Miller, and 115. Older Aguilar, A. M., L. A. Guethlein, E. J. Adams, L. Abi-Rached, A. K. Moesta, Downloaded from S. K. Anderson. 2007. Identification of bidirectional promoters in the human KIR and P. Parham. 2010. Coevolution of killer cell Ig-like receptors with HLA-C to genes. Genes Immun. 8: 245–253. become the major variable regulators of human NK cells. J. Immunol. 185: 4238– 105. Li, H., V. Pascal, M. P. Martin, M. Carrington, and S. K. Anderson. 2008. Ge- 4251. netic control of variegated KIR gene expression: polymorphisms of the bi- 116. Gonzalez-Galarza, F. F., S. Christmas, D. Middleton, and A. R. Jones. 2011. directional KIR3DL1 promoter are associated with distinct frequencies of gene Allelefrequencynet:adatabaseandonline repository for immune gene fre- expression. PLoS Genet. 4: e1000254. quencies in worldwide populations. Nucleic Acids Res. 39(Database issue): 106. Stulberg, M. J., P. W. Wright, H. Dang, R. J. Hanson, J. S. Miller, and D913–D919.

S. K. Anderson. 2007. Identiﬁcation of distal KIR promoters and transcripts. Genes 117. Clement, M., D. Posada, and K. A. Crandall. 2000. TCS: a computer program to http://www.jimmunol.org/ Immun. 8: 124–130. estimate gene genealogies. Mol. Ecol. 9: 1657–1659. by guest on September 24, 2021