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At least 19 recordsLinked to original sources
PubMed1996

NK cell receptor gene of the KIR family with two IG domains but highest homology to KIR receptors with three IG domains.

The killer cell inhibitory receptors (KIRs) are surface glycoproteins expressed by natural killer (NK) cells and some T cells. They recognize polymorphic human HLA class I molecules. Two families of KIRs have been identified and named p58 and p70. The p58 family of genes encode type I membrane proteins with two extracellular immunoglobulin (Ig) domains, while the p70 genes have three Ig domains. We here report the cloning and characterization of a novel KIR cDNA obtained from tumor cell lines with NK reactivity (YT and NK-92). This gene is also expressed in the normal cell line NK 3.3 and in NK cells obtained from some but not all normal donors. The clone, KIR103AS, has an open reading frame consistent with a KIR with two extracellular Ig domains, a transmembrane region and a 114 amino acid long cytoplasmic domain containing a single src homology 2 (SH2) binding motif. The membrane distal Ig domain of KIR103AS has highest homology with the first Ig domain of p70 KIRs and differs significantly from the first Ig domain of p58 KIRs. The second, membrane proximal Ig domain of KIR103AS has similar and high homology with the membrane proximal Ig domains of both p70 and p58 KIRs. The extracellular domains of KIR103AS therefore share characteristic features with both p70 and p58 genes: the domain structure is identical to p58 KIRs but the sequence homology matches closely with p70 KIRs. The putative transmembrane and cytoplasmic domains are distinctly different from all previously reported KIR cDNAs.

Amino Acid Sequence↗
PubMed2006

Identification of a single killer immunoglobulin-like receptor (KIR) gene in the porcine leukocyte receptor complex on chromosome 6q.

Human killer immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and are involved in their immunoreactivity. While KIR with a long cytoplasmic tail deliver an inhibitory signal when bound to their respective major histocompatibility complex class I ligands, KIR with a short cytoplasmic tail can activate NK responses. The expansion of the KIR gene family originally appeared to be a phenomenon restricted to primates (human, apes, and monkeys) in comparison to rodents, which via convergent evolution have numerous C-type lectin-like Ly49 molecules that function analogously. Further studies have shown that multiple KIR are also present in cow and horse. In this study, we have identified by comparative genomics the first and possibly only KIR gene, named KIR2DL1, in the domesticated pig (Sus scrofa) allowing further evolutionary comparisons to be made. It encodes a protein with two extracellular immunoglobulin domains (D0 + D2), and a long cytoplasmic tail containing two inhibitory motifs. We have mapped the pig KIR2DL1 gene to chromosome 6q. Flanked by LILRa, LILRb, and LILRc, members of the leukocyte immunoglobulin-like receptor (LILR) family, on the centromeric end, and FCAR, NCR1, NALP7, NALP2, and GP6 on the telomeric end, pig demonstrates conservation of synteny with the human leukocyte receptor complex (LRC). Both the porcine KIR and LILR genes have diverged sufficiently to no longer be clearly orthologous with known human LRC family members.

Amino Acid Sequence↗
PubMed2000

The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster.

Natural killer (NK) immunoglobulin-like receptors (KIRs) are a family of polymorphic receptors which interact with specific motifs on HLA class I molecules and modulate NK cytolytic activity. In this study, we analyzed a recently sequenced subgenomic region on chromosome 19q13.4 containing eight members of the KIR receptor repertoire. Six members are clustered within a 100-kb continuous sequence. These genes include a previously unpublished member of the KIR gene family 2DS6, as well as 2DL1, 2DL4, 3DL1, 2DS4, 3DL2, from centromere to telomere. Two additional KIR genes, KIRCI and 2DL3, which may be located centromeric of this cluster were also analyzed. We show that the KIR genes have undergone repeated gene duplications. Diversification between the genes has occurred postduplication primarily as a result of retroelement indels and gene truncation. Using pre- and postduplication Alu sequences identified within these genes as evolutionary molecular clocks, the evolution and duplication of this gene cluster is estimated to have occurred 30-45 million years ago, during primate evolution. A proposed model of the duplication history of the KIR gene family leading to their present organization is presented.

Alleles↗
PubMed2005

Killer cell immunoglobulin-like receptors (KIR) of the African-origin sabaeus monkey: evidence for recombination events in the evolution of KIR.

Killer cell immunoglobulin (Ig)-like receptors (KIR) were characterized in the West African sabaeus monkey (Chlorocebus sabaeus) to elucidate the mechanism by which diversity evolves in this family of molecules. Complementary DNA encoding four forms of KIR molecules, including KIR3DL, KIR2DL4, KIR2DL5, and KIR3DH forms, were identified in two unrelated sabaeus monkeys. A novel hybrid form showing features found in both KIR2DL5 and KIR3DH was also identified. Both the KIR3DL and KIR3DH forms from the sabaeus monkey were considerably more polymorphic than any KIR form identified in great apes or humans. The polymorphic residues of the three Ig-like domains were frequently located in structural loops, indicating that point mutations have occurred in these regions. The three Ig-like domains of the KIR3D forms of six primate species were found to have different patterns of clustering in phylogenetic trees, suggesting that each Ig-like domain has a distinct phylogenetic history. This variation in relationships suggests that repeated recombination events have occurred between the Ig-like domains during the evolution of the KIR family in primates. Recombination between individual Ig-like domains, in addition to point mutations, provides a mechanism for generating the diversity of the KIR genes.

Amino Acid Sequence↗
PubMed2006

An improved RT-PCR method for the detection of killer-cell immunoglobulin-like receptor (KIR) transcripts.

Killer cell immunoglobulin-like receptors (KIRs) are expressed on human natural killer (NK) cells and a proportion of T cells. As the specificity of these NK and T cells is, at least in part, determined by the combination of KIRs they express, it is important to be able to determine the KIR expression pattern of NK and T cell clones to understand their function. However, for most KIR genes, specific reagents to detect expression are currently either unavailable or sensitive to allelic variations. In this study, a reverse transcriptase-polymerase chain reaction (RT-PCR) that uses new primer sets for the gene-specific detection of KIR transcripts is presented and validated. The key advantage of this RT-PCR method over previously published ones is that it was designed to detect transcripts of all confirmed allelic variants of the KIR genes, while remaining gene-specific.

Animals↗
PubMed1999

The cytoplasmic tail of killer inhibitory receptor (KIR) associates with TCR zeta in a phosphorylation-dependent manner.

Killer inhibitory receptor (KIR) inhibits cytolytic function of killer cells by specific interaction with class I MHC molecules. The inhibitory effect mediated by KIR requires co-engagement of KIR with an activating receptor, such as TCR or FcR. This implies that KIR may function in the immediate vicinity of activating molecules, and previous studies have shown that p58 KIR is associated with TCR zeta- and FcR gamma-chain in NK cells. To better understand the molecular interaction between KIR and TCR zeta-chain, we generated a His-tag fusion protein of a p70 KIR cytoplasmic tail (His-CytKIR) and used this protein to coprecipitate TCR zeta-chain from Jurkat T cells. Western blots of the resolved coprecipitates showed that the cytoplasmic tail of KIR associates with TCR zeta in vitro. Interestingly, the association between the His-CytKIR and TCR zeta was dependent on the phosphorylation of the His-CytKIR. Unlike the unphosphorylated His-CytKIR, the phosphorylated form no longer associated with TCR zeta. However, the association was not affected by the tyrosine phosphorylation of TCR zeta. These results suggest that the cytoplasmic tail of KIR may couple to TCR zeta in a phosphorylation-dependent manner, so it could fine-tune the activation signals induced via the TCR.

Humans↗
PubMed2006

Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter.

Variegated expression of inhibitory killer cell Ig-like receptors (KIRs) for MHC class I molecules helps NK cells distinguish normal from aberrant self and avoid autoreactivity. Prior studies of KIR promoters have produced conflicting results and no cis-acting sites have been independently confirmed. We took a comprehensive linker-scanning mutagenesis approach and substituted 24 consecutive 10-bp segments in the human KIR3DL1 promoter. Our analysis revealed eight segments that activated and three segments that repressed KIR transcription. Site-directed mutagenesis and electrophoretic mobility shift assays indicated that optimal KIR transcription requires a proximal Ets site that binds several Ets family members, a cAMP response element (CRE), a Runx site and a site that mediates complex interactions between Ets family members, signal transducer and activator of transcription 5 (STAT5) and YY1; Sp1 also contributes to KIR transcription. KIR transcription was greatly reduced by several compound mutations and was abrogated by a combination of mutations that affected the proximal Ets site, and the CRE, Runx, Sp1 and Ets/STAT sites. The many transcription factors that contribute to KIR transcription are partially redundant in the setting of transient transfection assays, helping to explain why only 0-2 activating sites had been reported in each of three prior studies. We propose that the multiplicity of transcription factors enables NK cells to sustain continuous KIR expression in diverse cellular and cytokine milieus, thus preventing NK autoreactivity.

Base Sequence↗
PubMed2002

Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family.

The killer cell immunoglobulin-like receptors (KIR) form a family of highly homologous immune receptors that regulate the response of natural killer (NK) cells and some T cells. The genetics of the human KIR family is reviewed in this article. In human populations, diversity in KIR genotype arises from variations in gene content and allelic polymorphism. Comparisons of 81 human KIR sequences reveal past events ofgene duplication and recombination, and indicate that individual KIR genes have diversified from the influence of natural selection. Comparison and compilation of population studies reveal extensive KIR genotype variability within human populations and among them. Genomic analysis shows the KIR genes to be close to each other and separated by homologous sequences that promote haplotype diversification through assymetric recombination. In contrast, homologous recombination appears favored at a unique sequence in the center of the KIR locus, and much haplotypic diversity can be explained by recombination between a limited number of gene-content motifs in the centromeric and telomeric halves of the locus. The importance of NK cells for early defenses against infection suggests that human KIR genotype diversity is the accumulated consequence of a history of numerous and successive selective episodes by different pathogens on human NK-cell responses.

Evolution, Molecular↗
PubMed2006

Killer cell immunoglobulin-like receptor (KIR) genes in the Basque population: association study of KIR gene contents with type 1 diabetes mellitus.

Killer cell immunoglobulin-like receptors (KIR) form a group of regulatory molecules that specifically recognize HLA class I molecules, modulating cytolytic activity of natural killer cells. The number of KIR genes can vary between individuals, significant allelic variations have been described, and KIR genes are organized in a complex and heterogeneous family. In the present study we have performed KIR genotype analysis in the Basque general population. Additionally, we have tested the possible association between KIR gene content (in combination with its HLA ligand) and type 1 diabetes mellitus (T1DM). KIR genotyping was performed using a commercial sequence-specific primer amplification genotyping kit and amino acid position 80 of HLA-C was genotyped by specific amplification and direct sequencing. Haplotypes and genotypes were deduced based on previous studies, and frequencies were compared between disease and control groups. All KIR genes tested were present in Basques and several of these genes (KIR2DS5, KIR3DS1, and KIR2DL2) displayed significant differences from corresponding genes in other Caucasoid populations. In general, Basques present an increase in activating KIR gene frequency and, consequently, the proportion of B haplotypes is higher. Three novel haplotypes were identified in the Basque population. Overall, our results confirm the particular genetic characteristics of the Basque population. No association between KIR gene content and susceptibility to T1DM was observed.

Diabetes Mellitus, Type 1↗
PubMed2005

Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates.

The human killer immunoglobulin-like receptors (KIR) are encoded within the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4. Here we report the comparative genomic analysis of single KIR haplotypes in two other primates. In the common chimpanzee (Pan troglodytes), seven KIR genes (ptKIRnewI, ptKIRnewII, ptKIR2DL5, ptKIRnewIII, ptKIR3DP1, ptKIR2DL4, ptKIR3DL1/2) have been identified, and five KIR genes (mmKIRnewI, mmKIR1D, mmKIR2DL4, mmKIR3DL10, mmKIR3DL1) are present in the haplotype sequenced for the rhesus macaque (Macaca mulatta). Additional cDNA analysis confirms the genes predicted from the genomic sequence and reveals the presence of a fifth novel KIR gene (mmKIRnewII) in the second haplotype of the rhesus macaque. While all known human haplotypes contain both activating and inhibitory KIR genes, only inhibitory KIR genes (characterized by long cytoplasmic tails) were found by in silico and cDNA analyses in the two primate haplotypes studied here. Comparison of the two human and the two non-human primate haplotypes demonstrates rapid diversification of the KIR gene family members, many of which have diverged in a species-specific manner. An analysis of the intronic regions of the two non-human primates reveals the presence of ancient repeat elements, which are indicative of the duplication events that have taken place since the last common ancestor.

Amino Acid Sequence↗
PubMed2005

Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3.

The generation of killer cell Ig-like receptor (KIR) expression patterns in NK cells involves variegated silencing of KIR genes by DNA methylation. To identify regulatory elements involved in KIR gene activation, upstream regions of KIR genes were functionally characterized in NK3.3 cells as well as in primary NK cells. Three kinds of KIR promoters were defined, controlling clonally expressed KIR genes, the constitutively active KIR2DL4, and the weakly expressed KIR3DL3. Upstream of a short core promoter common to all KIR genes, a region containing functionally divergent elements was characterized. Although this region had no impact on the activity of the KIR2DL3 promoter, an inhibitory element was identified in the KIR2DL4 promoter and an activating element was found in the KIR3DL3 promoter. Upon treatment with a methyltransferase inhibitor, KIR3DL3 expression could be readily induced showing that the low levels of KIR3DL3 expression in peripheral blood are due to sustained DNA methylation of an otherwise fully functional promoter. Analysis of transcription factor binding sites identified a functional acute myeloid leukemia (AML) site common to all three KIR promoters. Mutation of this site led to a substantial increase in activity of all KIR promoters. Among the different members of the AML family, AML-2 was identified as the predominant KIR binding factor. The present study suggests that AML-2 acts as a repressor of KIR expression in mature NK cells and opens the possibility that AML factors and associated cofactors are involved in regulation of KIR expression during NK cell development.

Binding Sites↗
PubMed2001

Cloning of rhesus monkey killer-cell Ig-like receptors (KIRs) from early pregnancy decidua.

To define the killer-cell Ig-like receptors (KIR) molecules expressed within the decidua in the rhesus monkey, an early pregnancy rhesus decidual library was screened with an oligonucleotide located within the KIR D2 domain. We obtained 26 full-length clones which represented 11 mRNAs. The cDNAs encode proteins containing 2 or 3 Ig domains, and short or long cytoplasmic domains. The long domains contained immunotyrosine inhibitory motifs (ITIM) motifs indicating inhibitory function. Three clones contained single or dinucleotide deletions within the D1 domain, which would result in proteins truncated within this domain. Phylogenetic analysis of the Ig domains supports a D0 - D2 organization of rhesus KIR2DL4.1, similar to human KIR2DL4 and KIR2DL5. The rhesus KIR2DL4.1 transcript contains a long cytoplasmic tail homologous with human KIR2DL4.

Amino Acid Motifs↗
PubMed2006

Receptor-ligand analyses define minimal killer cell Ig-like receptor (KIR) in humans.

Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and human leukocyte antigen (HLA) class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR receptors and HLA class I ligands and their independent segregation results in a variable number and type of iKIR + HLA pairs inherited in individuals. The diversity in the co-inheritance of iKIR + HLA pairs and activating KIR (aKIR) genes in 759 unrelated individuals from four ethnic populations was analyzed. Every individual studied inherited a minimum of one iKIR + HLA pair; suggesting that major histocompatibility complex class I-dependent inhibitory KIR signaling is essential for human NK cell function. In contrast, 13.4% of the study group lacked all aKIR genes. Twenty percent of the study group carried only one of the four iKIR + HLA pairs. Interestingly, 3% of the study group carrying only KIR2DL3 + HLA-C1 as an iKIR + HLA pair lacked aKIR genes. These data suggest that a single iKIR can constitute the minimal KIR repertoire for human NK cells. Genotypes carrying an equal number of iKIR + HLA pairs and aKIR genes represented 20% of the study group. The remaining individuals had either a dominant inhibitory KIR genotype (iKIR + HLA > aKIR) or a dominant activating KIR genotype (iKIR + HLA < aKIR). Genotypes encoding these imbalanced inhibitory and activating interactions may contribute to susceptibility or resistance to human diseases.

Epitope Mapping↗
PubMed2006

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility.

Killer immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and some T-cell subsets and produce either activation or inhibitory signals upon binding with the appropriate human leucocyte antigen (HLA) ligand on target cells. Recent genetic association studies have implicated KIR genotype in the development of several inflammatory conditions. Ulcerative colitis (UC) is an inflammatory disorder of the colonic mucosa that results from an inappropriate activation of the immune system driven by host bacterial flora. We developed a polymerase chain reaction-sequence specific primer (SSP)-based assay to genotype 194 UC patients and 216 control individuals for 14 KIR genes, the HLA-Cw ligand epitopes of the KIR2D receptors and a polymorphism of the lectin-like-activating receptor NKG2D. Initial analysis found the phenotype frequency of KIR2DL2 and -2DS2 to be significantly increased in the UC cohort (P=0.030 and 0.038, respectively). Logistic regression analysis revealed a protective effect conferred by KIR2DL3 in the presence of its ligand HLA-Cw group 1 (P=0.019). These results suggest that KIR genotype and HLA ligand interaction may contribute to the genetic susceptibility of UC.

Base Sequence↗
PubMed2002

The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism.

Recent genetic studies have established that the killer cell immunoglobulin-like receptor (KIR) genomic region displays extensive diversity through variation in gene content and allelic polymorphism within individual KIR genes. It is demonstrated by family segregation analysis, genomic sequencing, and gene order determination that genomic diversity by gene content alone gives rise to more than 20 different KIR haplotypes and at least 40-50 KIR genotypes. In the most reductionist format, KIR haplotypes can be accommodated within one of 10 different prototypes, each with multiple permutations. Our haplotype model considers the KIR haplotype as two separate halves: the centromeric half bordered upstream by KIR3DL3 and downstream by 2DL4, and the telomeric half bordered upstream by 2DL4 and downstream by 3DL2. There are rare KIR haplotypes that do not fit into this model. Recombination, gene duplication, and inversion can however, readily explain these haplotypes. Additional allelic polymorphism imposes extensive individual variability. Accordingly, this segment of the human genome displays a level of diversity similar to the one observed for the human major histocompatibility complex. Recent application of immunogenetic analysis of KIR genes in patient populations implicates these genes as important genetic disease susceptibility factors.

Alleles↗
PubMed2002

Natural killer cell immunoglobulin-like receptor (KIR) locus profiles in African and South Asian populations.

Natural killer (NK) and some T cells express killer cell immunoglobulin-like receptors (KIRs), which interact with HLA class I expressed by target cells and consequently regulate cytolytic activity. The number of KIR loci can vary and so a range of genetic profiles is observed. We have determined the KIR genetic profiles from one African (n = 62) and two South Asian (n = 108, n = 78) populations. Several of the KIRs are present at significantly different frequencies between the two major ethnic groups (eg KIR2DS4 gene frequency 0.82 African, 0.47 S Asian. Pc < 1 x 10(-6)) and this is due to uneven distribution of two KIR haplotype families 'A' and 'B'. All three populations described here displayed a greater degree of diversity of KIR genetic profiles than other populations investigated, which indicates further complexity of underlying haplotypes; in this respect we describe two individuals who appear homozygous for a large deletion including the previously ubiquitous 2DL4. We have also reanalysed three populations that we studied previously, for the presence of a KIR which is now known to be an indicator of the 'B' haplotype. South Asians had the highest overall frequencies of all KIR loci characteristic of 'B' haplotypes (Pc < 0.0001 to < 0.004). Furthermore, gene frequency independent deviances in the linkage disequilibrium were apparent between populations.

Africa, Western↗
PubMed1998

Nucleotide and amino acid sequence alignment for human killer cell inhibitory receptors (KIR), 1998.

We present alignments of nucleotide sequences and deduced amino acid sequences for all currently identified killer cell inhibitory receptors (KIR). The genes for these receptors have been localized to human chromosome 19q13.4 and constitute a large gene family. They all encode structures typical of type I transmembrane molecules belonging to the immunoglobulin superfamily (Ig-SF). Extensive polymorphism exists within the genes and many of the currently identified cDNA clones represent alternatively spliced forms of previously reported full-length clones. The sequence alignments have been posted on the World Wide Web and are accessible at the Tissue Antigens web site at: http://www.tissue-antigens.dk/kir-align.html. The alignments will be updated at intervals.

Amino Acid Sequence↗
PubMed2000

Altered expression of natural killer cell inhibitory receptors (KIRs) on T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients.

BACKGROUND AND AIM OF THE WORK: The role for natural killer cell inhibitory receptors (KIRs) on T cells is not fully understood, but signalling through KIRs on T cells may inhibit T cell receptor mediated activation, and KIR expression has been suggested to be one mechanism of controlling T cell mediated immune responses. An aberrant KIR expression on T cells could thus be of importance in autoimmune as well as infectious disorders. Sarcoidosis patients have several immunological impairments that have not been clarified, and we here examined the KIR expression on CD4+ and CD8+ peripheral blood (PBL) and bronchoalveolar lavage (BAL) T cells of sarcoidosis patients and controls. METHODS: We used three KIR specific monoclonal antibodies, namely DX9 (specific for p70), DX27 (p58) and DX22 (specific for CD94, that belongs to another major group of KIRs) and flow cytometry. RESULTS: p70 was expressed lower in patient CD8+ PBL (median 2.3%) compared to controls (6.3%) (p < 0.01). In patients, p58 was expressed by less CD8+ BAL lymphocytes (median 1.2%) compared to PBL (6.8%) (p < 0.01) while CD94 was expressed by more CD8+ BAL lymphocytes (median 14.5%) compared to PBL (9.6%) (p < 0.01). Moreover, in CD8+ PBL, CD94 and p58 were expressed significantly lower in patients with an active vs. inactive disease, and in patients with chest radiographic stage I vs. stage II, respectively. CONCLUSIONS: The significantly altered expression of distinct KIRs on CD8+ T cells in sarcoidosis, especially in patients with signs of an active disease, indicate these cells to be dysregulated and implicate them in the pathogenesis of the disease.

Adult↗