Journal articles on the topic 'Killer immunoglobulin like receptors (KIR)'
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1
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Littera, Roberto, Luchino Chessa, Silvia Deidda, Goffredo Angioni, Marcello Campagna, Sara Lai, Maurizio Melis, et al. "Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection." PLOS ONE 16, no. 8 (August 5, 2021): e0255608. http://dx.doi.org/10.1371/journal.pone.0255608.
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Background The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study’s focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. Methods KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. Results Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1–2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3–0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3–0.7), PM = 0.0005, PMC = 0.005]. Conclusions The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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Stuebig, Thomas, Michael Lioznov, Ulrike Fritsche-Friedland, Haefaa Alchalby, Christine Wolschke, Francis Ayuk, Ulrike Bacher, Axel R. Zander, and Nikolaus Kroeger. "Recovery of KIR Expression After Allogeneic Stem Cell Transplantation in Multiple Myeloma Patients." Blood 118, no. 21 (November 18, 2011): 4555. http://dx.doi.org/10.1182/blood.v118.21.4555.4555.
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Abstract Abstract 4555 Introduction: Activating and inhibitory killer immunoglobulin like receptors (KIR) are predominantly expressed on natural killer (NK) cells. KIR mismatch allogeneic stem cell transplantation (alloSCT) has been reported to provide beneficial effects for Multiple Myeloma (MM). However, their recovery in MM patients remains poorly understood. We, therefore, analysed KIR recovery in 90 MM patients after alloSCT. Methods: KIR expression (CD158a/h, CD158b/b2, CD158e1/e2) on NK cells and T cell subsets was measured by flow cytometry at different time points after alloSCT. Results: During the first 90 days after alloSCT NK cells represent the largest lymphocyte subset. Activating receptors like NKp30 and NKp44 showed a fluctuating expression while members of the KIR family were expressed at a constant rate (20% of NK cells). There was no significant difference in the early post transplantation period (day 0–90) compared to later time points (day 360). In contrast, T cells showed increased KIR expression during the first 30 days after alloSCT, which was highly significant for CD158e (p=0,0001). After 30 days the expression declined to baseline. Furthermore, T cell activation marker HLA-DR reached its highest expression between days 60 and 90 when KIR receptors were expressed at their lowest level (27% vs. 8%, p < 0,0001). Conclusions: We conclude that KIR receptors were differentially expressed on NK and T cells. Because KIR receptors are constantly expressed by NK cells and NK cells are the most frequent lymphocyte populations early after alloSCT, NK cells may be useful for KIR mismatch cellular therapy. Disclosures: No relevant conflicts of interest to declare.
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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.
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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.
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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.
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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)
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Sosnina, K., D. Zastavna, O. Terpyliak, L. Bober, and H. Makukh. "P004 Killer Cell Immunoglobulin-like Receptors (KIR) genes repertoire among cystic fibrosis patients." Journal of Cystic Fibrosis 18 (June 2019): S57—S58. http://dx.doi.org/10.1016/s1569-1993(19)30299-1.
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Aranda-Romo, Saray, Christian A. Garcia-Sepulveda, Andreu Comas-García, Fernando Lovato-Salas, Mariana Salgado-Bustamante, Alejandro Gómez-Gómez, and Daniel E. Noyola. "Killer-cell immunoglobulin-like receptors (KIR) in severe A (H1N1) 2009 influenza infections." Immunogenetics 64, no. 9 (June 1, 2012): 653–62. http://dx.doi.org/10.1007/s00251-012-0623-3.
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Epling-Burnette, P. K., Jeffrey S. Painter, H. S. Lee, Jong Park, Michael Clemente, Christine O’Keefe, Tie-Ying Wei, et al. "Genetic Disparities in Killer Cell Immunoglobulin-Like Receptors (KIR) and MHC Class I in Bone Marrow Failure Syndromes." Blood 112, no. 11 (November 16, 2008): 4121. http://dx.doi.org/10.1182/blood.v112.11.4121.4121.
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Abstract BACKGROUND: Activating (KIRDS) natural killer cell receptors (NKR) containing an intracellular ITAM activation domain are expressed on NK and some T-cells to invoke effector responses against MHC class I-deficient tumor cells and virus-infected cells. Effector cell activation is abrogated by inhibitory forms (KIRDL) of killer cell immunoglobulin-like receptors (KIR) that bind specific epitopes of MHC class I and prevent reaction against normal cells. Since HLA class I and KIR genes are not linked, KIR gene inheritance may occur in the absence of self HLA-class I alleles (i.e., KIR/HLA-class I mismatch) and thus increase the potential for generation of autoreactive T-cells in autoimmune-mediated bone marrow failure (BMF) syndromes such as LGL leukemia, aplastic anemia (AA), and myelodysplastic syndromes (MDS). METHODS: Genotypic KIR analysis and HLA typing was performed on peripheral blood from 157 cases recruited by the Bone Marrow Failure Rare Disease Clinical Research Network and compared to 93 healthy controls. T-LGL leukemia was defined as increased numbers of CD3+, CD8+, or CD57+ lymphocytes with T-cell receptor clonality (N=35). The diagnosis of AA (N=47) and MDS (N=53) was established by bone marrow biopsy and 22 patients displayed BMF syndromes with overlapping characteristics or presence of paroxysmal nocturnal hemaglobuinuria (PNH). RESULTS: Individual KIR gene content was similar in BMF cases and healthy controls although patients with 2–3 activating KIR genes were more common among cases compared to controls (33% in cases vs. 23% in controls, p=0.1). Antigens at the HLA-C locus were divided into two groups, HLA C1 Group with alleles encoding Ser-77-Asn80 (consisting of Cw01, 03, 07, 08, 12, 14 and 16) and HLA C2 alleles encoding Asn-77-Lys-80 (Cw02, 04, 05, 06, 15, 17, and 18). The frequency of a KIR2DL2 or KIR2DL3 positive haplotype in the absence of the corresponding C1 allele in BMF patients (C1 inhibitory mismatch) in marrow failure cases was 20% compared to 8% in controls (p=0.05). There was no difference in the frequency of KIR-C1 mismatch by disease diagnosis (20% BMF vs 21% AA, 16% MDS, and 19% LGL) but all were greater than controls. The presence of KIR2DL1 and the absence of the C2 allele was not statistically different between cases and controls. The activating counterparts of these inhibitory KIRs bind their putative HLA ligands but may also bind alternative activating ligands with similar structural determinants and/or immunoglobulin domains. We compared the frequencies of mismatches in the activating KIR genes and their ligands and found that the combined the presence of KIR2DS2 or KIR2DS3 and absence of the appropriate HLA C1 allele (KIR-C1 mismatch) was more frequent in BMF patients (12%) compared to that of healthy controls (0%) (p=0.007). The disease types of AA, MDS, and LGL leukemia displayed similar frequencies in KIR-C1 activating mismatches with 16%, 13%, and 6%, respectively (p=0.005 AA, p=0.01 MDS, and p=0.14 LGL leukemia). BMF syndromes have been linked to a T-cell dominant autoimmune process. KIR expression and other NKR expression in T-cells occurs after rearrangement of the TCR and thymic education suggesting that the KIR repertoire develops in memory T-cells. Since we have identified that clonal T-cells in LGL leukemia express a unique memory phenotype characterized by expression of CD45RA in the absence of the lymphoid homing receptor L-selectin (CD62L), we examined the phenotype of T-cells that express NK proteins including NKG2A, KIR2DL2/2DS2 (CD158b), KIR2DL1/DS1 (CD158a), and KIR3DL1 (NKB1). For all NKRs, only 0.5% ± .5 of naïve CD4+ T-cells expressed NKRs compared to 3% (p=0.01) and 6% (p=0.0003) of CD4+ effector and terminal effector memory cells, respectively. CD8+ T-cells with a naïve phenotype displayed higher NKR expression (2.6%±2.8) compared to CD4+ T-cells (0.006). The highest overall NKR expression compared to all other T cell types was present in CD8+ terminal effector memory cells (15.5%±15, p=0.006). Terminal effector memory cells (CD8+) are dramatically overrepresented in BMF syndromes particularly in association with bone marrow infiltration. CONCLUSIONS: KIR expression in the absence of HLA interactions may skew the memory T-cell compartment favoring autoreactivity and impaired peripheral self-tolerance due to expansion of NKR positive T-cells in patients with BMF syndromes. Infiltration of KIR+ T-cells in tissues has been linked to organ dysfunction in several autoimmune diseases including rheumatoid arthritis and diabetes.
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Dębska-Zielkowska, Joanna, Grażyna Moszkowska, Maciej Zieliński, Hanna Zielińska, Anna Dukat-Mazurek, Piotr Trzonkowski, and Katarzyna Stefańska. "KIR Receptors as Key Regulators of NK Cells Activity in Health and Disease." Cells 10, no. 7 (July 14, 2021): 1777. http://dx.doi.org/10.3390/cells10071777.
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Natural killer (NK) cells are part of the cellular immune response. They target mainly cancer and virally infected cells. To a high extent cytotoxic activity of NK cells is regulated inter alia by signals from killer immunoglobulin-like receptors (KIR). The major histocompatibility complex (MHC) class I molecules are important ligands for KIR receptors. Binding of ligands (such as MHC I) to the KIR receptors has the important role in solid organ or hematopoietic cell transplantation. Of note, the understanding of the relationship between KIR and MHC receptors may contribute to the improvement of transplant results. Donor-recipient matching, which also includes the KIR typing, may improve monitoring, individualize the treatment and allow for predicting possible effects after transplantation, such as the graft-versus-leukemia effect (GvL) or viral re-infection. There are also less evident implications of KIR/MHC matching, such as with pregnancy and cancer. In this review, we present the most relevant literature reports on the importance of the KIR/MHC relationship on NK cell activity and hematopoietic stem cell transplantation (HSCT)/solid organ transplantation (SOT) effects, the risk of allograft rejection, protection against post-transplant cytomegalovirus (CMV) infection, pregnancy complications, cancer and adoptive therapy with NK cells.
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Bernal, Enrique, Lourdes Gimeno, María J. Alcaraz, Ahmed A. Quadeer, Marta Moreno, María V. Martínez-Sánchez, José A. Campillo, et al. "Activating Killer-Cell Immunoglobulin-Like Receptors Are Associated With the Severity of Coronavirus Disease 2019." Journal of Infectious Diseases 224, no. 2 (April 30, 2021): 229–40. http://dx.doi.org/10.1093/infdis/jiab228.
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Abstract Background Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. In this study, we investigate the role of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. Methods We performed KIR and HLA-I genotyping and natural killer cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 noninfected controls. Results The NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe versus mild and/or moderate patients and controls (83.7%, 55.7% and 36.2%, P < 7.7 × 10−9). In patients with mild and/or moderate infection, HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared with patients with other HLA-B*15 subtypes and noninfected controls (90.9%, 42.9%, and 47.3%; P < .002; Pc = 0.022). This strongly suggests that HLA-B*15:01 specifically presenting severe acute respiratory syndrome coronavirus 2 peptides could form a neoligand interacting with KIR3DS1. Likewise, a putative neoligand for KIR2DS4 could arise from other HLA-I molecules presenting severe acute respiratory syndrome coronavirus 2 peptides expressed on infected an/or activated lung antigen-presenting cells. Conclusions Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/ligand interactions associated with disease severity.
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Chan, Huei-Wei, Zoya B. Kurago, C. Andrew Stewart, Michael J. Wilson, Maureen P. Martin, Brian E. Mace, Mary Carrington, John Trowsdale, and Charles T. Lutz. "DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells." Journal of Experimental Medicine 197, no. 2 (January 20, 2003): 245–55. http://dx.doi.org/10.1084/jem.20021127.
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Killer immunoglobulin-like receptors (KIR) bind self–major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4. We show that NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. Despite allele-independent expression, 3DL1 alleles differed in the core promoter by only one or two nucleotides. Allele-specific 3DL1 gene expression correlated with promoter and 5′ gene DNA hypomethylation in NK cells in vitro and in vivo. The DNA methylase inhibitor, 5-aza-2′-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes. Thus, NK cells use DNA methylation to maintain clonally restricted expression of highly homologous KIR genes and alleles.
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Chiorean, Elena G., Scott J. Dylla, Krista Olsen, Todd Lenvik, Yvette Soignier, and Jeffrey S. Miller. "BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs)." Blood 101, no. 9 (May 1, 2003): 3527–33. http://dx.doi.org/10.1182/blood-2002-04-1172.
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Natural killer (NK) cells decrease in function during chronic myelogenous leukemia (CML) progression from chronic phase to blast crisis, and they can becomeBCR/ABL+ late in the disease course. To study this altered function, NK92 cells were transduced with the BCR/ABL oncogene. In contrast to the parental cells, which died when deprived of interleukin 2 (IL-2), p210+ NK92 cells proliferated and survived indefinitely in the absence of IL-2. BCR/ABL also decreased the natural cytotoxicity of NK92 cells against K562 targets, without affecting IL-2, interferon γ (IFN-γ), or tumor necrosis factor α (TNF-α) production. Although the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI-571) had no effect on parental NK92 cells, it markedly decreased the growth and survival of IL-2–independent p210+ NK92 cells. In contrast to the parental cell line, serial analysis of p210+ NK92 cells detected small populations that clonally expressed one or more killer immunoglobulin-like receptors (KIRs). Unlike the decreased natural cytotoxicity, the function of the activating CD158j receptor remained intact. Southern blotting and hybridization with an enhanced green fluorescence protein (eGFP) probe showed that KIR− and KIR+ NK92 cells were all derived from the same clone, suggesting that KIR acquisition remains dynamic at the maturational stage represented by the NK92 cell line. When tested in primary CD56+bright NK cells, p210 induced partial IL-2–independent growth and increased KIR expression similar to findings in NK92 cells. This is the first study to show thatBCR/ABL, well known for its effects on the myeloid lineage, can alter the function of lymphoid cells, which may be associated with the defect in innate immunity associated with CML progression.
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Kogure, Toshiaki, Naoki Mantani, Shinya Sakai, Yutaka Shimada, Jun'ichi Tamura, and Katsutoshi Terasawa. "Natural killer cytolytic activity is associated with the expression of killer cell immunoglobulin-like receptors on peripheral lymphocytes in human." Mediators of Inflammation 12, no. 2 (2003): 117–21. http://dx.doi.org/10.1080/0962935031000097727.
Full textAbstract:
Although it has been shown that killer cell immunoglobulin-like receptors (KIRs) on peripheral lymphocytes are upregulated by interleukin-2 (IL-2), which activates natural killer (NK) activity, it has not been demonstrated whether the expression of KIRs is related to NK activity. Therefore, we investigated the association between the KIR expression on lymphocytes and NK activity. CD158a/b expression on lymphocytes obtained from 37 subjects was analyzed using flow cytometry. Simultaneously, NK activity was measured each sample using a51Cr-release assay. Additionally, lymphocytes were cultured in RPMI 1640 medium with or without IL-2 for 48 h, and then their CD158a/b expression and NK activity was analyzed. CD158a/b expression was significantly correlated with NK activity. Especially, the percentage of CD16+CD158a+ and CD8+CD158a/b+ cells in lymphocytes showed a highly significant correlation with NK activity. However, analysis of CD8+ and CD16+ cells revealed that there was only a significant correlation between the percentage of CD8+CD158a+ cells among only CD8+ cells and NK activity. The upregulation of CD16+CD158a+/b+ cells in response to IL-2 tended to be related to the increase of NK activity, but the relationship was not significant. In conclusion, the level of KIR expression was correlated with NK activity, and IL-2 treatment resulted in an increase of NK activity as well as KIR expression, suggesting that upregulation of KIRs enhances the ability to sort target cells, such as virus-infected cells from uninfected cells, according to major histocompatibility complex class I expression.
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Mehta, Rohtesh S., and Katayoun Rezvani. "Can we make a better match or mismatch with KIR genotyping?" Hematology 2016, no. 1 (December 2, 2016): 106–18. http://dx.doi.org/10.1182/asheducation-2016.1.106.
Full textAbstract:
Abstract Natural killer (NK) cell function is regulated by a fine balance between numerous activating and inhibitory receptors, of which killer-cell immunoglobulin-like receptors (KIRs) are among the most polymorphic and comprehensively studied. KIRs allow NK cells to recognize downregulation or the absence of HLA class I molecules on target cells (known as missing-self), a phenomenon that is commonly observed in virally infected cells or cancer cells. Because KIR and HLA genes are located on different chromosomes, in an allogeneic environment such as after hematopoietic stem cell transplantation, donor NK cells that express an inhibitory KIR for an HLA class I molecule that is absent on recipient targets (KIR/KIR-ligand mismatch), can recognize and react to this missing self and mediate cytotoxicity. Accumulating data indicate that epistatic interactions between KIR and HLA influence outcomes in several clinical conditions. Herein, we discuss the genetic and functional features of KIR/KIR-ligand interactions in hematopoietic stem cell transplantation and how these data can guide donor selection. We will also review clinical studies of adoptive NK cell therapy in leukemia and emerging data on the use of genetically modified NK cells that could broaden the scope of cancer immunotherapy.
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Cooley, Sarah, Peter Parham, and Jeffrey S. Miller. "Strategies to activate NK cells to prevent relapse and induce remission following hematopoietic stem cell transplantation." Blood 131, no. 10 (March 8, 2018): 1053–62. http://dx.doi.org/10.1182/blood-2017-08-752170.
Full textAbstract:
Abstract Natural killer (NK) cells are lymphocytes of innate immunity that respond to virus infected and tumor cells. After allogeneic transplantation, NK cells are the first reconstituting lymphocytes, but are dysfunctional. Manipulating this first wave of lymphocytes could be instrumental in reducing the 40% relapse rate following transplantation with reduced-intensity conditioning. NK cells express numerous activating and inhibitory receptors. Some recognize classical or nonclassical HLA class I ligands, others recognize class I–like ligands or unrelated ligands. Dominant in the NK-cell transplant literature are killer cell immunoglobulin-like receptors (KIRs), encoded on chromosome 19q. Inhibitory KIR recognition of the cognate HLA class I ligand is responsible for NK-cell education, which makes them tolerant of healthy cells, but responsive to unhealthy cells having reduced expression of HLA class I. KIR A and KIR B are functionally distinctive KIR haplotype groups that differ in KIR gene content. Allogeneic transplant donors having a KIR B haplotype and lacking a recipient HLA-C epitope provide protection against relapse from acute myeloid leukemia. Cytomegalovirus infection stimulates and expands a distinctive NK-cell population that expresses the NKG2C receptor and exhibits enhanced effector functions. These adaptive NK cells display immune memory and methylation signatures like CD8 T cells. As potential therapy, NK cells, including adaptive NK cells, can be adoptively transferred with, or without, agents such as interleukin-15 that promote NK-cell survival. Strategies combining NK-cell infusions with CD16-binding antibodies or immune engagers could make NK cells antigen specific. Together with checkpoint inhibitors, these approaches have considerable potential as anticancer therapies.
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Andersson, Sandra, Cyril Fauriat, Jenny-Ann Malmberg, Hans-Gustaf Ljunggren, and Karl-Johan Malmberg. "KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression." Blood 114, no. 1 (July 2, 2009): 95–104. http://dx.doi.org/10.1182/blood-2008-10-184549.
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Abstract Inhibitory killer cell immunoglobulin-like receptors (KIRs) preserve tolerance to self and shape the functional response of human natural killer (NK) cells. Here, we have evaluated the influence of selection processes in the formation of inhibitory KIR repertoires in a cohort of 44 donors homozygous for the group A KIR haplotype. Coexpression of multiple KIRs was more frequent than expected by the product rule that describes random association of independent events. In line with this observation, the probability of KIR acquisition increased with the cellular expression of KIRs. Three types of KIR repertoires were distinguished that differed in frequencies of KIR- and NKG2A-positive cells but showed no dependency on the number of self-HLA class I ligands. Furthermore, the distribution of self- and nonself-KIRs at the cell surface reflected a random combination of receptors rather than a selection process conferred by cognate HLA class I molecules. Finally, NKG2A was found to buffer overall functional responses in KIR repertoires characterized by low-KIR expression frequencies. The results provide new insights into the formation of inhibitory KIR repertoires on human NK cells and support a model in which variegated KIR repertoires are generated through sequential and random acquisition of KIRs in the absence of selection.
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Kogure, Toshiaki, Takeshi Tatsumi, Atsushi Niizawa, Hiroshi Fujinaga, Tomoyuki Ito, Yutaka Shimada, and Katsutoshi Terasawa. "No Correlation Exists between Disease Activity and the Expression of Killer-Cell Immunoglobulin-Like Receptors in Patients with Rheumatoid Arthritis." Mediators of Inflammation 2007 (2007): 1–4. http://dx.doi.org/10.1155/2007/65179.
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Objective. The genes for killer-cell immunoglobulin-like receptors (KIRs) have been cloned and their functions and expression in patients with rheumatoid arthritis (RA) have been partially clarified. However, the correlation between their expression and disease activity has not been analyzed in patients with RA. Thus, we measured KIR expression on lymphocytes in patients with RA, and assessed the correlation between KIR expression and disease activity.Patients and Methods. In the cross-sectional study, 15 patients (9 females and 6 males) who fulfilled the diagnostic criteria for RA were assessed. In the longitudinal study, patients who were followed-up for 3 months were assessed. CD158a/b expression on peripheral blood mononuclear cells (PBMC) of RA patients was analyzed using flow cytometry.Results. No significant correlation between KIR expression and CRP, ESR, or IgM-RF was observed. There was no remarkable change in the expression of KIRs between the baseline and after 3 months. Additionally, in the 5 patients whose expression of KIRs particularly changed, the time-related changes in the expression of KIRs were independent from those of inflammation parameters and IgM-RF.Conclusion. There was no correlation between KIR expression and disease activity; therefore, the clinical use of KIR expression should be limited, while unnatural KIR expression may be involved in the pathogenesis of RA, but not a recruitment of chronic inflammation to induce joint damage.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Boelen, Lies, Bisrat Debebe, Marcos Silveira, Arafa Salam, Julia Makinde, Chrissy h. Roberts, Eddie C. Y. Wang, et al. "Inhibitory killer cell immunoglobulin-like receptors strengthen CD8+ T cell–mediated control of HIV-1, HCV, and HTLV-1." Science Immunology 3, no. 29 (November 9, 2018): eaao2892. http://dx.doi.org/10.1126/sciimmunol.aao2892.
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Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell–mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1–, hepatitis C virus (HCV)–, and human T cell leukemia virus type 1 (HTLV-1)–infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections.
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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.
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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.
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Parham, Peter. "Evolution and Immunogenetics of Natural Killer Cell Receptors in Health and Disease." Blood 124, no. 21 (December 6, 2014): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v124.21.sci-25.sci-25.
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Abstract Natural killer (NK) cells are phenotypically diverse lymphocytes that contribute to innate immunity, adaptive immunity and placental reproduction. Unlike B and T cells, NK cells do not use rearranging genes to make diverse antigen receptors that are clonally expressed. Instead, NK cells express diverse combinations of a variety of receptors that are encoded by conventional non-rearranging genes. Several of these receptors are specific for conserved and variable determinants of major histocompatibility complex (MHC) class I molecules. In humans, the killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of NK-cell receptors that recognize determinants of human leukocyte antigen (HLA)-A, B and C, the polymorphic human MHC class I molecules. HLA-A, B and C are the most polymorphic of human genes, and they correlate with susceptibility to a wide range of diseases and clinical outcomes, including allogeneic hematopoietic cell transplantation (HCT). During NK-cell development, interactions between epitopes of HLA class I and KIR educate the NK cells to recognize the normal expression of these epitopes on healthy cells, and to respond to unhealthy cells in which that expression is perturbed. In the context of HCT, certain types of HLA class I mismatch enable donor-derived NK cells to make an alloreactive and beneficial graft-versus-leukemia response. Although it is likely that all placental mammals have NK cells, only a small minority of these species has a diverse KIR family like that in humans. These comprise the simian primates: New World monkeys, Old World monkeys and the great apes. Under pressure from diverse and rapidly evolving pathogens, both the MHC class I and KIR gene families have been driven to evolve rapidly. Consequently, much of their character is species-specific. This is especially true for the human KIR gene family, which is qualitatively different from that of our closest relatives, the chimpanzees. Whereas chimpanzee KIR haplotype diversity represents variations on a theme of genes encoding robust MHC class I receptors, humans have an even balance between group A KIR haplotypes encoding robust HLA class I receptors and group B KIR haplotypes encoding receptors that, to varying degree, have been subject to natural selection for reduced functional recognition of HLA class I. A balance of A and B is present in all human populations and thus appears essential for the long-term survival and competitiveness of human communities. Whereas the A KIR haplotypes correlate with successful defense against viral infection, maternal B KIR haplotypes correlate with reproductive success and donor B KIR haplotypes improve the outcome of allogeneic HCT as therapy for acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.
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Zhao, Xiang-Yu, Xing-Xing Yu, Zheng-Li Xu, Xun-Hong Cao, Ming-Rui Huo, Xiao-Su Zhao, Ying-Jun Chang, et al. "Donor and host coexpressing KIR ligands promote NK education after allogeneic hematopoietic stem cell transplantation." Blood Advances 3, no. 24 (December 23, 2019): 4312–25. http://dx.doi.org/10.1182/bloodadvances.2019000242.
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Abstract The rate and extent of natural killer (NK)–cell education after hematopoietic cell transplantation correlates with leukemia control. To study the effect of donor and host HLA on NK-cell reconstitution, single killer-cell immunoglobulin-like receptor (KIR)+ NK cells (exhibiting KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor) were grouped into 4 groups based on the interaction between donor/host HLA and donor inhibitory KIR in 2 cohorts (n = 114 and n = 276, respectively). On days 90 to 180 after transplantation, the absolute number and responsiveness against K562 cells (CD107a or interferon-γ expression) of single-KIR+ NK cells were higher in pairs where donor and host HLA both expressed ligands for donor inhibitory KIRs than in pairs where 1 or both of the donor and recipient HLA lacked at least 1 KIR ligand. NK-cell responsiveness was tuned commensurate with the number of inhibitory receptors from the donor. When both donor and host expressed the 3 major KIR ligands (HLA-C1, HLA-C2, and HLA-Bw4), NK cells expressing 3 inhibitory receptors (KIR2DL1/2DL3/3DL1) reached the maximum responsiveness against K562 cells compared with those NK cells expressing only 1 or 2 inhibitory receptors. When donor and host HLA both expressed all ligands for donor inhibitory KIRs, patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) showed the lowest recurrence rate after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In conclusion, this study demonstrates that when both donors and hosts present all the KIR ligands for donor KIRs, reconstituted NK cells achieve better functional education and contribute to least relapse among patients. This observation study was registered at www.clinicaltrials.gov as #NCT02978274.
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Henel, Gabriella, Karnail Singh, Dapeng Cui, Sergey Pryshchep, Won-Woo Lee, Cornelia M. Weyand, and Jörg J. Goronzy. "Uncoupling of T-cell effector functions by inhibitory killer immunoglobulin–like receptors." Blood 107, no. 11 (June 1, 2006): 4449–57. http://dx.doi.org/10.1182/blood-2005-06-2519.
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AbstractKiller immunoglobulin–like receptors (KIRs) are a family of regulatory cell-surface molecules expressed on natural killer (NK) cells and memory T-cell subsets. Their ability to prevent the formation of an activation platform and to inhibit NK cell activation is the basis of the missing self model of NK cell function. The benefits of KIR expression for T-cell biology are unclear. We studied how KIR2DL2 regulates T-cell function. Engagement of KIR2DL2 by the ligand human leukocyte antigen (HLA)–Cw3 did not affect conjugate formation between CD4+KIR2DL2+ T cells and superantigen-pulsed target cells or the development of mature immune synapses with lipid rafts. KIR2DL2 and the corresponding HLA-C ligand were initially recruited to the peripheral supramolecular activation cluster (pSMAC). Consequently, KIR2DL2 engagement did not inhibit the phosphorylation of early signaling proteins and T-cell–receptor (TCR)–mediated cytotoxicity or granule exocytosis. After 15-30 minutes, KIR2DL2 moved to the central supramolecular activation cluster (cSMAC), colocalizing with CD3. TCR synapses dissociated, and phosphorylated phospholipase C (PLC)–γ1, Vav1, and extracellular signal–regulated kinase 1/2 (ERK1/2) were reduced 90 minutes after stimulation. Gene array studies documented that the inhibition of late signaling events by KIR2DL2 affected transcriptional gene activation. We propose that KIRs on memory T cells operate to uncouple effector functions by modifying the transcriptional profile while leaving granule exocytosis unabated.
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Savoy, Sarah K. A., and Jeanette E. Boudreau. "The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control." Viruses 11, no. 10 (October 17, 2019): 959. http://dx.doi.org/10.3390/v11100959.
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Viruses and natural killer (NK) cells have a long co-evolutionary history, evidenced by patterns of specific NK gene frequencies in those susceptible or resistant to infections. The killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) ligands together form the most polymorphic receptor-ligand partnership in the human genome and govern the process of NK cell education. The KIR and HLA genes segregate independently, thus creating an array of reactive potentials within and between the NK cell repertoires of individuals. In this review, we discuss the interplay between NK cell education and adaptation with virus infection, with a special focus on three viruses for which the NK cell response is often studied: human immunodeficiency virus (HIV), hepatitis C virus (HCV) and human cytomegalovirus (HCMV). Through this lens, we highlight the complex co-evolution of viruses and NK cells, and their impact on viral control.
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Parham, Peter. "NK Cells and Trophoblasts." Journal of Experimental Medicine 200, no. 8 (October 18, 2004): 951–55. http://dx.doi.org/10.1084/jem.20041783.
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In placental mammals, viviparity—the production of living young within the mother's body—evolved under the auspices of the immune system. Elements of immunity were incorporated, giving pregnancy a mildly inflammatory character. Formation of the placenta, the organ that feeds the fetus, involves a cooperation between maternal natural killer (NK) cells and fetal trophoblast cells that remodels the blood supply. Recent research reveals that this process and human reproductive success are influenced by polymorphic HLA-C ligands and their killer cell immunoglobulin-like receptors (KIR).