Journal articles on the topic 'Killer immunoglobulin-like receptor (KIR)'
To see the other types of publications on this topic, follow the link: Killer immunoglobulin-like receptor (KIR).
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Killer immunoglobulin-like receptor (KIR).'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Harvey, D., J. J. Pointon, C. Sleator, A. Meenagh, C. Farrar, J. Y. Sun, D. Senitzer, D. Middleton, M. A. Brown, and B. P. Wordsworth. "Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis." Annals of the Rheumatic Diseases 68, no. 4 (November 19, 2008): 595–98. http://dx.doi.org/10.1136/ard.2008.095927.
Full textAbstract:
Objectives:To assess the possible association of killer immunoglobulin-like receptor (KIR) genes, specifically KIR3DL1, KIR3DS1 and KIR3DL2, with ankylosing spondylitis (AS).Methods:14 KIR genes were genotyped in 200 UK patients with AS and 405 healthy controls using multiplex polymerase chain reaction. Sequence-specific oligonucleotide probes were used to subtype 368 cases with AS and 366 controls for 12 KIR3DL2 alleles. Differences in KIR genotypes and KIR3DL2 allele frequencies were assessed using the χ2 test.Results:KIR3DL1 and KIR3DS1 gene frequencies were very similar in cases with AS and controls (odds ratio = 1.5, 95% confidence interval 0.8 to 3.0, and odds ratio = 1.02, 95% confidence interval 0.2 to 5.3, respectively). KIR3DL2 allele frequencies were not significantly different between cases with AS and controls.Conclusions:Neither the KIR gene content of particular KIR haplotypes nor KIR3DL2 polymorphisms contribute to AS.
2
Treanor, Bebhinn, Peter M. P. Lanigan, Sunil Kumar, Chris Dunsby, Ian Munro, Egidijus Auksorius, Fiona J. Culley, et al. "Microclusters of inhibitory killer immunoglobulin–like receptor signaling at natural killer cell immunological synapses." Journal of Cell Biology 174, no. 1 (June 26, 2006): 153–61. http://dx.doi.org/10.1083/jcb.200601108.
Full textAbstract:
We report the supramolecular organization of killer Ig–like receptor (KIR) phosphorylation using a technique applicable to imaging phosphorylation of any green fluorescent protein–tagged receptor at an intercellular contact or immune synapse. Specifically, we use fluorescence lifetime imaging (FLIM) to report Förster resonance energy transfer (FRET) between GFP-tagged KIR2DL1 and a Cy3-tagged generic anti-phosphotyrosine monoclonal antibody. Visualization of KIR phosphorylation in natural killer (NK) cells contacting target cells expressing cognate major histocompatibility complex class I proteins revealed that inhibitory signaling is spatially restricted to the immune synapse. This explains how NK cells respond appropriately when simultaneously surveying susceptible and resistant target cells. More surprising, phosphorylated KIR was confined to microclusters within the aggregate of KIR, contrary to an expected homogeneous distribution of KIR signaling across the immune synapse. Also, yellow fluorescent protein–tagged Lck, a kinase important for KIR phosphorylation, accumulated in a multifocal distribution at inhibitory synapses. Spatial confinement of receptor phosphorylation within the immune synapse may be critical to how activating and inhibitory signals are integrated in NK cells.
3
Castrillon, Marlon, Nancy D. Marin, Amado J. Karduss-Urueta, Sonia Y. Velasquez, and Cristiam M. Alvarez. "Killer-Cell Immunoglobulin-like Receptor Diversity in an Admixed South American Population." Cells 11, no. 18 (September 6, 2022): 2776. http://dx.doi.org/10.3390/cells11182776.
Full textAbstract:
Natural Killer (NK) cells are innate immune cells that mediate antiviral and antitumor responses. NK cell activation and induction of effector functions are tightly regulated by the integration of activating and inhibitory receptors such as killer immunoglobulin-like receptors (KIR). KIR genes are characterized by a high degree of diversity due to presence or absence, gene copy number and allelic polymorphism. The aim of this study was to establish the distribution of KIR genes and genotypes, to infer the most common haplotypes in an admixed Colombian population and to compare these KIR gene frequencies with some Central and South American populations and worldwide. A total of 161 individuals from Medellin, Colombia were included in the study. Genomic DNA was used for KIR and HLA genotyping. We analyzed only KIR gene-content (presence or absence) based on PCR-SSO. The KIR genotype, most common haplotypes and combinations of KIR and HLA ligands frequencies were estimated according to the presence or absence of KIR and HLA genes. Dendrograms, principal component (PC) analysis and Heatmap analysis based on genetic distance were constructed to compare KIR gene frequencies among Central and South American, worldwide and Amerindian populations. The 16 KIR genes analyzed were distributed in 37 different genotypes and the 7 most frequent KIR inferred haplotypes. Importantly, we found three new genotypes not previously reported in any other ethnic group. Our genetic distance, PC and Heatmap analysis revealed marked differences in the distribution of KIR gene frequencies in the Medellin population compared to worldwide populations. These differences occurred mainly in the activating KIR isoforms, which are more frequent in our population, particularly KIR3DS1. Finally, we observed unique structural patterns of genotypes, which evidences the potential diversity and variability of this gene family in our population, and the need for exhaustive genetic studies to expand our understanding of the KIR gene complex in Colombian populations.
4
Diaz-Peña, Roberto, Patricia Mondelo-Macía, Antonio José Molina de la Torre, Rebeca Sanz-Pamplona, Víctor Moreno, and Vicente Martín. "Analysis of Killer Immunoglobulin-Like Receptor Genes in Colorectal Cancer." Cells 9, no. 2 (February 24, 2020): 514. http://dx.doi.org/10.3390/cells9020514.
Full textAbstract:
Natural killer cells (NK cells) play a major role in the immune response to cancer. An important element of NK target recognition is the binding of human leucocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). Colorectal carcinoma (CRC) is one of the most common types of inflammation-based cancer. The purpose of the present study was to investigate the presence of KIR genes and HLA class I and II alleles in 1074 CRC patients and 1272 controls. We imputed data from single-nucleotide polymorphism (SNP) Illumina OncoArray to identify associations at HLA (HLA–A, B, C, DPB1, DQA1, DQB1, and DRB1) and KIRs (HIBAG and KIR*IMP, respectively). For association analysis, we used PLINK (v1.9), the PyHLA software, and R version 3.4.0. Only three SNP markers showed suggestive associations (p < 10−3; rs16896742, rs28367832, and rs9277952). The frequency of KIR2DS3 was significantly increased in the CRC patients compared to healthy controls (p < 0.005). Our results suggest that the implication of NK cells in CRC may not act through allele combinations in KIR and HLA genes. Much larger studies in ethnically homogeneous populations are needed to rule out the possible role of allelic combinations in KIR and HLA genes in CRC risk.
5
Jelčić, Ilijas, Katharine C. Hsu, Kristina Kakalacheva, Petra Breiden, Bo Dupont, Markus Uhrberg, Roland Martin, Christian Münz, and Jan D. Lünemann. "Killer immunoglobulin-like receptor locus polymorphisms in multiple sclerosis." Multiple Sclerosis Journal 18, no. 7 (December 20, 2011): 951–58. http://dx.doi.org/10.1177/1352458511431726.
Full textAbstract:
Objective: The objective of this study was to analyze whether inhibitory and activating killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I alleles defined by their KIR binding motifs are associated with multiple sclerosis (MS) susceptibility or severity. Method: We performed a population-based case–control study in 321 patients with clinically isolated syndrome (CIS) and clinically definite MS (CDMS) and 156 healthy blood donors (HD). Inhibitory and activating KIRs and HLA class I alleles were genotyped using polymerase chain reaction (PCR) sequence-specific primers. Allelic frequencies were correlated with prevalence, age of onset, disability and disease duration of CIS and CDMS. Results: The frequency of the inhibitory KIR2DL3 gene was significantly reduced in patients with CIS and CDMS ( p = 3.1 × 10−5). KIR2DL3-dependent risk reduction remained significant after elimination of patients carrying MS-associated DRB1*15, DRB1*03, DRB1*01 alleles. In addition, individuals carrying two copies for KIR2DL2/KIR2DS2 but lacking KIR2DL3 were overrepresented in the CIS/CDMS cohort. However, both genes did not affect disease risk in presence of KIR2DL3. We did not detect any association between the presence or absence of KIR genes with clinical disease parameters. Conclusion: Absence of the inhibitory KIR2DL3 gene is associated with the development of CIS/CDMS. These findings, if confirmed in larger cohorts, suggest that KIR-mediated recognition of HLA class I molecules should be further explored as potential disease mechanism in MS.
6
Marsh, S. G. E., P. Parham, B. Dupont, D. E. Geraghty, J. Trowsdale, D. Middleton, C. Vilches, et al. "Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002." Tissue Antigens 62, no. 1 (July 2003): 79–86. http://dx.doi.org/10.1034/j.1399-0039.2003.00072.x.
Full text
7
Marsh, S. G. E., P. Parham, B. Dupont, D. E. Geraghty, J. Trowsdale, D. Middleton, C. Vilches, et al. "Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002." European Journal of Immunogenetics 30, no. 3 (June 2003): 229–34. http://dx.doi.org/10.1046/j.1365-2370.2003.00383.x.
Full text
8
Marsh, Steven G. E., Peter Parham, Bo Dupont, Daniel E. Geraghty, John Trowsdale, Derek Middleton, Carlos Vilches, et al. "Killer-cell Immunoglobulin-like Receptor (KIR) Nomenclature Report, 2002." Human Immunology 64, no. 6 (June 2003): 648–54. http://dx.doi.org/10.1016/s0198-8859(03)00067-3.
Full text
9
Marsh, Steven G. E., Peter Parham, Bo Dupont, Daniel E. Geraghty, John Trowsdale, Derek Middleton, Carlos Vilches, et al. "Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002." Immunogenetics 55, no. 4 (July 1, 2003): 220–26. http://dx.doi.org/10.1007/s00251-003-0571-z.
Full text
10
Cremer, Anja, Ute Heider, Stefan Tomiuk, Andreas Arendt, Jurgen Schmitz, Andreas Bosio, Volker Huppert, and Christian Biervert. "Integrated Genotyping and mRNA Expression Profiling of Killer Immunoglobulin-Like Receptors." Blood 106, no. 11 (November 16, 2005): 3909. http://dx.doi.org/10.1182/blood.v106.11.3909.3909.
Full textAbstract:
Abstract Natural killer (NK) cells belong to a subgroup of lymphocytes (CD3-CD56+) which play an important role in the cellular immune response against virus-infected cells and tumors. The activity of NK cells is regulated by a balance of triggering and inhibitory receptors, including Killer Ig-like Receptor (KIR) molecules which interact with specific HLA class I molecules, predominantly HLA-C, on target cells. The 17 known KIR genes are divided into two classes: activating KIRs and inhibitory KIRs. There is strong evidence that inhibitory KIR mismatch between donor and recipient improves the outcome of haploidentical hematopoietic stem cell transplantation (HSTC) in leukemia patients (Ruggeri et al. 2002). In addition, the KIR-HLA constellation is assumed to have an influence on the severity of graft versus host disease (GvHD). Whether these activities of NK cells are clinically important and to what extent these processes are mediated only by KIR-HLA class I interactions remains to be determined. In human populations, KIR gene haplotypes vary in the number and type of KIR genes they contain. Further diversification is observed by expanded allelic polymorphism at the individual genes. In general, KIR haplotypes contain 7–12 genes plus 2 pseudogenes. Extra KIR heterogeneity is provided at the expression level: different subsets of NK cells within an individual express different KIRs. Recently, it was shown that KIR genotyping alone does not seem to be sufficient for donor KIR assessment because of the lack of gene expression in approximately one-fourth of the individuals for one of the inhibitory KIRs that recognize the three major groups of MHC class I ligands (Leung et al. 2005). KIR phenotyping by flow cytometry using monoclonal antibodies is insufficient due to the lack of specific monoclonal antibodies. For trustworthy analysis, one has to combine KIR genotyping with mRNA expression profiling and flow cytometry. Therefore, we developed a new set of sequence-specific primers (SSP). This primer set can be applied to perform either KIR genotyping or mRNA expression profiling despite the high degree of identity of the genes (80–90%, sometimes more than 95%). The primers of each KIR gene (15 genes and 2 pseudogenes) cover all allelic variants annotated by the IPD KIR Sequence Data Base (status quo July 05). Using this primer set, we genotyped 25 individuals, and compared the results with other sets of KIR primers published elsewhere. Additionally, we show the mRNA expression profile employing the same set of new primers. We confirmed these results on the protein level by flow cytometry.
11
Li, Guangjin, Mingcan Yu, Cornelia M. Weyand, and Jörg J. Goronzy. "Epigenetic regulation of killer immunoglobulin–like receptor expression in T cells." Blood 114, no. 16 (October 15, 2009): 3422–30. http://dx.doi.org/10.1182/blood-2009-01-200170.
Full textAbstract:
Abstract With increasing age, T cells gain expression of killer immunoglobulin–like receptors (KIRs) that transmit negative signals and dampen the immune response. KIR expression is induced in CD4 and CD8 T cells by CpG DNA demethylation suggesting epigenetic control. To define the mechanisms that underlie the age-associated preferential KIR expression in CD8 T cells, we examined KIR2DL3 promoter methylation patterns. With age, CD8 T cells developed a patchy and stochastic promoter demethylation even in cells that did not express the KIR2DL3-encoded CD158b protein; complete demethylation of the minimal KIR2DL3 promoter was characteristic for CD158b-expressing cells. In contrast, the promoter in CD4 T cells was fully methylated irrespective of age. The selectivity for CD8 T cells correlated with lower DNMT1 recruitment to the KIR2DL3 promoter which further diminished with age. In contrast, binding of the polycomb protein EZH2 known to be involved in DNMT1 recruitment was not different. Our data suggest that CD8 T cells endure increasing displacement of DNMT1 from the KIR promoter with age, possibly because of an active histone signature. The ensuing partial demethylation lowers the threshold for transcriptional activation and renders CD8 T cells more susceptible to express KIR, thereby contributing to the immune defect in the elderly.
12
Hidajat, Melanny, Dominik Selleslag, Achiel Van Hoof, Jan Van Droogenbroeck, Johan Billiet, and Arnold Criel. "Killer Immunoglobulin-Like Receptors (KIRs) Genotypes in a Belgian Population." Blood 104, no. 11 (November 16, 2004): 3852. http://dx.doi.org/10.1182/blood.v104.11.3852.3852.
Full textAbstract:
Abstract KIRs (Killer cell Immunoglobulin-like Receptors) are expressed on NK (Natural Killer) cells and a subpopulation of T lymphocytes namely memory CD8+ T cells. The distribution of KIR genes varies among individuals and populations. These genes are encoded on chromosome 19 (19q13.4). Till now 17 KIR genes and pseudogenes have been identified. KIRs recognise groups of HLA class I alleles. NK activity is partially controlled through the interaction between KIRs and their HLA ligands. Several studies report that KIRs may affect the outcome of Hematopoietic Stem-Cell Transplantations. We performed KIR typing of 17 genes and pseudogenes in 100 healthy Belgian unrelated individuals in “West-Vlaanderen” from Caucasoid origin using a PCR-SSP method. Three genes (KIR3DL3, 2DL4 and 3DL2), named frame-work genes, and the pseudogene 3DP1 were found in all individuals. KIR2DL1 and 2DP1 genes were present in a frequency of 99%. In addition, KIR3DL1 and 2DS4 genes represented a frequency of 97. The KIR2DL3 was found in 90% and the frequencies of other genes varied between 56% and 24%. The individual KIR gene content ranged from 8 to 17 genes. A total of 19 KIR locus profiles was observed. The most common KIR locus profile (32%) consisted of a combination of genes characterising A haplotypes (KIR2DL1 and 2DL3) without the presence of genes characteristic of B haplotypes (KIR2DL2 and 2DS2). The second most common KIR locus profile, accounting for 20% contained a combination of genes characteristics for both A and B haplotypes. The allele KIR2DS4*003 was found in 89% and KIR2DS4*00101/00102/002 only in 41%. KIR3DP1*00301/00302 was present in all individuals and KIR3DP1*001/002 only in 35%. Our results show that frequencies of most KIR loci in our Belgian population were comparable to literature data of other Caucasian populations. Only KIR2DS1 was lower (27% vs 47.7% with a p-value of 0.0002). In the future, KIR typing of donor and patient before a Hematopoietic Stem-cell Transplantation may be necessary, due to the diversity in KIR genotypes.
13
Varbanova, V., S. Mihaylova, E. Naumova, C. Cotoc, and A. Mihaylova. "Family-based Association Study of Killer Cell Immunoglobulin-Like Receptor Genes with Leukemia." Acta Medica Bulgarica 46, no. 3 (October 1, 2019): 10–17. http://dx.doi.org/10.2478/amb-2019-0023.
Full textAbstract:
Abstract NK cell function is controlled by the cell expression of killer immunoglobulin-like receptors (KIRs) and their ligation with the corresponding HLA ligands. Various malignancies have been associated with certain KIRs surface cell expression and various KIR/HLA ligand combinations. Prior research using case/control study design demonstrates the role of KIR and KIR HLA ligands as genetic factor involved in tumor susceptibility. The objective of this study was to investigate the family-based association of KIRs, HLA class I ligands and KIR/ligand combinations with leukemia diagnosis in families having a leukemia diagnosed child. Sixty-seven families that met the index leukemia case criteria (acute lymphoblastic leukemia, ALL, n = 45; acute myeloid leukemia, AML, n = 13; chronic myeloid leukemia, CML, n = 9; first degree healthy relatives n = 159) were examined. Our study consisted of two phases. In Phase1 case-control study, we primarily compared patients to their healthy siblings to asses if a marker or genotype may be associated with leukemia, excluding the impact of the environment. Phase 2 consisted of a secondary family-based association study. KIR genotyping was performed by PCR-SSP method. KIR HLA ligands were defined by direct method using PCR-SSP method and/or indirect base on high resolution typing of HLA-A, -B, -C alleles. Results of phase 1 showed an increase in the frequency of KIR genotype (with a ratio = 0.57; higher frequency for inhibitory KIRs vs. activating KIRs) among leukemia patients compared to healthy siblings. Results of the phase 2 familial study observed an association between HLA-C1+/BBw4+/ABw4+ haplotype (a mediator of inhibitory signals) and leukemia. Also, we concluded that the absence of HLA-ABw4 alleles was related to leukemia development.
14
Parham, Peter, Paul J. Norman, Laurent Abi-Rached, and Lisbeth A. Guethlein. "Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules." Philosophical Transactions of the Royal Society B: Biological Sciences 367, no. 1590 (March 19, 2012): 800–811. http://dx.doi.org/10.1098/rstb.2011.0266.
Full textAbstract:
In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity—combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands—drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species.
15
Cichocki, Frank, Todd Lenvik, Stephen K. Anderson, and Jeffrey S. Miller. "Antisense Transcripts Negatively Regulate Transcription of Multiple Variegated Killer Immunoglobulin-Like Receptor (KIR) Genes." Blood 112, no. 11 (November 16, 2008): 105. http://dx.doi.org/10.1182/blood.v112.11.105.105.
Full textAbstract:
Abstract Natural killer cells are CD3 negative large granular lymphocytes that lyse virally infected and malignantly transformed targets. NK cell functions are regulated by an array of inhibitory and activating receptors, including members of the killer immunoglobulin-like receptor (KIR) family. Human KIR genes are expressed in a variegated and clonally restricted manner on the surface of mature NK cells. While it is well established that individual KIR gene expression is strongly correlated with the DNA methylation status of CpG dinucleotides within the promoter region proximal to the transcriptional start site, the mechanisms that regulate variegated KIR expression are largely unknown. Our goal is to uncover the genetic mechanisms governing KIR transcriptional regulation. We have recently identified an active distal promoter element approximately 1 Kb upstream of the transcriptional start site. This region contains c-MYC binding sites, and KIR expression is increased when MYC is overexpressed in developing NK cells or when c-MYC is physiologically increased by IL-15 activation. Bi-directional promoter activity is found within the previously characterized proximal promoter of all KIR genes. Therefore, double-stranded RNA with homology to the KIR promoter can be generated within this non-coding region. The generation of double-stranded RNA has recently been shown to contribute to promoter DNA methylation of the p15 gene in mammalian cells through a Dicer-independent mechanism. Using quantitative real-time PCR, we found that purified peripheral blood CD56+/KIR3DL1− NK cells express 5-fold more KIR3DL1 antisense transcript than purified CD56+/KIR3DL1+ cells. Therefore, the transcriptional activation of the KIR3DL1 gene correlates with a significant decrease in KIR3DL1 antisense expression. To explore the possibility that KIR antisense transcripts can silence KIR expression, we over-expressed the KIR3DL1 antisense transcript in CD34+ hematopoietic precursor cells and differentiated these cells into NK cells in vitro. After 21 days in culture, we assayed KIR3DL1 mRNA levels using quantitative real-time PCR. KIR3DL1 expression was reduced 4-fold compared to eGFP control cultures, further supporting the hypothesis that antisense transcripts negatively regulate KIR expression. Importantly, expression of the KIR2DL4 gene, which does not contain a promoter with significant homology to KIR3DL1 promoter, was not affected by KIR3DL1 antisense overexpression. This provides the first evidence for gene silencing through double-stranded RNA in the immune system and may be the key mechanism for the establishment of DNA promoter methylation within the KIR locus. Understanding the mechanisms of KIR expression, a requisite for NK cell education/licensing, may allow us to understand the acquisition of effector function and manipulate it for therapeutic benefit.
16
Salim, P. H., M. Jobim, M. Bredemeier, J. A. B. Chies, J. Schlottfeldt, J. C. T. Brenol, L. F. Jobim, and R. M. Xavier. "Killer cell immunoglobulin-like receptor (KIR) genes in systemic sclerosis." Clinical & Experimental Immunology 160, no. 3 (January 15, 2010): 325–30. http://dx.doi.org/10.1111/j.1365-2249.2010.04095.x.
Full text
17
Obama, Kosuke, Yoshitaka Furukawa, Mitsutoshi Tara, Sara Marshall, Alison Levoguer, Mineki Saito, Charles Bangham, and Mitsuhiro Osame. "Killer Cell Immunoglobulin-Like Receptor Genotype and HTLV-1 Associated Disease’s Susceptibilities." Blood 106, no. 11 (November 16, 2005): 4481. http://dx.doi.org/10.1182/blood.v106.11.4481.4481.
Full textAbstract:
Abstract [Introduction] Natural killer (NK) cells show cytotoxicity against virus-infected cells and some tumor cells. The highly polymorphic killer cell immunoglobulin-like receptors (KIRs) which recognize HLA class 1 molecules play a major role in these cytotoxic activities, and also express on some T-cells. Human T-lymphotrophic virus-1 (HTLV-1) is a caucassive agent for leukemia and some autoimmune diseases. We investigated the correlations between the KIR genotype and susceptibilities to HTLV-1 associated diseases i.e. adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy (HAM). [Materials and Methods] Fifty six HTLV-1 carriers, fifty one ATL patients and fifty seven HAM patients were recruited in this study. Genotyping of six KIR genes (3DL1, 2DL5, 2DS1, 2DS2, 2DS3 and 3DS1) was performed using PCR amplification with sequence specific primers (Martin et al. J Immunol 2002). [Results and Conclusion] Frequencies of each KIR and genotype were analysed as described in Table. Genotype means the pattern of positive KIR combinations. Significant differences between carrier vs. HAM in genotype 2 (p=0.01), and ATL vs. HAM in genotype 4 (p=0.01) were observed. Increased frequencies of genotype 3 and 2DS3 allele in HAM compared to carrier were also observed although these tendencies were not statistically significant. These preliminary results suggest that KIR gene polymorphism may play a role in determining susceptibility to HTLV-1 associated diseases. KIR genetype and HTLV-1 associated diseases Genotype 3DL1 / 2DL5 2DS1 / 2DS2 2DS3 / 3DS1 Carrier (%) * ATL (%) * HAM (%) * * this measns the genotype frequency; Y, positive; N, negative 1 Y / N N / N N / N 51.8 47.1 63.2 2 Y / Y Y / N N / Y 26.8 21.6 8.8 3 Y / Y Y / N Y / Y 1.8 7.8 10.5 4 Y / N N / Y N / N 5.4 11.8 0 5 Y / Y N / Y Y / N 1.8 2.0 7.0 6 N / Y Y / N N / Y 1.8 2.0 3.5 7 Y / Y Y / Y N / Y 1.8 3.9 1.8 Others 8.9 3.9 3.5 Carrier (%) 96.5 / 42.9 39.3 / 16.1 10.7 / 35.7 ATL (%) 96.1 / 41.2 39.2 / 21.6 9.8 / 39.2 HAM (%) 94.7 / 36.8 29.8 / 14.0 22.8 / 28.1
18
Vojvodic, Svetlana, and D. Ademovic-Sazdanic. "Killer-cell immunoglobulin-like receptor genes linkage disequilibrium analysis in population of Vojvodina." Genetika 47, no. 2 (2015): 439–50. http://dx.doi.org/10.2298/gensr1502439v.
Full textAbstract:
Killer Immunoglobulin-like Receptors (KIRs) form a group of regulatory molecules that modulate cytolytic activity of natural killer cells and T cells through interaction with specific human leukocyte antigen (HLA) molecules on target cells. KIRs are encoded by the family of 16 homologous genes that vary substantially between haplotypes and display sequence polymorphism with allelic variation that also contributes to diversity within the complex. The aim of the study is to estimate two locus linkage disequilibrium for 16 KIR loci. In this study, we report the evaluation of KIR gene content, allele, haplotype and genotype frequencies in 175 unrelated healthy individuals from Vojvodina who were KIR typed by polymerase chain reaction-sequence specific primers genotyping assay. The linkage disequilibrium (LD) was studied at the structural level (presence or absence of 16 KIR genes). Our results revealed that linkage disequilibrium is present between telomeric gene pairs KIR2DL1~KIR2DL4, KIR2DP1~KIR2DL4, KIR2DP1~KIR3DL1, KIR2DL1~KIR3DL2, KIR2DP1~KIR3DL2, KIR2DL4~KIR3DL1, KIR2DL4~KIR2DS4, KIR2DL4~KIR3DL2 where (r2=1), but positive association between KIR genes, with higher observed than expected haplotype frequencies were observed for KIR3DS1~KIR2DS1 and KIR2DL5~KIR2DS1 pair of genes (r2=0.646) and (r2=0.371), respectively. Thirty-eight different genotypes were identified, where 12% of the individuals have unique genotype, present in only one person. Our results will help to understand the genetic background of the Vojvodina population, in illustrating the population migration events in the northern part of Serbia, in explaining the extensive genetic admixture amongst the different ethnic groups of the region and also in KIR-related disease studies.
19
Cichocki, Frank, Todd Lenvik, Stephen K. Anderson, and Jeffrey S. Miller. "Antisense transcripts negatively regulate transcription of multiple variegated killer immunoglobulin-like receptor (KIR) genes (136.38)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 136.38. http://dx.doi.org/10.4049/jimmunol.182.supp.136.38.
Full textAbstract:
Abstract The objective of this study is to understand the epigenetic mechanisms that regulate Killer Immunoglobulin-Like Receptor (KIR) gene regulation in human natural killer (NK) cells. We have previously identified both bidirectional transcription within the previously characterized KIR promoter and a novel promoter element upstream of the previously characterized promoter. Based on these findings, we propose that antisense transcripts homologous to the KIR promoter region participate in the establishment of the epigenetic modifications that silence individual KIR genes during human NK cell development. To test this prediction, we overexpressed KIR3DL1 antisense transcripts in developing NK cells and found that mature cells from these cultures exhibited a four-fold decrease in KIR expression relative to GFP-expressing controls. We have also identified 324 base pair and 28 base pair double-stranded RNA molecules homologous to the KIR3DL1 promoter region, suggesting that a siRNA mechanism may be responsible for establishment of the promoter methylation patterns within the KIR locus. Understanding the mechanisms of KIR expression, a requisite for NK cell education/licensing, may allow us to understand the acquisition of effector function and manipulate it for therapeutic benefit. R01 HL 55417
20
Rajagopalan, Sumati, and Eric O. Long. "Understanding how combinations of HLA and KIR genes influence disease." Journal of Experimental Medicine 201, no. 7 (April 4, 2005): 1025–29. http://dx.doi.org/10.1084/jem.20050499.
Full textAbstract:
Combinations of HLA and killer cell immunoglobulin–like receptor (KIR) genes have been associated with diseases as diverse as autoimmunity, viral infections, reproductive failure, and now cancer. Much as early observations of disease associations with HLA polymorphism preceded a detailed knowledge of HLA recognition by T cell receptors, the recently reported disease associations with HLA–KIR gene combinations beg for a better understanding of the underlying mechanisms.
21
Almalte, Zaema, Suzanne Samarani, Alexandre Iannello, Olfa Debbeche, Michel Duval, Claire Infante-Rivard, Devendra K. Amre, Daniel Sinnett, and Ali Ahmad. "Novel associations between activating killer-cell immunoglobulin-like receptor genes and childhood leukemia." Blood 118, no. 5 (August 4, 2011): 1323–28. http://dx.doi.org/10.1182/blood-2010-10-313791.
Full textAbstract:
Abstract Acute lymphoblastic leukemia of pre-B cells (pre-B ALL) is the most frequent form of leukemia affecting children in Western countries. Evidence is accumulating that genetic factors play an important role in conferring susceptibility/resistance to leukemia in children. In this regard, activating killer-cell immunoglobulin-like receptor (KIR) genes are of particular interest. Humans may inherit different numbers of the 6 distinct activating KIR genes. Little is known about the impact of this genetic variation on the innate susceptibility or resistance of humans to the development of B-ALL. We addressed this issue by performing a case-control study in Canadian children of white origin. Our results show that harboring activating KIR genes is associated with reduced risk for developing B-ALL in these children. Of the 6 activating KIR genes, KIR2DS2 was maximally associated with decreased risk for the disease (P = 1.14 × 10−7). Furthermore, our results showed that inheritance of a higher number of activating KIR genes was associated with significant reductions in risk for ALL in children. These results were also consistent across different ALL phenotypes, which included children with pre-T cell ALL. Our study provides novel insights concerning the pathogenesis of childhood leukemia in white children and has implications for the development of new immunotherapies for this cancer.
22
Gumá, Mónica, Ana Angulo, Carlos Vilches, Natalia Gómez-Lozano, Núria Malats, and Miguel López-Botet. "Imprint of human cytomegalovirus infection on the NK cell receptor repertoire." Blood 104, no. 12 (December 1, 2004): 3664–71. http://dx.doi.org/10.1182/blood-2004-05-2058.
Full textAbstract:
Expression of the activating CD94/NKG2C killer lectin-like receptor (KLR) specific for HLA-E was analyzed in peripheral blood lymphocytes (PBLs) from healthy adult blood donors; the expression of other natural killer (NK) cell receptors (ie, CD94/NKG2A, KIR, CD85j, CD161, NKp46, NKp30, and NKG2D) was also studied. Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression. The proportion of NKG2C+ lymphocytes varied within a wide range (<0.1% to 22.1%), and a significant correlation (r = 0.83; P < .001) between NKG2C+ NK and T cells was noticed. The HLA-E genotype and the number of activating KIR genes of the donors were not significantly related to the percentage of NKG2C+ lymphocytes. By contrast, a positive serology for HCMV, but not for other herpesviruses (ie, Epstein-Barr and herpes simplex), turned out to be strongly associated (P < .001) with increased proportions of NKG2C+ NK and T cells. Remarkably, the CD94/NKG2C+ population expressed lower levels of natural cytotoxicity receptors (NCRs) (ie, NKp30, NKp46) and included higher proportions of KIR+ and CD85j+ cells than CD94/NKG2A+ cells. Altogether, these data support that HCMV infection selectively shapes the natural killer cell receptor (NKR) repertoire of NK and T cells from healthy carrier individuals.
23
Marin, Wesley M., Ravi Dandekar, Danillo G. Augusto, Tasneem Yusufali, Bianca Heyn, Jan Hofmann, Vinzenz Lange, Jürgen Sauter, Paul J. Norman, and Jill A. Hollenbach. "High-throughput Interpretation of Killer-cell Immunoglobulin-like Receptor Short-read Sequencing Data with PING." PLOS Computational Biology 17, no. 8 (August 2, 2021): e1008904. http://dx.doi.org/10.1371/journal.pcbi.1008904.
Full textAbstract:
The killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.
24
Carrington, Mary, Sophia Wang, Maureen P. Martin, Xiaojiang Gao, Mark Schiffman, Jie Cheng, Rolando Herrero, et al. "Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci." Journal of Experimental Medicine 201, no. 7 (April 4, 2005): 1069–75. http://dx.doi.org/10.1084/jem.20042158.
Full textAbstract:
Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor–ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.
25
Abi-Rached, Laurent, and Peter Parham. "Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues." Journal of Experimental Medicine 201, no. 8 (April 18, 2005): 1319–32. http://dx.doi.org/10.1084/jem.20042558.
Full textAbstract:
Expression of killer cell Ig-like receptors (KIRs) diversifies human natural killer cell populations and T cell subpopulations. Whereas the major histocompatibility complex class I binding functions of inhibitory KIR are known, specificities for the activating receptors have resisted analysis. To understand better activating KIR and their relationship to inhibitory KIR, we took the approach of reconstructing their natural history and that of Ly49, the analogous system in rodents. A general principle is that inhibitory receptors are ancestral, the activating receptors having evolved from them by mutation. This evolutionary process of functional switch occurs independently in different species to yield activating KIR and Ly49 genes with similar signaling domains. Selecting such convergent evolution were the signaling adaptors, which are older and more conserved than any KIR or Ly49. After functional shift, further activating receptors form through recombination and gene duplication. Activating receptors are short lived and evolved recurrently, showing they are subject to conflicting selections, consistent with activating KIR's association with resistance to infection, reproductive success, and susceptibility to autoimmunity. Our analysis suggests a two-stage model in which activating KIR or Ly49 are initially subject to positive selection that rapidly increases their frequency, followed by negative selection that decreases their frequency and leads eventually to loss.
26
Luc-Aimé, Kagoué Simeni, Yindom Louis-Marie, Loni Ekali Gabriel, Clauvis Kunkeng Yengo, F. Esemu Livo, and Nguedia Jules Clement Assob. "Killer-Cell Immunoglobulin-Like Receptors (KIR) in HIV-Exposed Infants in Cameroon." Journal of Immunology Research 2021 (January 13, 2021): 1–7. http://dx.doi.org/10.1155/2021/9053280.
Full textAbstract:
The biological reason(s) behind persistent mother-to-child transmission (MTCT) of HIV (albeit at reduced rate compared to the preantiretroviral therapy era) in spite of the successful implementation of advanced control measures in many African countries remains a priority concern to many HIV/AIDS control programs. This may be partly due to differences in host immunogenetic factors in highly polymorphic regions of the human genome such as those encoding the killer-cell immunoglobulin-like receptor (KIR) molecules which modulate the activities of natural killer cells. The primary aim of this study was to determine the variants of KIR genes that may have a role to play in MTCT in a cohort of infants born to HIV-infected mothers in Yaoundé, Cameroon. We designed a cross-sectional study to molecularly determine the frequencies of 15 KIR genes in 14 HIV-exposed infected (HEI), 39 HIV-exposed/uninfected (HEU), and 27 HIV-unexposed/uninfected (HUU) infants using the sequence specific primer polymerase chain reaction (PCR-SSP) method. We found that all 15 KIR genes were present in our cohort. The frequency of KIR2DL1 was significantly higher in the unexposed (control) group than in the HIV-exposed group ( OR = 0.22 , P = 0.006 ). Stratifying analysis by infection status but focusing only on exposed infants revealed that KIR2DL5, KIR2DS1, and KIR2DS5 were significantly overrepresented among the HIV-exposed/uninfected compared to infected infants ( OR = 0.20 , P = 0.006 ). Similarly, the frequencies of KIR2DS1, KIR2DS5, and KIR2DL5 were significantly different between infants perinatally infected with HIV (HIV+ by 6 months of age) and HIV-negative infants. Our study demonstrates that KIR genes may have differential effects with regard to MTCT of HIV-1.
27
Beigmohammadi, Fereshteh, Mahdi Mahmoudi, Jafar Karami, Nooshin Ahmadzadeh, Nasser Ebrahimi-Daryani, and Nima Rezaei. "Analysis of Killer Cell Immunoglobulin-Like Receptor Genes and Their HLA Ligands in Inflammatory Bowel Diseases." Journal of Immunology Research 2020 (September 19, 2020): 1–9. http://dx.doi.org/10.1155/2020/4873648.
Full textAbstract:
Genetic studies have illustrated that killer cell immunoglobulin-like receptor (KIR) genes could participate in various autoimmune disorders. We aimed to clarify the role of KIR genes, HLA ligands, HLA-KIR interactions, and their genotypes in inflammatory bowel disease (IBD) susceptibility. The study population was composed of 183 IBD subjects, comprising 100 ulcerative colitis (UC) patients, 83 Crohn’s disease (CD) patients, and 274 healthy subjects. Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to evaluate the absence or presence of the 15 KIR genes, 5 HLA class I ligands, and 2 pseudogenes. We did not find any significant difference in allele frequency of KIRs and pseudogenes between IBD patients and healthy controls. In the case of HLA genes, there was a significant difference in HLA-B-Bw4Thr80 frequency between UC patients and healthy controls (P=0.03, OR=0.06, 95%CI=0.008-0.4). Furthermore, we found a significant difference in HLA-C1Asn80 frequency between CD patients and healthy controls (P=0.04, OR=0.49, 95% CI=0.3-0.8). In the full-array combination of KIR genes, there was no significant frequency difference between UC patients and healthy controls, while two KIR genotypes showed a significant susceptible association with CD. Our data do not support a strong role of NK cells in IBD susceptibility, but it does not rule out a role for KIR variability in IBD patients. However, there are some protective associations such as Bw4 alleles; these associations may be due to the interaction of the alleles to TCRs rather than KIRs.
28
Fauriat, Cyril, Martin A. Ivarsson, Hans-Gustaf Ljunggren, Karl-Johan Malmberg, and Jakob Michaëlsson. "Education of human natural killer cells by activating killer cell immunoglobulin-like receptors." Blood 115, no. 6 (February 11, 2010): 1166–74. http://dx.doi.org/10.1182/blood-2009-09-245746.
Full textAbstract:
Abstract Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self–major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)–C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1+ NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1+ NK cells coexpressing the inhibitory MHC class I–specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1+ NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.
29
Cooley, Sarah, Feng Xiao, Michelle Pitt, Michelle Gleason, Valarie McCullar, Tracy L. Bergemann, Karina L. McQueen, Lisbeth A. Guethlein, Peter Parham, and Jeffrey S. Miller. "A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature." Blood 110, no. 2 (July 15, 2007): 578–86. http://dx.doi.org/10.1182/blood-2006-07-036228.
Full textAbstract:
Abstract How receptor acquisition correlates with the functional maturation of natural killer (NK) cells is poorly understood. We used quantitative real-time polymerase chain reaction (PCR) assays to compare NKG2 and killer immunoglobulin-like receptor (KIR) gene expression in NK cells from allogeneic transplant recipients and their donors. Marked differences were observed in the NK subsets of recipients who had 8-fold more CD56bright cells, diminished KIR expression (except 2DL4), and increased NKG2A. In normal blood not all CD56dim cells express KIR, and a novel subpopulation of cells committed to the NK-cell lineage was defined. These cells, which comprise 19.4% ± 2.8% of the CD56dim NK population in healthy donors, express the activating NKG2D and NKG2E receptors but no KIR or NKG2A. Although the CD56dim NKG2A− KIR− NK cells lack “at least one” inhibitory receptor for autologous MHC class I, they are not fully responsive, but rather functionally immature cells with poor cytotoxicity and IFN-γ production. Upon culture with IL-15 and a stromal cell line, CD56dim and CD56bright KIR− NK cells proliferate, express KIR, and develop cytotoxicity and cytokine-producing potential. These findings have implications for the function of NK cells reconstituting after transplantation and support a model for in vivo development in which CD56bright cells precede CD56dim cells.
30
Geraghty, Daniel, Jodie Goodridge, Aura Burian, and Ni Lee. "HLA-F and MHC-I open conformers are ligands for natural killer cell receptor KIR3DL2. (P5004)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 41.3. http://dx.doi.org/10.4049/jimmunol.190.supp.41.3.
Full textAbstract:
Abstract Killer Immunoglobulin-like receptors (KIR) are innate immune receptors expressed by NK and T cells classically associated with the detection of missing-self through loss of their respective MHC ligand. Some KIR specificities for allelic classical class I MHC (MHC-I) have been described, while other KIR receptor-ligand relationships, including those associated with non-classical MHC-I, have yet to be clearly defined. We report here that KIR3DL2 and the non-classical antigen HLA-F, expressed as a free form devoid of peptide, physically and functionally interact. We further extend those results to include classical MHC-I open conformers as ligands, defining new allelic relationships with KIR3DL2 and MHC-I. The data collectively suggest a broader, previously unrecognized interaction between MHC-I open conformers - with HLA-F as a prototypical example - and KIR receptors, acting in an immunoregulatory capacity centered on the inflammatory response.
31
Alter, Galit, Suzannah Rihn, Hendrik Streeck, Nickolas Teigen, Alicja Piechocka-Trocha, Kristin Moss, Kristen Cohen, et al. "Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8+ T Cells in Human Immunodeficiency Virus Type 1 Infection." Journal of Virology 82, no. 19 (June 25, 2008): 9668–77. http://dx.doi.org/10.1128/jvi.00341-08.
Full textAbstract:
ABSTRACT Virus-specific CD8+ T cells play a central role in the control of viral infections, including human immunodeficiency virus type 1 (HIV-1) infection. However, despite the presence of strong and broad HIV-specific CD8+ T-cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions and fail to clear the infection. Mounting evidence suggests that the upregulation of several inhibitory regulatory receptors on the surface of CD8+ T cells during HIV-1 infection may contribute directly to the impairment of T-cell function. Here, we investigated the role of killer immunoglobulin receptors (KIR), which are expressed on NK cells and on CD8+ T cells, in regulating CD8+ T-cell function in HIV-1 infection. KIR expression was progressively upregulated on CD8+ T cells during HIV-1 infection and correlated with the level of viral replication. Expression of KIR was associated with a profound inhibition of cytokine secretion, degranulation, proliferation, and activation by CD8+ T cells following stimulation with T-cell receptor (TCR)-dependent stimuli. In contrast, KIR+ CD8+ T cells responded potently to TCR-independent stimulation, demonstrating that these cells are functionally competent. KIR-associated suppression of CD8+ T-cell function was independent of ligand engagement, suggesting that these regulatory receptors may constitutively repress TCR activation. This ligand-independent repression of TCR activation of KIR+ CD8+ T cells may represent a significant barrier to therapeutic interventions aimed at improving the quality of the HIV-specific CD8+ T-cell response in infected individuals.
32
Kim, Heeje, Tae-Hyang Lee, So-Hye Park, Hyun-Jeong Sohn, Hee-Baeg Choi, Yoo-Jin Kim, Tai-Gyu Kim, and Woo-Sung Min. "Killer Cell Immunoglobulin-Like Receptor (KIR) Ligands Predict Outcomes of Autologous Stem Cell Transplantation for AML." Blood 116, no. 21 (November 19, 2010): 3571. http://dx.doi.org/10.1182/blood.v116.21.3571.3571.
Full textAbstract:
Abstract Abstract 3571 The idea of natural killer (NK) cell alloreactivity after allogeneic stem cell transplantation (SCT) was developed from reports of patients with acute myelogenous leukemia (AML). However, little definite information exists about the killer cell immunoglobulin-like receptor (KIR) and its ligand activity in autologous SCT. Since whether autologous NK cells are involved in the eradication of leukemia cells is still unclear, we focused on whether autologous NK or CD8+ T cells are stimulated after myeloablative conditioning, according to the ligand match. In light of a previous report that KIR–HLA combinations have effects in lymphoma and solid tumors, we undertook this retrospective study of KIR–HLA interactions. To examine the impact of autologous KIR–HLA ligands, we analyzed the HLA epitopes in patients with adult AML who benefited from autologous SCT (n = 164). The median age of the patients was 34 years (range, 15–64) and the subjects consisted of 63 females and 101 males. All patients received our modified TAM conditioning, which consisted of fractionated total body irradiation (12 Gy, five fractions in 3 days) from day –8 to –6, followed by intermediate-dose cytarabine (Ara-C; 1.5 g/m2 over 3 h every 12 h for six doses) from day –5 to –3, and melphalan (100 mg/m2 over 30 min) on day –2 only. Following consolidation chemotherapy, we collected peripheral blood stem cells after administering granulocyte colony-stimulating factor in all patients, except for 17 poorly mobilizing patients who received peripheral blood stem cells plus bone marrow together. The median infused CD34+ cell dose was 4.2 × 106/kg (range, 0.4–40.7). Finally, the effects of the KIR genotype compared with HLA ligands on the autologous SCT outcomes were examined in 81 patients who were typed for the presence or absence of 19 different KIR genes and pseudogenes using a polymerase chain reaction-based sequence-specific primer method with the Pel-Freez kit, according to the manufacturer's protocol (Invitrogen, Carlsbad, CA). KIR and HLA typing are defined by two subgroups of KIR ligands called C1 and C2. Furthermore, we divided C1/C1 homozygotes into two different KIR ligand patterns according to the HLA typing results: C1 homozygote homodimers (such as HLA-Cw3 and -Cw3; n = 32) and C1 homozygote heterodimers (such as HLA-Cw3 and -Cw8; n = 71). Fifty-three patients were typed as C1/C2 heterozygotes. The median follow-up for surviving patients was 65 months (range, 5–121). The majority of patients had intermediate (n = 90) or unfavorable (n = 41) cytogenetic features. At present, 66 patients (40%) have relapsed, and 94 patients (57%) have survived, while 10 (6%) died due to non-relapse causes. The Kaplan–Meier estimated 5-year overall and event-free survival (EFS) rates were 55% (95% CI, 50–60%) and 52% (95% CI, 48–56%), respectively. According to the consistent results of analyses of the HLA epitopes and genotypes, HLA ligand C1/C2 heterozygotes were compared with C1/C1 homozygotes. Heterozygotes, defined as KIR-HLA ligand matches, tended to have a better long-term EFS (P = .0636) and had a significantly lower relapse rate (P = .031). The number of infused CD34+ cells at the time of autologous SCT (P = .0279), FAB subtypes (M2 vs. other subtypes) (P = .0375), and risk grouping by cytogenetics (P = .0005) were other factors showing statistical significance on EFS and relapse. Since our findings are based on a single disease entity (i.e., adult AML), they suggest that autologous KIR–HLA ligands are, at least in some ways, critical for the influence of autologous NK immunomodulation on antileukemic effects, especially considering the impact of activating KIR–ligand activity on the long-term survival. Therefore, the identification of “ receptor–ligand ” effects could be useful as a prognostic marker and may be important in predicting patients who can expect long-term leukemia-free survival after autologous SCT for AML. Disclosures: No relevant conflicts of interest to declare.
33
Yawata, Makoto, Nobuyo Yawata, Laurent Abi-Rached, and Peter Parham. "Variation Within the Human Killer Cell Immunoglobulin-Like Receptor ( KIR) Gene Family." Critical Reviews™ in Immunology 22, no. 5-6 (2002): 20. http://dx.doi.org/10.1615/critrevimmunol.v22.i5-6.70.
Full text
34
Bitar, Mohamad, Roy Khalaf, Wael Shamseddeen, Nady El Hajj, Georges Ibrahim, Layal Greige, Ghazi Zaatari, Nabil Fuleihan, Amira Sabbagh, and Rami Mahfouz. "Killer Cell Immunoglobulin-Like Receptor (KIR) Genotypes in Patients with Recurrent Tonsillitis." Genetic Testing 12, no. 4 (December 2008): 517–21. http://dx.doi.org/10.1089/gte.2008.0033.
Full text
35
Bani, Meriem, Jihen Seket, Houda Kaabi, Ghaya Cherif, Manel Chaabane, Hedi Bellali, and Slama Hmida. "Killer cell immunoglobulin-like receptor (KIR) locus profiles in the Tunisian population." Human Immunology 76, no. 5 (May 2015): 355–61. http://dx.doi.org/10.1016/j.humimm.2015.03.002.
Full text
36
Rocha, Vanderson, Annalisa Ruggeri, Stephen R. Spellman, Tao Wang, Medhat Askar, Ron Sobecks, Eliane Gluckman, and Mary Eapen. "Is There Any Effect of Killer Cell Immunoglobulin-like Receptor (KIR) on Outcomes after Single Unrelated Cord Blood Transplantation?" Blood 124, no. 21 (December 6, 2014): 48. http://dx.doi.org/10.1182/blood.v124.21.48.48.
Full textAbstract:
Abstract The effect of killer cell immunoglobulin-like receptor (KIR) ligand incompatibility on outcomes after unrelated cord blood transplantation (UCBT) has been controversial. Eurocord found that KIR ligand mismatching was associated with decreased relapse incidence (RI) and improved overall (OS) and leukemia-free survival (LFS) for patients with acute lymphoblastic leukemia (ALL) and for those with acute myeloid leukemia (AML). Recently, the Japanese registry found no association between KIR ligand matching and LFS or OS in 643 UCBT recipients with acute leukemia. However, both studies have analysed the KIR ligand matching effect using low resolution typing of HLA-A,-B,-C and HLA-DRB1 high resolution. With the aim to clarify the KIR effect on outcomes (mainly RI and OS) in a larger series of single-UCBT recipients in the era of HLA-allele typing, we have analysed 1098 patients with AML and ALL reported to Eurocord and CIBMTR. All patients received single UCBT and myeloablative conditioning regimen. HLA matching was defined using high resolution typing or imputation for HLA-A,-B,-C and DRB1. Patients and donors were categorized by their KIR-ligand expression for HLA C group 1 or 2 and Bw4 as KIR ligand matched or mismatched. Patients included in the earlier Eurocord analysis were excluded. Univariate and multivariate models were built to analyse the effect of KIR ligand matching on outcomes. Results: None of the 8/8 HLA-matched transplants were KIR ligand mismatched, therefore they were excluded. Since HLA-match and KIR ligand mismatch were confounded, we conducted 2 separate analyses: a) 6-7/8 HLA-matched (n=501) and b) 3-5/8 HLA-matched transplants (n=586). In the group of 6-7/8 HLA matched, 291 recipients (58%) were KIR ligand-matched and 210 (42%) were mismatched. There were no statistically significant differences, between these two groups for gender, age, CMV serostatus, type and remission disease status, cell dose, conditioning regimen, in vivo T-cell depletion, transplant period and follow-up (around 40 months). In the group of 3-5/8 HLA matched, 176 recipients (30%) were KIR ligand-matched and 410 (70%) were mismatched. In this HLA group (i.e 3-5/8), KIR ligand-matched patients were younger (<16y, p=0.02) compared to the KIR ligand-mismatched patients. Other characteristics were similar between the KIR ligand matched and mismatched groups. In multivariate models for outcomes in both HLA groups (6-7/8 HLA and 3-5/8 HLA), KIR-match status was not associated with non-relapse mortality (NRM), RI, LFS and OS. However, KIR ligand-mismatch was associated with lower risks of grade 2-4 acute GVHD for transplants that were 3-5/8, HLA-matched (Hazard ratio, HR= 0.63, p=0.001) but not for transplants that were 6-7/8 HLA-matched. KIR ligand-matching was not associated with chronic GVHD. The effect of KIR ligand-mismatching in the GVH direction, HVG direction and bi-directional were also examined and findings were consistent with the main analysis. Lower acute GVHD rates in the worst HLA-match group (3-5/8) with KIR ligand mismatch did not translate into a survival advantage when compared to similarly HLA-matched KIR ligand matched group. Disease-specific analysis were undertaken to further explore the effects of KIR ligand matching for ALL and AML separately. For patients with ALL, KIR match status was not associated with NRM, RI, LFS or OS in either HLA group. For patients with AML KIR ligand match status was not associated with any transplantation outcome after 6-7/8 HLA-matched transplants. However, KIR ligand mismatching was associated with higher NRM (HR1.94, p=0.02) and lower OS (HR 1.51, p=0.03) after 3-5/8 HLA-matched transplants. In conclusion, in the setting of 6-7/8 HLA-matched transplants KIR ligand match status was not associated with leukemia recurrence or survival. Our observation for AML, in the 3-5/8 HLA-matched group with KIR ligand mismatching is contradictory to the earlier Eurocord report. We hypothesize the observed differences may be attributable to better HLA-matching in the current analysis. Taken together, the data does not support selecting units based on KIR ligand match status as categorized in this analysis, when donor-recipient HLA-match considers allele-level HLA typing. It remains to be seen whether assignment of KIR ligand match status by genotyping will offer additional information. Disclosures No relevant conflicts of interest to declare.
37
Igarashi, Takehito, Jason Wynberg, Ramprasad Srinivasan, Brian Becknell, J. Phillip McCoy, Yoshiyuki Takahashi, Dante A. Suffredini, W. Marston Linehan, Michael A. Caligiuri, and Richard W. Childs. "Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells." Blood 104, no. 1 (July 1, 2004): 170–77. http://dx.doi.org/10.1182/blood-2003-12-4438.
Full textAbstract:
Abstract Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell–mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus–transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand–matched counterparts. Bulk NK populations (CD3–/CD2+/CD56+) expanded 104-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand–mismatched tumor cells but only minimal cytotoxicity against KIR ligand–matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.
38
Epling-Burnette, Pearlie Kay, Jeffrey S. Painter, Pratima Chaurasia, Fanqi Bai, Sheng Wei, Julie Y. Djeu, and Thomas P. Loughran. "Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes." Blood 103, no. 9 (May 1, 2004): 3431–39. http://dx.doi.org/10.1182/blood-2003-02-0400.
Full textAbstract:
Abstract The natural killer (NK) type of lymphoproliferative disease of granular lymphocytes (LDGL) is associated with the expansion of CD3-, CD16+, and/or CD56+ lymphocytes. We have examined the repertoire of NK receptors expressed on these cells and delineated the functional activity. We found skewed NK receptor expression on patient NK cells. Reactivity to a single anti-killer cell immunoglobulin-like receptor (anti-KIR) antibody was noted in 7 of 13 patients. LDGL patients variably expressed NKp30, NKp44, and NKp46 RNA. In contrast, CD94 and its inhibitory heterodimerization partner NKG2A were homogenously expressed at high levels on these NK cells. Interestingly, these patients expressed a large number of activating KIR receptors by genotype analysis. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that lower than normal levels of RNA of the inhibitory KIR was present in some patients in contrast to normal NK cells. Consistent with a high level of activating receptors, we found the NK-LDGL cells have potent cytolytic function in both direct and redirected cytotoxicity assays. These results demonstrate that patients with NK-LDGL have an increased activating-to-inhibitory KIR ratio. This altered ratio might induce inappropriate lysis or cytokine production and impact the disease pathogenesis. (Blood. 2004;103:3431-3439)
39
Yawata, Makoto, Nobuyo Yawata, Monia Draghi, Ann-Margaret Little, Fotini Partheniou, and Peter Parham. "Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function." Journal of Experimental Medicine 203, no. 3 (March 13, 2006): 633–45. http://dx.doi.org/10.1084/jem.20051884.
Full textAbstract:
Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand–receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR–HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population.
40
Rhee, F. van, J. Shi, S. Szmania, N. Rosen, A. Moreno, R. Walker, B. Dupont, et al. "Killer Immunoglobulin-Like Receptor Ligand (KIR-L) Mismatched Natural Killer (NK) Cells for Relapsed Myeloma." Journal of Immunotherapy 28, no. 6 (November 2005): 618–19. http://dx.doi.org/10.1097/01.cji.0000190966.65407.8e.
Full text
41
Rettman, Pauline, Matthew D. Blunt, Rebecca J. Fulton, Andres F. Vallejo, Leidy Y. Bastidas-Legarda, Laura España-Serrano, Marta E. Polak, Aymen Al-Shamkhani, Christelle Retiere, and Salim I. Khakoo. "Peptide: MHC-based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors." Journal for ImmunoTherapy of Cancer 9, no. 5 (May 2021): e001912. http://dx.doi.org/10.1136/jitc-2020-001912.
Full textAbstract:
BackgroundNatural killer (NK) cells are increasingly being recognized as agents for cancer immunotherapy. The killer cell immunoglobulin-like receptors (KIRs) are expressed by NK cells and are immunogenetic determinants of the outcome of cancer. In particular, KIR2DS2 is associated with protective responses to several cancers and also direct recognition of cancer targets in vitro. Due to the high homology between activating and inhibitory KIR genes to date, it has been challenging to target individual KIR for therapeutic benefit.MethodsA novel KIR2DS2-targeting therapeutic peptide:MHC DNA vaccine was designed and used to immunize mice transgenic for KIR genes (KIR-Tg). NK cells were isolated from the livers and spleens of vaccinated mice and then analyzed for activation by flow cytometry, RNA profiling and cytotoxicity assays. In vivo assays of NK cell function using a syngeneic cancer model (B16 melanoma) and an adoptive transfer model for human hepatocellular carcinoma (Huh7) were performed.ResultsInjecting KIR-Tg mice with the vaccine construct activated NK cells in both liver and spleens of mice, with preferential activation of KIR2DS2-positive NK cells. KIR-specific activation was most marked on the CD11b+CD27+ mature subset of NK cells. RNA profiling indicated that the DNA vaccine upregulated genes associated with cellular metabolism and downregulated genes related to histone H3 methylation, which are associated with immune cell maturation and NK cell function. Vaccination led to canonical and cross-reactive peptide:MHC-specific NK cell responses. In vivo, DNA vaccination led to enhanced antitumor responses against B16F10 melanoma cells and also enhanced responses against a tumor model expressing the KIR2DS2 ligand HLA-C*0102.ConclusionWe show the feasibility of a peptide-based KIR-targeting vaccine strategy to activate NK cells and hence generate functional antitumor responses. This approach does not require detailed knowledge of the tumor peptidomes nor HLA matching with the patient. It therefore offers a novel opportunity for targeting NK cells for cancer immunotherapy.
42
Giebel, Sebastian, Aleksandra Holowecka-Goral, Izabela Nowak, Tomasz Czerw, Jerzy Wojnar, Malgorzata Krawczyk-Kulis, Joanna Dziaczkowska, et al. "Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation." Blood 110, no. 11 (November 16, 2007): 2167. http://dx.doi.org/10.1182/blood.v110.11.2167.2167.
Full textAbstract:
Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.
43
Hassan, Norfarazieda, Le Jie Lee, Jun Hao Tan, Siti Zuleha Idris, Hishamshah Mohd Ibrahim, Raudhawati Osman, Heng Fong Seow, Norhafizah Mohtaruddin, Andi Anggeriana Andi Asri, and Maha Abdullah. "Expression of Killer Cell Immunoglobulin-like Receptors (KIR) in Sex-associated Malignancies." JULY ISSUE 18, no. 4 (July 1, 2022): 96–103. http://dx.doi.org/10.47836//mjmhs18.4.14.
Full textAbstract:
Introduction: Sex shapes immune response with possible consequence on tumor immune escape. Acute lymphoblastic leukemia (ALL) predominates in males while ovarian cancer (OC) occurs in females. NK cells essential for tumor killing may have male preponderance. Association of sex, NK cell activity and malignancies is unclear. We hypothesize that sex differentially affects KIR expressions in sex-biased cancers. Method: Expression of inhibitory (KIR2DL1-5 and KIR3DL1-3) and activating (KIR2DS1-2 and 4-5 and KIR3DS1) genes in B-, T-cell ALL, OC and normal controls were determined by reverse-transcription polymerase-chain-reaction. Result: All normal males (but not females) expressed the framework genes and generally maintained haplotype A, except KIR3DL1. Normal females expressed more activating KIRs. Frequencies of KIR2DL1, 2DL4 and 2DS2 were significantly reduced among ovarian cancer patients. Sex difference in frequencies of KIR expression was not detected in ALL as majority were undetectable except framework gene KIR3DL2, was more frequent among T-ALL. Conclusion: Cancers may be associated with reduced KIR expression and influence of sex requires investigation.
44
Mulrooney, Tiernan, and Carolyn Hurley. "DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors on natural killer cells (P1323)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 63.16. http://dx.doi.org/10.4049/jimmunol.190.supp.63.16.
Full textAbstract:
Abstract Killer Ig-like receptors (KIR) aid in the regulation of natural killer (NK) cell activity. In this study, the effect of the interaction between the two domain stimulatory KIR (KIR2DS) and their adapter, DAP12, was investigated beyond the previously defined signaling function. Flow cytometry analysis showed enhanced KIR2DS surface expression on NKL cells when co-transfected with DAP12. Conversely, KIR2DS4 surface expression on primary cells was decreased when the cells were treated with DAP12 specific siRNA. Treatment of the KIR2DS and DAP12 transfected cells with either cycloheximide or Brefeldin A repressed KIR2DS surface expression revealing a role for DAP12 in trafficking newly synthesized KIR to the cell surface. Immunoprecipitation of DAP12 revealed an interaction of DAP12 with an immature isoform of KIR2DS indicating the interaction likely initiates within the endoplasmic reticulum. An internalization assay demonstrated a significant impact of DAP12 on KIR2DS surface stability. Confocal microscopy showed internalized KIR2DS molecules are recruited to lysosomal compartments independent of DAP12 expression. Our results suggest in vivo conditions that adversely affect DAP12 expression will indirectly reduce surface expression and stability of KIR2DS. These effects could significantly impact ligand recognition and strength of signaling through KIR2DS molecules.
45
Pende, Daniela, Stefania Marcenaro, Michela Falco, Stefania Martini, Maria Ester Bernardo, Daniela Montagna, Elisa Romeo, et al. "Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity." Blood 113, no. 13 (March 26, 2009): 3119–29. http://dx.doi.org/10.1182/blood-2008-06-164103.
Full textAbstract:
Abstract We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)–like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1+ NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3+ NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3+ (or by NKG2A+) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.
46
Vey, Norbert, and Daniel Olive. "Anti-natural Killer Inhibitory Receptors in Elderly Patients with Acute Myeloid Leukaemia." European Oncology & Haematology 06, no. 01 (2010): 86. http://dx.doi.org/10.17925/eoh.2010.06.1.86.
Full textAbstract:
Treatment with anti-killer-cell immunoglobulin-like receptor (KIR) monoclonal antibody (mAb) is a new approach aimed at harnessing the antileukaemic potential of natural killer (NK) cells for the treatment of acute myeloid leukaemia (AML). NK cell antitumour activity is regulated by a balance between activating and inhibitory receptors (KIR). 1-7F9/IPH2101 is a fully human immunoglobulin G4 (IgG4) mAb that binds to inhibitory KIR and blocks binding with its ligand (human leukocyte antigen C [HLA-C] molecule) on leukaemic cells.In vitro,and in a surrogatein vivomodel in mice, treatment with 1-7F9/IPH2101 was able to induce NK cell activation and cytotoxicity against leukaemic cells. Patients with AML often display abnormal NK cell function, while evidence of an impact of NK cell status on AML outcome has been reported in allogeneic transplantation. 1-7F9/IPH2101 is currently under clinical investigation in patients with AML. This article reviews the mechanisms of NK cell antileukaemic activity and its role and defects in AML. Currently available data on the pre-clinical and clinical development of 1-7F9/IPH2101 are presented, and the rationale for its future use as a single agent or in combination is discussed.
47
Li, Guangjin, Cornelia M. Weyand, and Jorg J. Goronzy. "Epigenetic Control of Killer Immunoglobulin-like Receptor (KIR) Expression in T cells (35.40)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S9. http://dx.doi.org/10.4049/jimmunol.178.supp.35.40.
Full textAbstract:
Abstract Killer immunoglobulin-like receptors (KIR), usually restricted to NK cells, are expressed on T-cells with increasing age and contribute to age-related diseases. We examined the epigenetic changes associated with KIR expression. In T cells with absent KIR2DL4 transcripts such as the Jurkat cell line or CD4+CD28+ T cells, CpG sites of the proximal KIR2DL4 promoter were hypermethylated. DNMT inhibition in such cells induced low but appreciable KIR2DL4 transcription. DNMT inhibition was strikingly more effective in T cells that had some constitutive KIR2DL4 transcription, such as CD4 and CD8 T cells from elderly adults or the CD4+CD28−T cell line HUT78. Such cells had evidence of partial promoter demethylation; however, although the proximal nucleosome was partially relaxed, the only histone modification was an increase in dimethylated H3-Lys 4. In contrast, NK cells had a fully demethylated KIR2DL4 promoter and the full spectrum of histone modifications indicative of active transcription with H3 and H4 acetylation, di- and trimethylated H3-Lys 4, and reduced dimethylated H3-Lys 9. These results suggest that early steps of promoter activation in T cells include selective increase in H3-Lys 4 dimethylation and limited DNA demethylation. This partially accessible promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription without further histone acetylation and methylation. Supported by NIH grant AG 15043
48
Farag, Sherif, Andrea Bacigalupo, Bo Dupont, Michael Caligiuri, Gene Nelson, Jeffrey Miller, and Stella Davies. "The Effect of Killer Immunoglobulin-Like Receptor (KIR) Ligand Incompatibility on Outcome of Unrelated Donor Bone Marrow Transplantation (UDT)." Blood 104, no. 11 (November 16, 2004): 434. http://dx.doi.org/10.1182/blood.v104.11.434.434.
Full textAbstract:
Abstract KIR ligand incompatibility in the graft-versus-host (GvH) direction has been associated with a significant reduction in relapse, graft rejection and graft-versus-host disease (GvHD) in patients with high-risk acute myeloid leukemia (AML)undergoing full haplotype-mismatched, T-cell depleted transplants. The effect in UDT has been less consistent. This study investigates the effect of KIR ligand mismatching on the outcome of UDT in a large combined data set from the National Marrow Donor Program and the European Group for Blood and Marrow Transplantation, comparing the outcome of 1,816 KIR ligand matched and mismatched transplants for AML (n=501), chronic myelogenous leukemia (n=1024), and myelodysplasia (n=291). All cases had high-resolution HLA typing, and were matched for HLA-A, and -DRB1 alleles. Based on HLA typing for -B and -C alleles, cases were divided into one of 4 groups for comparison of outcome: KIR ligand incompatible in GvH direction (n=156), KIR ligand incompatible in host-versus-graft (HvG) direction (n=185), HLA mismatched for -B and/or -C, KIR ligand compatible (n=301), and fully HLA matched (n=1174). All received myeloablative preparative regimens, and ex-vivo T-cell depletion of the graft was performed in 18%, 22%, 16% and 15% of patients in the 4 groups, respectively. Overall, a beneficial effect of KIR ligand incompatibility in the GvH direction could not be demonstrated. KIR ligand incompatibility was associated with increased risk of grade III/IV acute GvHD and worse overall survival (OS). However, the effect varied according to whether or not ex-vivo T-cell depletion of the graft was performed (see Table). Our results suggest a detrimental effect of KIR ligand incompatibility in unmanipulated UDT, whereas this negative effect is lost with ex-vivo T-cell depletion. With ex-vivo T-cell depletion, KIR ligand incompatibility in the GvH direction may be associated with a reduced risk of severe acute GvHD and improved OS compared to HLA mismatched, KIR ligand matched transplants, with the outcome approaching that of fully HLA matched transplants. Therefore, full MHC class I matching remains the best option in UDT. KIR ligand mismatching in the GvH direction may be considered if only HLA-B and or -C incompatible donors are available and ex-vivo T-cell depletion is performed. This requires validation in prospective studies. GvH KIR ligand mismatch HvG KIR ligand mismatch No KIR ligand mismatch, HLA mismatch HLA matched P-value T-cell depleted UDT Treatment mortality 51% ± 17% 64% ± 14% 61% ± 13% 47% ± 7% 0.12 Grade III/IV acute GvHD 14% ± 13% 25% ± 13% 37% ± 13% 17% ± 6% 0.04 Chronic GvHD at 3 years 50% ± 21% 39% ± 17% 32% ± 15% 53% ± 8% 0.09 Relapse 18% ± 14% 12% ± 9% 22% ± 11% 20% ± 6% 0.49 OS 31% ± 17% 27% ± 14% 18% ± 11% 38% ± 7% 0.06 T cell replete UDT Treatment mortality 63% ± 8% 63% ± 8% 54% ± 6% 44% ± 3% <0.0001 Grade III/IV acute GvHD 47% ± 9% 45% ± 8% 31% ± 6% 28% ± 3% <0.0001 Chronic GvHD at 3 years 45% ± 10% 67% ± 9% 61% ± 7% 63% ± 3% 0.005 Relapse 22% ± 7% 12% ± 5% 15% ± 4% 17% ± 2% 0.09 OS 19% ± 7% 28% ± 8% 33% ± 6% 43% ± 3% <0.0001
49
Ritari, Jarmo, Kati Hyvärinen, Jukka Partanen, and Satu Koskela. "KIR gene content imputation from single-nucleotide polymorphisms in the Finnish population." PeerJ 10 (January 7, 2022): e12692. http://dx.doi.org/10.7717/peerj.12692.
Full textAbstract:
The killer cell immunoglobulin-like receptor (KIR) gene cluster on chromosome 19 encodes cell surface glycoproteins that bind class I human leukocyte antigen (HLA) molecules as well as some other ligands. Through regulation of natural killer (NK) cell activity KIRs participate in tumour surveillance and clearing viral infections. KIR gene gene copy number variation associates with the outcome of transplantations and susceptibility to immune-mediated diseases. Inferring KIR gene content from genetic variant data is therefore desirable for immunogenetic analysis, particularly in the context of growing biobank genome data collections that rely on genotyping by microarray. Here we describe a stand-alone and freely available gene content imputation for 12 KIR genes. The models were trained using 807 Finnish biobank samples genotyped for 5900 KIR-region SNPs and analysed for KIR gene content with targeted sequencing. Cross-validation results demonstrate a high mean overall accuracy of 98.5% (95% CI [97.0–99.2]%) which compares favourably with previous methods including short-read sequencing based approaches.
50
Jamil, Khaleel M., and Salim I. Khakoo. "KIR/HLA Interactions and Pathogen Immunity." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/298348.
Full textAbstract:
The innate immune system is the first line of defence in response to pathogen infection. Natural killer (NK) cells perform a vital role in this response with the ability to directly kill infected cells, produce cytokines, and cross-talk with the adaptive immune system. These effector functions are dependent on activation of NK cells which is determined by surface receptor interactions with ligands on target cells. Of these receptors, the polymorphic killer immunoglobulin-like receptors (KIRs), which interact with MHC class 1 (also highly polymorphic), are largely inhibitory, and exhibit substantial genetic diversity. The result is a significant variation of NK cell repertoire between individuals and also between populations, with a multitude of possible KIR:HLA combinations. As each KIR:ligand interaction may have differential effects on NK cell activation and inhibition, this diversity has important potential influences on the host response to infections. Genetic studies have demonstrated associations between specific KIR:ligand combinations and the outcome of viral (and other) infections, in particular hepatitis C and HIV infection. Detailed functional studies are not required to define the mechanisms underpinning these disease associations.