Killer cell immunoglobulin-like receptors (KIRs) are members of a group of regulatory molecules found on subsets of lymphoid cells. They were first identified by their ability to impart some specificity on natural killer (NK) cytolysis (1, 2). The KIR locus, containing a family of polymorphic and highly homologous genes, maps to chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC; Figure 1). The LRC also encodes the leukocyte Ig-like receptor family (LILR; see Box 1 and discussion below), the leukocyte-associated inhibitory receptor (LAIR) family, and the Fcα receptor. KIR genes are tandemly arrayed over about 150 kb, with the remarkable feature that gene content varies between haplotypes (3). The discovery of KIR has also imparted an additional function on the human leukocyte antigen (HLA) class I molecules, which are encoded by genes within the major histocompatibility complex (MHC; chromosome 6). Through their interaction with KIR isotypes that inhibit natural killer (NK) cell activity, certain HLA class I molecules are now known to protect healthy cells from spontaneous destruction by NK-cell-mediated cytolysis. Other KIR isotypes stimulate the activity of NK cells. Thus, KIR are likely to play a significant role in the control of the immune response, which would explain the associations observed between certain KIR genes in rheumatoid arthritis (4), psoriatic arthritis (5) and control of HIV disease progression (6). The degree of HLA/KIR compatibility may also determine the success rate of haematopoietic cell replacement therapy for certain leukemias (7, 8).
NK cells are an important component of the innate immune system; they participate in early responses against infected or transformed cells by production of cytokines and direct cytotoxicity (9–13). HLA molecules precipitate adaptive aspects of anti-pathogen defense by presenting peptide fragments to immune effector cells (14, 15). Cytotoxic T lymphocytes (CTL) interact with the HLA class I-peptide complex on target cells via the T cell receptor (TCR), which instigates cytolytic activity if the peptide is considered foreign. HLA class I expression can be down-regulated in virally-infected or transformed cells, rendering the cells resistant to cytolysis by CTLs. However, aberrant levels of class I expression can result in spontaneous destruction by NK cells (16–18), a concept originally termed the "missing-self hypothesis" (19). Although neither the ligand nor the direct mode of action of many NK receptors is known, it is widely accepted that normal cells are protected from spontaneous killing when they express an appropriate ligand for an inhibitory receptor expressed by the cytotoxic cell (NK or CTL). NK cells need to discriminate between healthy and infected or transformed cells, corresponding with the observed phenotypic dominance of KIR-mediated inhibition over activation (20–23). Furthermore, inhibition by non-HLA specific NK receptors can override potential activation signals (24).
Studies performed over the last few years have revealed extensive diversity at the KIR gene locus, which stems from both its polygenic and multi-allelic polymorphism (3). As a consequence, there is only a small probability that two randomly selected individuals will have the same KIR genotype (25). KIR gene expression patterns can vary clonally (26), adding yet another layer of complexity to the system. Diversity at the locus may be the result of selection pressures, in a manner analogous to that proposed for the HLA loci. Thus, disease resistance conferred by the KIR locus is likely to vary in a haplotypic manner depending on disease type.
LILR are genetically, structurally and functionally related to KIR and may be their ancestral predecessors (27) (Box 1). Several investigators identified the molecules independently, which has led to inconsistencies in nomenclature systems. The LILRs are also known as ILT [immunoglobulin-like transcript; (28)], LIR [leukocyte inhibitory receptor; (29)], MIR [macrophage inhibitory receptor; (30)] and HM transcripts (31). LILR is the more recently derived and HUGO-endorsed nomenclature. The molecules were identified in binding studies of immune evasion by CMV (29), and in expression screening for human homologues of mouse leukocyte inhibitory receptors (28, 30, 31). Like KIRs, LILRs can interact with HLA class I (29, 32–34), are expressed by a range of immunologically active cells, including NK (31, 35), and have the potential to regulate the immune response through inhibition or activation of cytolytic activity (28, 35–37). LILR genes have been found in a wide variety of species (38–40) and the number of loci appears to be relatively stable (41). The duplicated sub-cluster organization of the LILR gene complex is conserved between humans and chimpanzees (38), unlike KIR haplotypes, which have distinct arrangements that are specific to each of these species (42). LILRs have either two or four extracellular Ig domains and a long or short cytoplasmic tail. Long cytoplasmic tails contain up to four immunoreceptor tyrosine-based inhibitory molecules (ITIM) (43) and therefore have the capacity to inhibit cellular activity. LILR with short cytoplasmic domains can associate with molecules containing ITAMs and contribute to cell activation. LILRA3 (ILT6) is unique in that it does not possess a cytoplasmic domain, and may be secreted (31, 44). Also, much of the LILRA3 gene is missing on some haplotypes due to a 7kb deletion in the region (45). Ligands are not known for all of the LILR, but some, such as LILRB1 (ILT2), can bind to HLA class I (Table 1). Thus, their functions and ligand specificities described so far suggests that LILR and KIR have overlapping and potentially complementary functions.
The LILR region in both human and chimpanzees consists of two sub-clusters of six or seven loci in opposite transcriptional orientation separated by two LAIR genes (27, 38, 46), which encode molecules that interact with epithelial cell adhesion molecule (EpCAM) (47). LILRB3 is highly polymorphic, as 18 variants were observed among only 50 individuals (45, 48). Twelve alleles have been identified for LILRA3 (Table 1) (49).
About 14 expressed KIR genes have been identified (Table 2) and two systems have been generated for naming them. The most commonly used nomenclature system accounts for their protein structure and consists of four major subdivisions based on two features: the number of extracellular Ig domains (2D or 3D) and characteristics of the cytoplasmic tail (Figure 2) (see PROW and/or the HUGO-endorsed nomenclatures). They have also been named according to the CD nomenclature system as CD158a, CD158b, etc., based on an approximate centromeric–telomeric order of the genes on chromosome 19 (50). Unfortunately, the CD nomenclature does not reflect structure, function, expression or localization (51). This system also presents the possibility of confusion with the monoclonal antibodies, CD158a and CD158b, since each binds to several different KIR molecules. The CD nomenclature is not used routinely, and the Human Genome Organization (HUGO) nomenclature system will be used throughout this report.
Irrespective of the number of Ig subunits, the cytoplasmic domain of KIR are either long (designated "L") or short ("S"). KIR with long cytoplasmic domains are inhibitory by virtue of the immunoreceptor tyrosine-based inhibition motifs (ITIMs) present in their cytoplasmic domains. Short-tailed KIR transmit activating signals through their interaction with the adaptor molecule, DAP-12 (DNAX activation protein of 12kD; this molecule is also known as killer cell activating receptor-associated protein or KARAP), which contains immunoreceptor tyrosine-based activation motifs (ITAMs) (52, 53). DAP-12 is also a member of the immunoglobulin superfamily and is encoded at the centromeric end of the LRC. ITIMs and ITAMs are characteristic of several immunologically important receptors, such as CD5, CD22 and FcγRII (54).
Two KIR pseudogenes (2DP or 3DP) have been identified (Table 2): 2DP1, which shares high sequence similarity with two-domain KIR genes, and 3DP1, which is similar to 3DL3 in portions of the gene, but may represent an ancestral KIR gene. The pseudogenes have been given various names in the literature, and an alias key and Accession numbers are provided at (www.gene.ucl.ac.uk/nomenclature/genefamily/kir.html).
Allelic variation has been observed for most of the KIR genes and names for alleles at several of the most polymorphic loci have been specified based on nomenclature used for HLA loci (25, 55). The nomenclature for allelic variants is not complete, but a report that goes some way toward addressing this issue is now available (215).
KIR Gene Sequences
Well over 100 KIR sequences have been deposited into either the EMBL or GenBank nucleotide sequence databases. A number of the entries are partial cDNA or genomic sequences and some are identical to a portion of the full-length version. We have generated an alignment of the full-length cDNA sequences (Box 2). Accession numbers of these sequences are provided in Table 2. Each unassigned KIR sequence identified in GenBank was designated as an allele of a specific KIR gene if it differed by <2% from the consensus sequence of that KIR gene (42, 56).
Exon–Intron Structure of the KIR Genes
Organization of the exon–intron structure of the various KIR genes is fairly consistent with the following basic arrangement: the signal sequence is encoded by the first two exons, each Ig domain (D0, D1, and D2, starting from the N-terminus) corresponds to a single exon (exons 3–5, respectively), the linker and transmembrane regions are each encoded by a single exon (exons 6 and 7), and the cytoplasmic domain is encoded by two final exons (Figure 3) (27, 57, 58). KIR2DL1, 2DL2/3, and all 2DS genes [known as Type 1 two-domain KIR genes (59)] have an identical genomic organization to that encoding KIR molecules with three Ig domains. However, exon 3 is a pseudoexon in these two-domain KIR genes, which often remains in-frame but is eventually spliced out, possibly due to a three-base-pair deletion (59). The protein products of type 1 two-domain KIR are therefore missing the D0 domain (60). All NK cells express at least one type 1 2D KIR (61). The Type 2 two-domain KIR, which include 2DL4, 2DL5A, and 2DL5B (59), are characterized by the complete absence of exon 4 (62), and therefore their protein product has no D1 domain. The 3DL3 gene closely resembles the other 3D genes, except that it is missing exon 6.
Two KIR pseudogenes have been identified and named, although others that closely resemble intact KIR genes (and therefore go undetected) may exist on certain haplotypes. KIR2DP1 (KIRZ) is closely related to 2DL2/3 and 2DL1 (>97% homology at the nucleotide level), and contains two pseudoexons, 3 and 4. Pseudoexon 3 of 2DP1 contains the same aberrations as those identified in the Type 1 two-domain KIR genes, and a single base pair deletion in pseudoexon 4 of 2DP1 causes a frame shift that introduces a stop codon. A second KIR pseudogene, 3DP1 (KIRX), is severely truncated and alternate forms of the gene are differentiated by a 1.5kb deletion, which removes exon 2 (27). No transcripts for either 2DP1 or 3DP1 have been identified to date.
KIR Gene Order and Haplotypic Variability
The KIRs are situated within a segment of DNA that has undergone expansion and contraction over time, and inspection of KIR haplotypes suggests a history of gene duplication and unequal crossing over in the region. The order of the KIR genes along the chromosome has been determined for two distinct haplotypes (Figure 4), providing a framework for their genomic order (27, 46, 63). The genes are organized in a head-to-tail fashion, and each gene is roughly 10–16 kb in length with a sequence of about 2 kb separating each pair of genes, except for a 14 kb stretch of unique sequence upstream of 2DL4. Variation at the KIR gene complex is a function of both allelic polymorphism at several KIR genes and variability in the number and types of genes present on any given haplotype (3, 25, 64).
Although KIR haplotypes vary in the number and type of genes present (3, 65, 66, 70), the genes 2DL4, 3DP1, 3DL2, and 3DL3 are present on virtually all haplotypes and have therefore been termed framework loci (27). All others exist on only a fraction of the total haplotypic pool. The number of putatively expressed KIR genes present on a single haplotype ranges from about 7–12, depending primarily on the presence or absence of activating KIR loci (3, 27, 66). Based on gene content, the haplotypes have been divided into two primary sets, termed A and B, which were originally differentiated by the presence of a 24 kb HindIII fragment on Southern blot analysis (3). Haplotype A has seven loci; 2DL1, 2DL3, 2DL4, 2DS4, 3DL1, 3DL2 and 3DL3. Perhaps the most functionally relevant distinction between haplotypes A and B is the number of stimulatory receptors present. Haplotype A contains only a single stimulatory KIR gene, 2DS4, whereas haplotype B contains various combinations of 2DS1, 2DS2, 2DS3, 2DS5, 3DS1, and 2DS4. Furthermore, the 2DS4 gene has a null allele with a population frequency of about 84% (allele frequency of 60%) (67) (and PN, unpublished observation). Thus, some individuals are homozygous for an A haplotype from which no activating KIR is expressed (68). The phenomenon of framework genes supporting areas of variable polygeny is analogous to that seen for HLA-DR, in which the DRA genes are always present, whereas the DRB gene number is variable (69).
The frequencies of haplotypes A and B are roughly equal in Caucasian populations, but on the basis of gene content, haplotype B displays a much greater variety of subtypes. Patterns of linkage disequilibrium (LD) between KIR loci (as opposed to LD between alleles of two genes that are both present on all haplotypes) are fixed for the A haplotypes (i.e. A haplotypes differ at the allelic level (25), but not in gene content). Much of what we know about LD patterns among the B haplotypes is based on studies of KIR profiles (presence or absence of each gene in a given individual) in groups of unrelated individuals, and they indicate that LD is quite strong between many pairs of genes represented in the group of B haplotypes (3, 65, 66, 70–72). Over 100 different KIR profiles have been identified among unrelated individuals, and many distinct gene-content haplotypes have been identified from segregation analysis (Figure 5) (68, 73, 74). The numbers will undoubtedly continue to grow as more individuals and families are screened.
Expansion and contraction of the KIR region appears to have occurred due in part to unequal crossing over. One consequence of such molecular genetic events is the possible generation of KIR haplotypes that have two (or more) copies of a gene on a single haplotype and the rearrangement of gene order. 2DL5 is the most recently identified KIR gene (75) and segregation analysis has indicated that what were once considered alleles of a single 2DL5 locus are actually two different loci, both of which can be present on a single haplotype (74, 76). Interestingly, these genes, termed 2DL5A and 2DL5B, are not tandemly located on haplotypes containing both genes, suggesting that they may have arisen due to a mechanism involving nonreciprocal crossing over. The two genes share >99% sequence similarity in both their exons and introns, and would not have been identified as separate loci if family studies of 2DL5 inheritance had not been performed (74, 76). There is at least one haplotype with several KIR deleted, including 2DL4 and 3DL1 (72). Since most KIR typing methods are designed to determine presence or absence of genes and subtyping of individual KIR genes in families has been performed in only a limited number of studies (25, 55, 77), haplotypes containing multiple copies of the same gene would remain undisclosed, further underestimating KIR haplotypic diversity.
Frequencies of specific KIR haplotypes and the two major haplotypic groups, A and B, vary across ethnically defined populations (65, 66, 70–72, 78–80). The A haplotype has an allele frequency of 75% in Japanese but only 15% in Australian Aborigines [estimated from (71, 79)]. The greatest intra-population haplotype diversity would appear to be in South Asians (72, 80) and the least in Japanese (79). It will be of interest to determine whether significant differences in KIR haplotypes across populations might account for variation in disease susceptibility among these groups.
Sequence analysis of KIR cDNA has shown that most KIR genes contain variable sites, and that some are quite polymorphic (25, 55, 64, 77, 81–91). Allelic polymorphism provides additional diversity to the extent that unrelated individuals identical for both KIR haplotypes are unlikely to be observed (25). The variation in KIR sequences can occur at positions encoding residues that affect interaction with HLA class I (92–95). Variation tends to occur throughout the gene, unlike the pattern observed in HLA class I and II genes where nucleotide variation is restricted primarily to one or two exons (96).
Similarity amongst KIR gene sequences and a history of unequal crossing over in the region has clouded the distinction between alleles of a single locus and separate gene loci. 2DS4 and 2DS1 were suggested to be allelic variants of a single locus (3), although more recent data suggests that they represent distinct loci (27, 65). 3DL1 and 3DS1 appear to occupy the same position on different haplotypes (27), and segregation analysis has indicated that they are indeed alleles of a single locus (55). We have previously proposed that 3DS1, which is substantially less frequent than 3DL1, arose by an unequal crossover between an ancestral 3DL1 gene and an ancestral activating KIR gene (6), based on the high sequence similarity between their extracellular domains and the observation that they segregate as alleles of a single gene. Nevertheless, rare haplotypes missing both or containing both 3DL1 and 3DS1 have been observed (55, 70). Haplotypes characterized by deletion of 3DL1/3DS1 or by the presence of both 3DL1 and 3DS1 may have been derived from unequal crossovers that occurred subsequent to the event that formed 3DS1. Wilson et al. (27) proposed that 2DL2 arose from a non-reciprocal recombination between 2DL1 and 2DL3 based on sequence similarity patterns, which would explain the observation that 2DL2 and 2DL3 also segregate as alleles of the same locus (65, 66, 70, 71). Moreover, the 2DP1 pseudogene, which is located between 2DL1 and 2DL3 and would have been lost in the cross over event, is indeed missing on 2DL2 haplotypes.
KIR3DL1 and 3DL2, which encode molecules that bind certain allotypes of the HLA-B and HLA-A, are both quite polymorphic, although the source of variability in the two genes appears to be distinct (55). Recombination is likely to have generated much of the diversity in both genes (25). KIR3DL1 alleles encode molecules that appear to be expressed at different levels on the surface of NK cells based on antibody binding to 3DL1 allotypes. Allotypes with high, low and no binding have been observed and expression levels correlate with variation at specific amino acid residues of the 3DL1 molecule (55). It will be interesting to consider the functional consequences of these differences in expression patterns. Like the variability that is observed based on KIR gene content, allelic variability and frequencies also appear to distinguish different ethnic groups (83).
Linkage disequilibrium (LD) studies between pairs of polymorphic genes within the KIR locus are starting to emerge (25) revealing a pattern of strong allelic disequilibrium between pairs of genes located centromeric and pairs located telomeric of 2DL4. Although significant in many instances, weaker disequilibrium patterns were observed between pairs of genes located in opposite halves of the locus. In general, patterns of LD that have been observed to date appear to correspond quite well with physical distance between genes.
Promoter Region Variability
The promoter regions of most KIR genes share >91% sequence similarity (26), and may therefore be controlled by similar mechanisms. The promoter regions of 3DL3 and 2DL4, on the other hand, are more divergent (89% and 69% sequence similarity, respectively). Differences in promoter regions of these framework loci may account for the lack of 3DL3 expression and, alternatively, the expression of 2DL4 in virtually 100% of NK cell clones, a characteristic unique to 2DL4 (26). 2DL5A appears to be expressed based on measurements of mRNA in NK cells, but the most common allele of 2DL5B (in Caucasoids) is not expressed (76). Lack of 2DL5B expression correlates with a mutation in a putative AML1 transcription factor site in the promoter region, a variant that is also present in the pseudogene 3DP1 (76) and that may prevent expression of these two genes.
KIR genotyping can be locus or allele specific. Locus only typing detects presence or absence of each gene in a given individual, thus providing a profile of the KIR repertoire (KIR profile). The PCR sequence-specific priming (PCR-SSP) method for KIR typing first described by Uhrberg and coworkers (3) has been updated to account for newly discovered loci and previously undetected alleles (65, 72, 78, 97, 98). A PCR sequence-specific oligonuleotide probe (PCR-SSOP) method has also been developed (70, 99). Inter-laboratory collaboration has helped to authenticate the molecular genotyping assay for KIR loci (100). Over 100 different KIR genotype profiles have been found so far; a summary of those published is shown in Figure 6.
Medium- to high-resolution allele-specific reactions (PCR-SSP) have been described for 2DL1, 2DL3, 3DL1 and 3DL2 (25, 55), and a single-stranded conformational polymorphism (SSCP) assay has been used to genotype 2DL4 (77, 91). Development of a comprehensive assay was required for 2DL5 in order to distinguish the two highly homologous loci, 2DL5A and 2DL5B (97). Reverse-transcriptase PCR (RT-PCR) based on PCR-SSP is the method of choice for allotyping NK cell clones and remains largely unchanged from that described previously (3). Various monoclonal antibodies are available for this purpose, but specificity is limited by the high homology between KIR isotypes.
Comparisons of KIR sequences and haplotypes within and across species indicate that the KIR gene family is evolving rapidly, perhaps in response to species-specific pathogenic organisms (42, 101–103). It was initially thought that KIR were only present in higher primates, although KIR-like sequences have been found recently in lower primates (104, 105), ungulates (106) and other mammals (40). In chimpanzee, the closest living species to humans, ten KIR genes have been identified, only three of which appear to be direct orthologues of human KIR (42). Non-orthologous KIR genes have also been identified in pygmy chimpanzee (102), orangutan (101), rhesus monkeys (105), and baboon (104). The phylogenetic relationship of KIR genes from four different primate species is shown in Figure 7 [reproduced from (59); see also (101, 107)]. Primate species vary in ratios of long tail to short tail KIR genes, and haplotypic structure may also distinguish some species. For example, a common short haplotype of only three KIR genes distinctly characterizes pygmy chimpanzees (102). Comparisons of KIR gene sequences from five species of primates have revealed most lucidly the historical instability of the KIR genes in primate species. Nevertheless, similarities have persisted over millions of years, including the maintenance of 2DL4 in all primate species tested (although all 2DL4 transcripts examined in orangutan prematurely terminated). Further, identical receptor specificity for MHC-Cw molecules was observed in human and chimpanzees, and the two species are xenocompatible in that KIR receptors from chimpanzee can functionally recognize some human MHC class I molecules and vice versa.
Rapid evolution of the KIR locus may have resulted in species-specific characteristics across orders of mammals (108), potentially hampering attempts to clone KIR homologues in some species. KIR have now been detected in rodents (see; XM_142159, XM_142160, AF548540, AF548541, AY152727). Ly49 receptors, which belong to the C-type lectin domain family and are structurally unrelated to KIR, appear to perform the same function in rodents. Ly49 haplotypes are also complex, containing variable numbers of inhibitory and stimulatory genes (109), some of which are known to recognize mouse class I molecules. Genomes of humans and other primate species contain a single Ly49-like gene, which is a pseudogene in humans, gorilla, and chimpanzee (104, 110, 111), but may be functional in cow, baboon and orangutan (101, 104, 106).
It has been suggested that MHC class I and KIR (and also Ly49 in mouse) are coevolving (42, 112), such that as selection through infectious disease morbidity alters the frequencies and repertoire of class I variants, KIR/Ly49 must evolve to maintain or expand the ability to interact with class I in a beneficial manner. Evidence for the co-evolutionary process is illustrated by the observation that mouse class I allotypes lack determinants recognized by KIR, as do human class I allotypes for mouse Ly49 (86). Along these same lines, the orangutan have KIR2D genes that are predicted to encode receptors that specify only the Cw1 epitope (asparagine at position 80) of MHC-Cw molecules, correlating in an evolutionary sense with the observation that allotypes with the Cw2 epitope (lysine at position 80) are missing in this species and only MHC-Cw allotypes with the Cw1 epitope are available for interaction with 2D molecules (101). Additional selective pressures may also act directly on the KIR loci during early phases of infection by selecting for variants that enhance innate immune responsiveness, potentially increasing the rate of evolution at a speed surpassing that at the HLA class I loci (42, 113). Conforming to this hypothesis, all functional HLA class I genes have chimpanzee orthologues (114), but there are only three human-chimpanzee KIR orthologues (113). Thus, the portrayal of the KIR gene complex as the epitome of "eternal evolutionary restlessness" (58) appears to represent a precise account of the region.
Individual Molecular Characteristics
KIR2DL1 is a member of the type 1 (D1-D2) 2DL subfamily of inhibitory receptors. Exon 3 of 2DL1 is a pseudoexon that would otherwise encode the D0 domain. Ligands for 2DL1 are HLA-Cw molecules that have Asn77 and Lys80 (Cw*02/4/5/6/707/12042/15/1602/17). Monoclonal antibodies EB6 (CD158a) and HP3E4 recognize 2DL1, both of which also react with 2DS1 (115, 116). 2DL1*004 (2DL1v; inhibitory) appears to have been formed by a recombination between 2DL1 and 2DS1.
KIR2DL2 is a member of the type 1 (D1-D2) 2DL subfamily of inhibitory receptors. Exon 3 of 2DL2 is a pseudoexon that would otherwise encode the D0 domain. Ligands for 2DL2 are HLA-Cw molecules that have Ser77 and Asn80 (Cw*01/3/7/8/12/13/14/1507/1601 and B*4601). Monoclonal antibodies GL183 (CD158b) and CH-L recognize 2DL2 as well as 2DL3 and 2DS2 (211, 212).
Key references: 2DL2 arose from a non-reciprocal recombination between 2DL1 and 2DL3 (27); 2DL2 and 2DL3 are alleles (66); crystal of 2DL2 (117); crystal structure of 2DL2 contacting HLA-Cw3 (1EFX) (93).
KIR2DL3 is a member of the type 1 (D1-D2) 2DL subfamily of inhibitory receptors. Exon 3 of 2DL3 is a pseudoexon that would otherwise encode the D0 domain. Ligands for 2DL3 are HLA-Cw molecules that have Ser77 and Asn80 (Cw*01/3/7/8/12/13/14/1507/1601). Monoclonal antibodies GL183 (CD158b) and CH-L recognize 2DL3 as well as 2DL2 and 2DS2 (211, 212).
KIR2DS1 is a type 1 (D1-D2) two-domain activating receptor. Exon 3 of 2DS1 is a pseudoexon that would otherwise encode the D0 domain. Ligands for 2DS1 may be HLA-Cw molecules that have Asn77 and Lys80 (Cw*02/4/5/6/707/12042/15/1602/17). Activating KIR signal by virtue of non-covalent association with the ITAM-bearing adaptor molecule, DAP-12. Monoclonal antibodies EB6 (CD158a) and HP3E4 recognize 2DS1, both of which also react with 2DL1 (115, 116).
Key references: 2DS1 associated with psoriatic arthritis when ligand for corresponding inhibitory receptor was absent (5).
KIR2DS2 is a type 1(D1-D2) two-domain activating receptor. Exon 3 of 2DS2 is a pseudoexon that would otherwise encode the D0 domain. 2DS2 ligands are HLA-Cw molecules that have Ser77 and Asn80 (Cw*01/3/7/8/12/13/14/1507/1601). Activating KIR signal by virtue of non-covalent association with the ITAM-bearing adaptor molecule, DAP-12. Monoclonal antibodies GL183 (CD158b) and CH-L recognize 2DS2 as well as 2DL2 and 2DL3 (211, 212).
Key references: 2DS2 implicated in rheumatoid vasculitis (119); single substitution lowers binding affinity compared with 2DL2 (120); 2DS2 associated with psoriatic arthritis when ligand for corresponding inhibitory receptor was absent (5).
KIR2DS3 is a type 1 (D1-D2) two-domain activating receptor. Exon 3 of 2DS3 is a pseudoexon that would otherwise encode the D0 domain. Its ligand is unknown. Activating KIR signal by virtue of non-covalent association with the ITAM-bearing adaptor molecule, DAP-12.
KIR2DS4 is a type 1 (D1-D2) two-domain activating receptor. Exon 3 of 2DS4 is a pseudoexon that would otherwise encode the D0 domain. Ligand unknown. Activating KIR signal by virtue of non-covalent association with the ITAM-bearing adaptor molecule, DAP-12. Some alleles of 2DS4 have a 22bp deletion, which may lead to a truncated molecule (67), occasionally termed KIR1D (68).
KIR2DS5 is a type 1 (D1-D2) two-domain activating receptor. Exon 3 of 2DS5 is a pseudoexon that would otherwise encode the D0 domain. Ligand unknown. Activating KIR signal by virtue of non-covalent association with the ITAM-bearing adaptor molecule, DAP-12.
Key references: (90)
- Pseudoexon 3: AF215833
KIR2DL4 is a member of the type 2 (D0-D2) two-domain receptors. There is no exon 4 (D1). 2DL4 may transmit inhibitory, stimulatory, or both types of signals. 2DL4 probably binds to HLA-G. Some alleles of 2DL4 do not have a complete transmembrane domain but it is not clear whether these retain any function.
2DL4 is present on most haplotypes (a KIR framework locus).
Key references: 2DL4 binds to HLA-G (122, 123); or does it?(124); truncated alleles described (77); SNP (rs649216) (T) associated with truncated 2DL4 (91); 2DL4 is not always present (72); 2DL4 truncated in Orangutan (101); 2DL4 signaling (125, 126).
- 2DL4*001: X99480 (NK3.3)
- 2DL4*00201: X97229
- 2DL4*00202: AF034772
- 2DL4*003: AF003116 (KIR103)
- 2DL4*004: AF002979
- 2DL4*005: AF034771
- 2DL4*006: AF034773
- 2DL4*007: AF276292
KIR2DL5 is a member of the type 2 (D0-D2) two-domain receptors. There is no exon 4 (D1). 2DL5 is likely to transmit inhibitory signals (Figure 2). Ligand is unknown. 2DL5 is the locus that caused the extra RFLP fragment reported by Uhrberg and coworkers and thus originally defined the KIR `B' haplotype (3, 59). There are two paralogous loci for this KIR. 2DL5A is in the telomeric KIR region and has one known allele, 2DL5A*001 (see below). 2DL5B is found in the centromeric KIR region and has three known alleles. 2DL5B*002 is not expressed.
KIR3DL1 is a three-immunoglobulin-domain inhibitory receptor. One allele, 3DS1, is a three-immunoglobulin-domain activating receptor. 3DL1 interacts with HLA-B molecules that contain a Bw4 motif. Two commercially available clones, DX9 and Z27 react with 3DL1. DX9 and Z27 will bind to variants of 3DL1 with differing degrees of affinity; neither bind to 3DS1(55).
Key references: 3DL1 polymorphic(83); 3DL1 and 3DS1 alleles: high, low and no expression variants of 3DL1 (55); 3DS1 slows HIV disease progression if the correct HLA ligand is also present (6); 3DS1 rare in Africans (72); locus duplicated on some haplotypes (99).
- 3DL1*00102: AF262968
- 3DL1*003: AF022049
- 3DL1*00401: AF262969
- 3DL1*00402: AF262970
- 3DL1*005: AF262971
- 3DL1*006: AF262972
- 3DL1*007: AF262973
- 3DL1*008: AF262974
- 3DS1*004: AF022044
- 3DS1: AJ417558
- #3DS1*001: L76661
- #3DS1*002: X97233
- #3DS1*003: U73396
- 3DL1/3DL2 hybrid: AY059417
#not detected by PCR (55).
KIR3DL2 is a three-immunoglobulin-domain inhibitory receptor, which interacts with some HLA-A alleles. Monoclonal antibody DX31 binds to 3DL2.
3DL2 is present on most, if not all KIR haplotypes (a KIR framework locus).
- 3DL2*004: X93595
- 3DL2*005: L76666
- 3DL2*006: AF262966
- 3DL2*007: AF262965
- 3DL2*008: AF262967
- 3DL2*009: AF263617
- 3DL2*010: AY054918
- 3DL2*011: AY054919
- 3DL2*012: AY054920
- X93596 (NK18)
- 3DL1/3DL2 hybrid: AY059417
KIR3DL3 is a three-immunoglobulin-domain receptor of unknown function or ligand. The 3DL3 gene closely resembles the other 3D genes, except that it is missing exon 6 (stalk region). 3DL3 is present on most, if not all KIR haplotypes (a KIR framework locus).
- AF352324 (3DL7)
KIR are expressed by classical NK and subpopulations of T cells (127, 128). NK clones from a single individual can vary substantially in the type of KIR molecules they express. Each cell requires at least one inhibitory receptor, such that when there is no appropriate inhibitory KIR–ligand combination, then other types of inhibitory receptor interactions will compensate (26, 129–131). With the exception of null alleles and possibly 3DL3, all known KIR in a given individual's KIR gene repertoire are expressed, albeit apparently stochastically in order to generate a large number of different and overlapping subsets of KIR expression patterns (26, 132, 133). In heterozygous individuals, NK clones can express none, one or both alleles of 3DL1 and 3DL2, but usually both alleles of 2DL4 (134). This somatic diversity means that there should be at least one NK clonal population that can respond to downregulation of any single HLA class I isotype (59, 135, 136).
KIR expression is likely to involve up to 15 different transcription promoter sequences which are located within 500 bp and 5' to the initiation codon (58). Other mechanisms controlling KIR levels are also apparent, including hormonal and cytokine regulation of expression (122, 137). Despite the many potential factors contributing to altered expression, long-term expression levels appear stable (131). The KIR locus maps to chromosome 19, whereas HLA maps to chromosome 6, and therefore the two loci segregate independently. Thus, NK cells can express KIR for which no known HLA ligand is present (129, 138, 139) and can also be expressed in individuals with very low HLA class I expression (140). Nevertheless, HLA can influence the number of peripheral blood KIR-expressing cells, but not the level of expression (131).
The ligands for several of the inhibitory KIR have been shown to be subsets of HLA class I molecules based on assays measuring binding of inhibitory KIR to specific HLA molecules and inhibition of NK-mediated cytolysis of target cells bearing those HLA allotypes [see (59, 141, 142)].
Dimorphisms in the HLA-Cw α1 domain that are characterized by Ser77/Asn80 and Asn77/Lys80 define serologically distinct allotypes of HLA-Cw (Cw group 1 and group 2, respectively). KIR2DL1 and 2DS1 interact with group 2 allotypes, while 2DL2, 2DL3 and 2DS2 interact with the alternative group 1 allotypes (143–145). The specificity for Cw type is defined entirely by a single substitution at KIR2D position 44 (145, 146). Importantly, NK cells expressing only Cw group 2 specific inhibitory receptors can lyse targets that are homozygous for the Cw group 1 allotypes and vice versa.
KIR3DL1 interacts with HLA-B allotypes that contain Bw4 (112, 147), a serologically-defined motif, and 3DL2 interacts with some HLA-A allotypes (87, 89). No KIR has yet been shown to bind allotypes containing Bw6, the alternative to Bw4 positive allotypes. Bw4 and Bw6 are also distinguished by polymorphism at positions 77 and 80. However, additional residues must be required for interaction with 3DL1, as some HLA-A allotypes possess the Bw4 motif but are not able to bind 3DL1 (112).
KIR2DL4, which is unusual by nature of its extracellular domain organization and the possession of only one ITIM, probably interacts with HLA-G (122, 123, 148). A summary of KIR isotypes and their specificity are shown in Table 3.
Crystal images of the two Ig domains for each of 2DL1 [1NKR; (94)], 2DL2 [1EFX; (117)] and 2DL3 [1B6U; (118)] are presently available. The ligand-contacting region falls at the membrane distal side of the junction between the Ig domains, which folds the D1 domain towards the cell surface. 2DL1–3 have similar structures but are distinguished by the angle between the Ig domains. This (hinge) angle appears to be stable (93), so morphological changes upon ligation are unlikely.
Type 1 2D KIR interact directly with the α-helices and bound peptide of their HLA ligands (92, 93). Ribbon diagrams of KIR-HLA interactions determined from crystal structures are shown in Figure 8. Six loops contact the MHC molecule, three from D1, one from the hinge and two from D2; all contact points result from complementary charges (93). There are also several hydrogen bonds, salt bridges and a degree of hydrophobic interaction. These high-resolution images also indicated that the KIR molecule contacts two residues from the bound peptide and forms a hydrogen bond with one of them (92, 93).
The D1 and D2 domains of three Ig domain KIR are likely to form a similar interface with Class I as those described for type I 2D KIR (120). Directed mutation experiments have shown that the D0 domain increases the avidity of this interaction (149), although all three Ig domains of 3DL1 were required for binding to HLA-B*51 (150).
KIR and TCR have overlapping footprints and therefore cannot bind to the same HLA/peptide complex concurrently (92, 93). This may impart some control over T cell activity over and above direct intracellular signaling, since KIR and TCR would be in competition for HLA ligand binding. The KIR\HLA interaction forms the basis of a natural killer immune synapse during immunosurveillance (151, 152), a process that has been illustrated by confocal microscopy (153). In these images, KIR can be seen inducing a ring formation of HLA-Cw molecules around a cluster of adhesion molecules at the cell surface. Receptor co-aggregation is likely to increase the signaling potential (117, 120). HLA and other membrane molecules may even be captured by the NK cell and either be internalized or remain at the NK cell surface (154, 155). The physiological role for intercellular transfer of HLA molecules remains to be determined, but may represent a novel mechanism for controlling NK cell activity.
Inhibitory KIR can actively prevent the localization of lipid rafts to the immune synapse (156, 157). Rafts contain complexes of activating accessory molecules, potentially explaining the dominant phenotype displayed by inhibitory receptors. The distinct binding affinities of activating compared to inhibitory KIR may also contribute to the dominance of inhibition. For example, 2DL2 has a higher affinity than 2DS2 for HLA-Cw3 due to a single amino acid substitution (120).
NK cells will become activated when inhibition is removed, so activation must involve stimulatory receptors (17). Based on assays measuring target cell killing, stimulatory KIR can mediate NK cell activity through recognition of HLA ligands (158), but little if any direct binding of activating KIR molecules to their putative HLA ligands has been detected and their high affinity, physiological ligands remain in question. Candidate ligands include non-MHC molecules, such as foreign or microbial antigens expressed on infected cells, normal cell surface proteins that are aberrantly expressed, stress-induced proteins or complexes of pathogen-derived peptides bound to MHC class I molecules. Recently, the mouse cytomegalovirus m157 gene product was shown to bind the mouse activating NK cell receptor Ly49H, an interaction that leads to NK cell killing of the infected targets (159–164). Although they lack sequence homology, the mouse Ly49 and human KIR families are considered to be functionally equivalent (165). Ly49H recognition of m157 provides strong support for the possibility that non-HLA molecules can behave as ligands for activating KIR.
As discussed under the section entitled KIR Ligands, specificity of inhibitory KIR for HLA-Cw allotypes is dictated to a large extent by the presence of asparagine or lysine at position 80 of the HLA-Cw molecule (115). Crystal structures supported this division of ligand specificity and suggested that the bound peptide also affects KIR binding, as there is a size limit to one of the KIR-contacting residues (92, 93). Although some interactions with KIR have been shown to be independent of peptide (166), several early studies also indicated that specificity depends on the presented peptide (167–171). Peptide-dependent protection of killing by NK cells has been observed (172, 173). Therefore, it has been suggested that inhibiting and activating receptors specific for the same HLA may respond differentially depending on bound peptides (138, 174). Peptide recognition could provide KIR with one further means for mediating pathogen-specific immunity.
The exact mechanism for signal transmission to KIR transmembrane domains has not been elucidated. Most inhibitory KIR have two ITIMs (Box 2) and these operate in tandem to mediate inhibition (175, 176). ITIM phosphorylation results in association with SHP (Src-homology domain-bearing tyrosine phosphatase), which specifically inhibits the proteins involved in the intracellular activation cascade (177). Activating KIR have no direct signaling properties but associate with the ITAM-bearing adaptor molecule, DAP12. DAP12 and short-tailed KIR associate due to complementarily charged transmembrane residues (52, 53). Ligation of activating KIR leads to phosphorylation of DAP12, recruitment of ZAP-70/Syk kinase and the induction of an intracellular signaling cascade (178, 179). Also, ligation of activating KIR may control the response by inducing apoptosis of mature cytotoxic cells (180).
One exception to the pattern of division described for stimulatory and inhibitory receptors is 2DL4 (123, 148, 181), which has a long cytoplasmic tail containing only a single ITIM motif. 2DL4 also contains a charged arginine residue in the transmembrane region, which may facilitate interaction with DAP12. Thus, it has been proposed that 2DL4 may transmit inhibitory, stimulatory, or both types of signals (125, 126). Some alleles of 2DL4 do not have a complete transmembrane domain (77), but it is not clear whether these are expressed at the cell surface or retain any function.
Classical NK cells develop from CD34pos progenitor cells in the bone marrow, in the presence of stromally derived cytokines such as IL15. KIR may be involved in this development (182), suggesting some form of selection for the NK cell receptor repertoire. A sequential pattern of KIR expression during NK maturation may occur, which could ensure self tolerance (133, 183). Clonal NK cell expression of a subset of KIR is stable over time and is predominantly determined by KIR genotype, with only moderate influence from HLA (131), if at all (182). KIR promoter methylation correlates with stable KIR expression, but it is not clear at which stage in development methylation patterns are established (134, 184). As KIR can be expressed for which there is no known HLA ligand and vice-versa (129, 138), there appears to be no mechanism for maturation of NK cell clones through selection. The number of functional HLA genes, for example, is controlled to some extent by selection processes in the thymus, where too many HLA molecules would restrict the TCR repertoire and thus reduce immune potential (185). Thus, the constraint placed on MHC polygeny may not apply to KIR, potentially explaining the large and varying number of KIR genes.
Also known as N-CAM (neural cell adhesion molecule), CD56 is expressed on all NK as well as subpopulations of T cells (186), but its function remains elusive. NK cells expressing low levels of CD56 (CD56dim) tend to have more resting cytotoxic activity than those with high levels (CD56bri) (13). CD56dim NK cells express KIR, whereas CD56bri cells do not (187). It is unclear whether CD56 (and KIR) expression on a given NK cell changes with activation state (188) or if two developmental lineages occur (13). Regardless, these observations indicate that KIR expression is intrinsically linked to the cytotoxic potential of an immune cell. CD56bri cells are scarce in the periphery but have been found in lymph nodes, where they may play a role in the adaptive immune response (189).
Disease Phenotypes and Molecular Medicine
KIR in Adaptive Immunity
KIR can be expressed by αβ- and γδ- T cells, and they appear to be characteristic of memory CD8+ T cells, through which they may modify the response to antigenic re-challenge (137, 190, 191). KIR expression appears to be inducible during early clonal expansion of T cells (192). KIR may also be important in the transition to a memory phenotype (183, 193). As the spectrum of response occurs during infection, including self-reactivity, the capacity for reactivation must be controlled. Inhibition of T cell activity by KIR may ensure that a secondary response only occurs when the danger is sufficiently strong. Moreover, expression of inhibitory KIR by T cells during an active response may help cytolytic T cells to remain focused on infected cells (137). T cells that acquire NK activating receptors may be harmful if they do not express appropriate inhibitory KIR (194). Conversely, T cells aberrantly expressing inhibitory KIR may not remove disease cells effectively (137).
KIR and Disease
Only a limited number of studies addressing genetic associations between KIR genes and specific diseases have been reported to date, primarily due to the very recent and ongoing characterization of the genes and their haplotypes. Natural killer cells have been implicated in the defense against infectious diseases, particularly viral infections, through mechanisms involving cytotoxicity and cytokine production (10), presumably mediated in part by stimulatory KIR molecules. Given the receptor–ligand relationship between certain combinations of KIR and HLA class I molecules, it is reasonable to hypothesize a synergistic relationship between these polymorphic loci that may ultimately regulate NK cell mediated immunity against infectious pathogens. Recently, we showed that 3DS1 in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile) resulted in delayed progression to AIDS after HIV infection (6). An additive genetic effect of the two loci was deemed unlikely on the basis that HLA-B Bw4-80Ile alleles in the absence of 3DS1 were not associated with AIDS progression, and 3DS1 in absence of HLA-B Bw4-80Ile was significantly associated with more rapid progression to AIDS. Thus, a model involving a protective epistatic interaction between 3DS1 and HLA-B Bw4-80Ile was proposed whereby 3DS1 receptors bind HLA-B Bw4-80Ile (perhaps when they contain HIV peptides), leading to NK cell activation and elimination of HIV-1 infected cells.
Natural selection for resistance to a pathogen can lead to the increase in frequency of alleles that are otherwise deleterious. The extensive diversity of KIR haplotypes might suggest the possibility of pleiotropic KIR effects on different diseases, whereby a KIR gene conferring protection against one disease may predispose to another, perhaps less deadly disease. Two studies have implicated stimulatory KIR genes in increased risk of developing specific autoimmune diseases (5, 119). In the first study, 2DS2 was significantly more prevalent amongst patients with rheumatoid vasculitis compared to either normal individuals or patients with rheumatoid arthritis, but no vasculitis (119, 194). CD4+CD28null T cells, as opposed to NK cells, that expressed 2DS2 were implicated in vascular damage possibly due to stimulatory effects of 2DS2. The second study reported increased susceptibility to developing psoriatic arthritis amongst individuals with 2DS1 and/or 2DS2, but only when HLA ligand for their homologous inhibitory receptors, 2DL1 and 2DL2 /3, were missing (5). The data suggested that absence of ligands for inhibitory KIRs could potentially lower the threshold for NK (and/or T) cell activation mediated through stimulatory receptors, thereby contributing to disease pathogenesis.
Genome-wide linkage studies of celiac disease have suggested that candidate susceptibility loci map to the region of 19q13.4 (5, 195). Using association analyses, Moodie et al. (196) showed no association between celiac disease and KIR haplotypes distinguished by the presence or absence of 2DL1, 2DL2, 2DL3 and 2DL5 that could account for the linkage studies. However, this does not rule out allelic variation at any of the loci.
2DL4 binds to HLA-G (122, 123), a nonclassical class I molecule that is expressed on the human trophoblast (197), and this receptor-ligand interaction may confer some protection against maternal NK or T cell-mediated rejection of the hemi-allogeneic fetus. Several alleles of 2DL4 have been identified, some of which are characterized by a single nucleotide deletion that results in the elimination of exon 6 during mRNA production (77), raising the possibility that 2DL4 alleles may vary in their ability to control fetus rejection. However, a study of 2DL4 allelic variation and KIR gene frequencies in 45 women who experienced pre-eclampsia compared to 48 normotensive controls indicated no significant differences between the two groups (91).
Recently, KIR molecules have been implicated in reduced risk of relapse in patients with acute myeloid leukemia (AML) who received hematopoietic transplants that were mismatched for KIR ligands (7, 198). KIR ligand incompatibility was defined as absence in recipients of donor class I allelic groups known to be ligands for inhibitory KIRs (3DL1, 2DL2 /3, 2DL1 and 3DL2). The data indicated that donor-versus-recipient NK cell alloreactivity was capable of eliminating leukemia relapse and graft rejection, and it also protected patients against graft-versus-host-disease.
KIR binding specificity for groups of HLA molecules raises the possibility that mechanisms responsible for HLA associations with some diseases may stem from interactions with KIR molecules on NK or T cells, and a limited number of studies have lent strong support to this hypothesis. Further delineation of the diversity at the KIR gene complex and development of efficient typing systems will surely foster disease association studies that are as plentiful and varied as those that have addressed the HLA loci.
We are very grateful to Gary Smythers and Pat Martin for alignment of the KIR cDNA sequences.
We would also like to thank Robert Vaughan and South Thames Clinical Transplantation Laboratory for support during the preparation of this article.
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Mary Carrington1 and Paul Norman2.
Created: May 28, 2003.
National Center for Biotechnology Information (US), Bethesda (MD)
Carrington M, Norman P. The KIR Gene Cluster. 2003 May 28. In: Carrington M, Norman P. The KIR Gene Cluster [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2003 May 28.