Journal articles: 'KIR3DL1'

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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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Forlenza, Christopher J., Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu. "KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma." Journal of Clinical Oncology 34, no. 21 (July 20, 2016): 2443–51. http://dx.doi.org/10.1200/jco.2015.64.9558.

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Purpose In patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect. Methods KIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry. Results KIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(−)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(−) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4–expressing NB targets. Conclusion We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.

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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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O'Connor, Geraldine M., Julian P. Vivian, Emma Gostick, Phillip Pymm, Bernard A. P. Lafont, David A. Price, Jamie Rossjohn, Andrew G. Brooks, and Daniel W. McVicar. "Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1." Journal of Virology 89, no. 10 (March 4, 2015): 5213–21. http://dx.doi.org/10.1128/jvi.03586-14.

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ABSTRACTKiller cell immunoglobulin-like receptors (KIRs) play an important role in the activation of natural killer (NK) cells, which in turn contribute to the effective immune control of many viral infections. In the context of HIV infection, the closely related KIR3DL1 and KIR3DS1 molecules, in particular, have been associated with disease outcome. Inhibitory signals via KIR3DL1 are disrupted by downregulation of HLA class I ligands on the infected cell surface and can also be impacted by changes in the presented peptide repertoire. In contrast, the activatory ligands for KIR3DS1 remain obscure. We used a structure-driven approach to define the characteristics of HLA class I-restricted peptides that interact with KIR3DL1 and KIR3DS1. In the case of HLA-B*57:01, we used this knowledge to identify bona fide HIV-derived peptide epitopes with similar properties. Two such peptides facilitated productive interactions between HLA-B*57:01 and KIR3DS1. These data reveal the presence of KIR3DS1 ligands within the HIV-specific peptide repertoire presented by a protective HLA class I allotype, thereby enhancing our mechanistic understanding of the processes that enable NK cells to impact disease outcome.IMPORTANCENatural killer (NK) cells are implicated as determinants of immune control in many viral infections, but the precise molecular mechanisms that initiate and control these responses are unclear. The activating receptor KIR3DS1 in combination with HLA-Bw4 has been associated with better outcomes in HIV infection. However, evidence of a direct interaction between these molecules is lacking. In this study, we demonstrate that KIR3DS1 recognition of HLA-Bw4 is peptide dependent. We also identify HIV-derived peptide epitopes presented by the protective HLA-B*57:01 allotype that facilitate productive interactions with KIR3DS1. Collectively, these findings suggest a mechanism whereby changes in the peptide repertoire associated with viral infection provide a trigger for KIR3DS1 engagement and NK cell activation.

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Erer, B., M. Takeuchi, D. Ustek, I. Tugal-Tutkun, E. Seyahi, Y. Özyazgan, J. Duymaz-Tozkir, et al. "Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet’s disease." Genes & Immunity 17, no. 7 (October 6, 2016): 396–99. http://dx.doi.org/10.1038/gene.2016.36.

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Gabriel, Ian H., Ruhena Sergeant, Richard Szydlo, Jane F. Apperley, Hugues deLavallade, Abdullah Alsuliman, Ahmad Khoder, et al. "Interaction between KIR3DS1 and HLA-Bw4 predicts for progression-free survival after autologous stem cell transplantation in patients with multiple myeloma." Blood 116, no. 12 (September 23, 2010): 2033–39. http://dx.doi.org/10.1182/blood-2010-03-273706.

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Abstract Natural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1+ (P = .01). This was most evident for patients in complete or partial remission (good risk; GR) at ASCT. The relative risk (RR) of progression or death for patients with KIR3DS1+ compared with KIR3DS1− was 1.9 (95% CI, 1.3-3.1; P = .002). The most significant difference in PFS was observed in patients with GR KIR3DS1+ in whom HLA-Bw4, the ligand for the corresponding inhibitory receptor KIR3DL1, was missing. Patients with KIR3DS1+KIR3DL1+HLA-Bw4− had a significantly shorter PFS than patients who were KIR3DS1−, translating to a difference in median PFS of 12 months (12.2 vs 24 months; P = .002). Our data show that KIR–human leukocyte antigen immunogenetics represent a novel prognostic tool for patients with myeloma, shown here in the context of ASCT, and that KIR3DS1 positivity may identify patients at greater risk of progression.

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Jia, Jie, Keqin Lin, Hao Sun, Jie‐Jie Dai, and Zhao‐Qing Yang. "Identification of two novel KIR3DL1 subtypes, KIR3DL1*0010104 and KIR3DL1*0010105." HLA 93, no. 2-3 (January 16, 2019): 138–39. http://dx.doi.org/10.1111/tan.13457.

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Gabriel, Ian H., Ruhena Sargent, Hugues de Lavallade, Richard Szydlo, Jane Apperley, Ahmad Khoder, Abdullah Alsuliman, et al. "Presence of the Killer Immunoglobulin-Like Gene KIR3DS1 Is Associated with Poor Progression Free and Overall Survival Following Autologous Stem Cell Transplantation in Patients with Myeloma." Blood 114, no. 22 (November 20, 2009): 2840. http://dx.doi.org/10.1182/blood.v114.22.2840.2840.

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Abstract Abstract 2840 Poster Board II-816 Multiple myeloma (MM) remains incurable with a median survival of 3–4 years. Despite high dose therapy and autologous stem cell transplant (ASCT) most patients relapse with median progression-free survival (PFS) of 2.5–4 years and overall survival (OS) of 4–5 years. Although allogeneic SCT (allo-SCT) is potentially curative due to a graft-versus-myeloma effect, its applicability is significantly limited by high transplant related mortality (TRM). Therefore, the identification of additional independent biological predictors of outcome is required in order to tailor therapy to disease. Natural killer (NK) cells provide first line defence against tumors. NK cells have been shown to recognize and kill myeloma cells both in the allogeneic and autologous settings and donor NK genotype has been shown to influence leukemia free survival following allo-SCT. The aim of this study was to investigate the impact of KIR genotype on event-free (EFS) and OS following ASCT for MM. We performed KIR genotyping on 190 patients with MM receiving a first autologous transplant. KIR genotype and haplotype frequencies were comparable to those published for normal controls. Factors found on univariate analysis to be associated with a shorter EFS included haplotype Bx (containing at least 1 of the KIR B haplotype-defining loci- KIR2DL5, 2DS1, 2DS2, 2DS3, 2DS5, or 3DS1) (median 547 vs 656 days, P = 0.036), ≥3 activating KIR genes (median 547 vs 615 days, P = 0.046), the presence of activating KIR genes KIR2DS1 and KIR3DS1 (median 456 vs 589 days, and 464 vs 619 days, P=0.045 and 0.01 respectively). Disease status at ASCT was the most highly predictive factor for EFS. In patients with good risk disease (CR or PR at ASCT) KIR3DS1 status was highly predictive for EFS 464 days (341–586) vs 731 days (599–862) (P = 0.003) and OS 807days (713-901) vs 967 (925-1009) (P=0.023). KIR3DS1 was not predictive in patients with poor risk disease (P=0.36). Of note KIR3DS1+ve patients were equally represented in good risk (CR and PR) and poor risk (refractory or relapsed) groups at ASCT (around 30% in both groups). Notably the median EFS for KIR3DS1+ good risk patients was not significantly different to poor risk disease patients (P = 0.061). ASCT outcome was then determined according to 3 main groups based on disease status and KIR3DS1 status; A: Good Risk, KIR3DS1-ve; B: Good Risk, KIRDS1+ ve; and C Poor risk (KIR3DS1+ve or -ve). The RR of relapse or death was 1.0, 1.9 (P=0.002, 95% CI 1.3-3.1), and 3.0 (P=0.0001, 95% CI 1.9-4.8) respectively. By multivariate analysis, after adjusting for the presence of adverse cytogenetics and serum albumin and β2m, the KIR3DS1 status and grouping remained highly predictive of poor EFS, RR of 1.0, 2.7 (P= 0.021, 95%CI 1.2-6.2) and 5.3 (P= < 0.0001, 95%CI 2.4-11.7) respectively. The prognostic value of KIR3DS1 however, was greatest in patients in whom the ligand for the corresponding inhibitory KIR3DL1, Bw4 was missing. KIR3DS1+ KIR3DL1+ HLA-Bw4 negative patients had significantly reduced median EFS of 400d (315-495) vs 615 (545-684) for all other patients (P=0.048). Again this was most striking in good risk patients. Patients who had the genotype KIR3DS1+ KIR3DL1+ HLA-Bw4 –ve had a significantly shorter EFS survival of 372 days compared to 509 days in KIR3DS1+KIR3DL1+HLA-Bw4+ patients and 793 days for KIR3DS1 negative individuals (P=0.004). In conclusion: Our data from 190 patients with MM suggests that KIR3DS1, a gene previously linked to an increase risk of progression to invasive cervical carcinoma, independently predicts for poor EFS and OS following ASCT. A significant proportion (30%) of patients who are defined as good risk at ASCT (CR and PR) are KIR3DS1+ve and have an EFS which is not significantly different from patients who have refractory/relapsed disease at ASCT. This effect of KIR3DS1 is more significant in the absence of HLA-Bw4, the ligand for the inhibitory receptor KIR3DL1. The mechanism for this is effect is unclear and we are currently performing functional studies to further understand these findings. Disclosures: Apperley: Novartis: Consultancy, Honoraria. Marin:Novartis: Consultancy, Research Funding.

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Saunders, Philippa M., Phillip Pymm, Gabriella Pietra, Victoria A. Hughes, Corinne Hitchen, Geraldine M. O’Connor, Fabrizio Loiacono, et al. "Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition." Journal of Experimental Medicine 213, no. 5 (April 4, 2016): 791–807. http://dx.doi.org/10.1084/jem.20152023.

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Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1–HLA-I interface, the structures of these three KIR3DL1–HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs.

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Lang, Kathrin, Marie Guenther, Stefan Bentink, Alexander H. Schmidt, Gerhard Schoefl, and Vinzenz Lange. "P108 Phased whole-gene characterization of novel KIR3DL1 , KIR3DL2 , and KIR3DL3 alleles using a dual redundant sequencing strategy." Human Immunology 78 (September 2017): 133. http://dx.doi.org/10.1016/j.humimm.2017.06.168.

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Vendelbosch, S., M. de Boer, D. van der Heijde, T. K. van den Berg, F. A. van Gaalen, and T. W. Kuijpers. "KIR3DL1 and KIR3DL2 gene copy number variation in axial spondyloarthritis." Tissue Antigens 85, no. 6 (May 4, 2015): 497–98. http://dx.doi.org/10.1111/tan.12563.

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Alter, Galit, Suzannah Rihn, Katharine Walter, Anne Nolting, Maureen Martin, Eric S. Rosenberg, Jeffrey S. Miller, Mary Carrington, and Marcus Altfeld. "HLA Class I Subtype-Dependent Expansion of KIR3DS1+ and KIR3DL1+ NK Cells during Acute Human Immunodeficiency Virus Type 1 Infection." Journal of Virology 83, no. 13 (April 22, 2009): 6798–805. http://dx.doi.org/10.1128/jvi.00256-09.

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ABSTRACT NK cells are critical in the early containment of viral infections. Epidemiological and functional studies have shown an important role of NK cells expressing specific killer immunoglobulin-like receptors (KIRs) in the control of human immunodeficiency virus type 1 (HIV-1) infection, but little is known about the mechanisms that determine the expansion of these antiviral NK cell populations during acute HIV-1 infection. Here we demonstrate that NK cells expressing the activating receptor KIR3DS1+ and, to a lesser extent, the inhibitory receptor KIR3DL1+ specifically expand in acute HIV-1 infection in the presence of HLA-B Bw480I, the putative HLA class I ligand for KIR3DL1/3DS1. These data demonstrate for the first time the HLA class I subtype-dependent expansion of specific KIR+ NK cells during an acute viral infection in humans.

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Shaffer, Brian C., Glenn Heller, Jean-Benoit Le Luduec, Jack Vahradian, Miguel Perales, Sergio A. Giralt, Roni Tamari, et al. "Selection of Unrelated Allogeneic Hematopoietic Cell Donors Based on KIR3DL1 Allotypes Is Feasible and Results in Improved Disease-Free Survival in Transplant Recipients with MDS and AML." Blood 128, no. 22 (December 2, 2016): 990. http://dx.doi.org/10.1182/blood.v128.22.990.990.

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Abstract Donor natural killer (NK) cells impart a potent anti-leukemia effect after allogeneic hematopoietic cell transplantation (allo HCT). The killer Ig-like receptors (KIR) play a central role in modulating NK effector function. Chief among them, the inhibitory KIR3DL1 exhibits a high degree of allelic polymorphism. We previously demonstrated that highly expressed KIR3DL1 alleles (KIR3DL1 allele groups *001 and *002) bind preferentially to HLA-Bw4 with I80 to confer a high degree of inhibitory signaling. Similarly, poorly expressed KIR3DL1 alleles (KIR3DL1 allele groups *005 and *007) bind to HLA-Bw4 with T80 to confer a strong inhibitory signal. In a retrospective cohort of 299 patients undergoing allo HCT for AML, we demonstrated that these highly inhibitory donor KIR3DL1/recipient HLA-Bw combinations (KIR3DL1-HIGH) resulted in a greater incidence of recipient relapse when compared to other donor/recipient KIR3DL1/HLA-Bw pairings with low or absent inhibitory signal (KIR3DL1-LOW/NO). (Giglio F et al, ASH Annual Meeting Abstracts, 2012) Here, we evaluated whether it was feasible to prospectively type and use KIR3DL1 allotypes in unrelated allo HCT donor selection, and whether this intervention would result in improved outcomes in patients undergoing transplant for AML and MDS. We performed PCR-SSP based intermediate resolution KIR3DL1 allele typing on all unrelated adult donors evaluated for patients with MDS and AML at our center from 2013 to present as previously described. (Boudreau J et al, PLoS One, 2014) KIR3DL1 status was provided to the treating physicians, who made the final donor selection. A total of 941 prospective allo HCT donors underwent high resolution HLA typing and KIR3DL1 allotyping for 252 patients (median per patient = 4, range 1-12). Among all donors evaluated, 27% were found to be KIR3DL1-HIGH when considering the respective recipient HLA-Bw. Having multiple donors evaluated improved the likelihood of avoiding a KIR3DL1-HIGH donor: Among recipients with one donor evaluated, 27% had only KIR3DL1-HIGH donors available compared to 12% in recipients with 2-3 donors evaluated and 4% for recipients with >3 donors evaluated (P < 0.0001). Among all evaluated patients, 41% had both KIR3DL1-HIGH and KIR3DL1-LOW/NO donors available, indicating a potential selection based on KIR3DL1 was possible. Among 252 patients evaluated, 115 proceeded to allo HCT (48 with MDS, 67 with AML). The median age at transplant was 62 years (range 3.6-78). Donors were HLA matched in 105 transplants and were single loci mismatched in 10 transplants. Conditioning was myeloablative in 73 (11 with total body irradiation). GVHD prophylaxis was with ex vivo CD34+ selection in 65 patients and with tacrolimus/methotrexate in the remaining patients. The median follow-up in transplanted patients was 13.1 months (range 0.5-43.3 months). On univariate analysis, the 2-year disease-free survival was 64% (95% confidence interval: 54-76%) in those with KIR3DL1-LOW/NO donors versus 39% (22-68%) in recipients with KIR3DL1-HIGH donors (P = 0.05). The incidence of relapse was similar but favored patients with KIR3DL1-LOW/NO donors (26% [15-37%] versus 35% [13-57%], P = 0.5). 2-year overall survival was similar between those with KIR3DL1-LOW/NO versus KIR3DL1-HIGH donors (75% [65-86%] versus 69% [52-91%], P = 0.43). The time from the initiation of a formalized donor search to transplant did not differ between recipients with KIR3DL1-LOW/NO versus KIR3DL1-HIGH donors (median 81 v. 83 days, respectively, P = 0.97). Recipients with KIR3DL1-LOW/NO donors were CIBMTR Transplant Risk Score low = 53, intermediate = 6, and high = 33; whereas recipients of KIR3DL1-HIGH donors were low = 17, intermediate = 2, and high = 4 (P = 0.15). These results indicate that disease severity and transplant urgency did not influence whether a KIR3DL1-LOW/NO donor was able to be selected. In summary, these prospective data on 115 patients from a single center support improved outcomes in patients with AML and MDS undergoing unrelated donor allo HCT using a donor with low or absent KIR3DL1 inhibition. A multi-center, prospective study to evaluate the prospective use of HLA and KIR genotype based selection of URDs for patients undergoing allo HCT for AML is underway (NCT02450708). Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kernan: Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding.

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Khakoo, Salim I., Ron Geller, Sunny Shin, Jomaquai A. Jenkins, and Peter Parham. "The D0 Domain of KIR3D Acts as a Major Histocompatibility Complex Class I Binding Enhancer." Journal of Experimental Medicine 196, no. 7 (October 7, 2002): 911–21. http://dx.doi.org/10.1084/jem.20020304.

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In contrast to the KIR2D:HLA-C interaction, little is known of KIR3DL1's interaction with HLA-B or the role of D0, the domain not present in KIR2D. Differences in the strength and specificity for major histocompatibility complex class I of KIR3DL1 and its common chimpanzee homologue Pt-KIR3DL1/2 were exploited to address these questions. Domain-swap, deletion, and site-directed mutants of KIR3DL1 were analyzed for HLA-B binding using a novel, positively signaling cell–cell binding assay. Natural ‘deletion’ of residues 50 and 51 from its D0 domain causes Pt-KIR3DL1/2 to bind Bw4+ HLA-B allotypes more avidly than does KIR3DL1. Deletion of these residues from KIR3DL1, or their substitution for alanine, enhanced binding of Bw4+ HLA-B. None of 15 different point mutations in D0 abrogated KIR3DL1 binding to Bw4+ HLA-B. In contrast point mutations in the D1 and D2 domains of KIR3DL1, made from knowledge of KIR2D:HLA-C interactions, disrupted binding to Bw4+ HLA-B. The results are consistent with a model in which D1 and D2 make the principal contacts between KIR3DL1 and HLA-B while D0 acts through a different mechanism to enhance the interaction. This modulatory role for D0 is compatible with natural loss of expression of the D0 domain, a repeated event in the evolution of functional KIR genes.

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SORGHO, Abel Pegdwendé, Jeremy James MARTINSON, Florencia Wendkuuni Djigma, Albert Théophane YONLI, Bolni Marius NAGALO, Rebeca Tégwindé COMPAORE, Dorcas OBIRI-YEBOAH, et al. "Insights into the interplay between KIR gene frequencies and chronic HBV infection in Burkina Faso." Mediterranean Journal of Hematology and Infectious Diseases 10 (November 1, 2018): e2018060. http://dx.doi.org/10.4084/mjhid.2018.060.

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Background/Objective: The receptors of natural killer cells "Killer Cell Immunoglobulin-Like Receptor" (KIR) regulate the activity of Natural killer cells in the innate response against viral infections. To date there is no accurate method to identify high risk groups for cirrhosis and HCC in Sub-Saharan Africa. Therefore, this investigation was undertaken to assess the association between KIR genes frequencies and chronic infection HBV infection in Burkina Faso’s population. Methods: Chronic HBV carriers and healthy patients were selected for this study. The viral load for HBV were performed to confirm the serological status for HBV of the studied cohort. In addition, SSP-PCR was used to characterize the frequencies of KIR genes.Results: The study suggested that inhibitory genes KIR2DL2, KIR2DL3 and activator gene KIR2DS2 (p˂0.001 for all and OR = 2.82; 2.48 and 3.84 respectively) might be associated with chronic stages of HBV infection. While inhibitory genes KIR3DL1 (p = 0.0018 OR = 0.49), KIR3DL2 (p = 0.005 OR = 0.40), the activator gene KIR2DS1 (p = 0.014 OR = 0.47) and the pseudo gene KIR2DP1 (p = 0.011 OR = 0.49) could be associated with immunity against HBV infection. Patients who carried the KIR3DL2 gene had a high HBV viral load compared to the rest of the study population. Conclusion: Our data showed an evidence of correlation between the propensity of developing chronic HBV infection and certain KIR gene frequencies and that KIR3DL1, KIR3DL2, KIR2DS1 and KIR2DP1 might confer a protective status against chronic HBV infection in Burkina Faso’s patients.

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Grifoni, Alba, Carla Montesano, Atanas Patronov, Vittorio Colizzi, and Massimo Amicosante. "Immunoinformatic Docking Approach for the Analysis of KIR3DL1/HLA-B Interaction." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/283805.

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KIR3DL1 is among the most interesting receptors studied, within the killer immunoglobulin receptor (KIR) family. Human leukocyte antigen (HLA) class I Bw4 epitope inhibits strongly Natural Killer (NK) cell’s activity through interaction with KIR3DL1 receptor, while Bw6 generally does not. This interaction has been indicated to play an important role in the immune control of different viral infectious diseases. However, the structural interaction between the KIR3DL1 receptor and different HLA-B alleles has been scarcely studied. To understand the complexity of KIR3DL1-HLA-B interaction, HLA-B alleles carrying Bw4/Bw6 epitope and KIR3DL1*001 allele in presence of different peptides has been evaluated by using a structural immunoinformatic approach. Different energy minimization force fields (ff) have been tested and NOVA ff enables the successful prediction of ligand-receptor interaction. HLA-B alleles carrying Bw4 epitope present the highest capability of interaction with KIR3DL1*001 compared to the HLA-B alleles presenting Bw6. The presence of the epitope Bw4 determines a conformational change which leads to a stronger interaction between nonpolymorphic arginine at position 79 of HLA-B and KIR3DL1*001 136–142 loop. The data shed new light on the modalities of KIR3DL1 interaction with HLA-B alleles essential for the modulation of NK immune-mediated response.

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Mulrooney, Tiernan J., Aaron C. Zhang, Yehuda Goldgur, Jeanette E. Boudreau, and Katharine C. Hsu. "KIR3DS1-Specific D0 Domain Polymorphisms Disrupt KIR3DL1 Surface Expression and HLA Binding." Journal of Immunology 195, no. 3 (June 24, 2015): 1242–50. http://dx.doi.org/10.4049/jimmunol.1500243.

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McCappin, J., D. Harvey, B. P. Wordsworth, and D. Middleton. "No association of KIR3DL1 or KIR3DS1 or their alleles with ankylosing spondylitis." Tissue Antigens 75, no. 1 (January 2010): 68–73. http://dx.doi.org/10.1111/j.1399-0039.2009.01392.x.

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Boudreau, Jeanette E., Jean-Benoit Le Luduec, and Katharine C. Hsu. "KIR3DL1 and HLA-Bw4 Allotypes Predict The Extent Of NK Cell Licensing." Blood 122, no. 21 (November 15, 2013): 1043. http://dx.doi.org/10.1182/blood.v122.21.1043.1043.

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Abstract Members of the killer immunoglobulin family (KIR) and their HLA class I ligands contribute to establishing natural killer cell reactive potential. NK cells bearing inhibitory KIR that bind self-HLA are termed “licensed” and are highly responsive to targets lacking self HLA, but tolerant to autologous, healthy cells. Among KIR:HLA partnerships, KIR3DL1 and HLA-Bw4 alleles demonstrate the greatest polymorphism. Allelic subgroups of KIR3DL1 are distinguished by their density on the surface of NK cells and demonstrate different sensitivity to inhibition by HLA-Bw4 allotypes. Specifically, KIR3DL1 alleles expressed with high surface density (3DL1high) are more potently inhibited by HLA-Bw4 epitopes possessing isoleucine (80I) compared with threonine (80T) at position 80. It is not currently known whether the same KIR-HLA interactions that mediate higher inhibitory response also endow higher effector capacity. Retrospective analyses of patients with HIV have demonstrated that the same allelic combinations of HLA-B and KIR3DL1 predictive of high inhibition are associated with delayed progression to AIDS. Indeed, a potential target for NK cells is created by the HIV nef protein, which mediates downregulation of HLA-B expression. Taken together, these finding have led us to hypothesize that the sensitivity of NK cells for inhibition by HLA predicts the extent to which they may be licensed for functional responsiveness. We undertook functional analyses of NK cells exclusively expressing KIR3DL1 from healthy HLA-Bw4+ or Bw4-/- donors, using HLA-negative 721.221 target cells to examine licensing function. First, we developed and validated a multiplex PCR array allowing identification of allelic groups of KIR3DL1 that correspond to expression densities. This genomic analysis informed the division of 59 subjects into groups stratified by the inhibitory potential conveyed by self HLA-B and KIR3DL1+ alleles. As expected and consistent with NK education or “licensing” by self-specific inhibitory KIR with cognate HLA ligand, KIR3DL1+Bw4+ NK cells demonstrated greater responsiveness 721.221 cells compared with KIR3DL1+ cells obtained from Bw4-/- donors, as assessed by CD107α externalization. The proportion of KIR3DL1+ NK cells degranulating in response to HLA class I-negative target cells was highly variable and not reflective of either HLA-Bw4 nor KIR3DL1 allele groups alone; however, when both KIR3DL1 and Bw4 allele groups were considered, highly inhibitory allotype pairs were indeed associated with higher NK effector function (p=0.0065). This finding was particularly pronounced among partnerships involving high-density KIR3DL1 alleles: compared with 80T, 80I conditioned 3DL1high NK cells for superior 721-221-stimulated degranulation (p=0.0035). We further investigated whether NK cell licensing could be mediated and/or maintained by HLA intrinsic to NK cells. We found that diminution of HLA expression in licensed KIR3DL1+ by shRNA-mediated knockdown reduced responsiveness to HLA class I-negative target cells, demonstrating that HLA is required on NK cells to maintain their licensed potential. Collectively, these findings reveal that an NK cell’s capacity for effector response is not only determined by the presence of a self-specific receptor, but that functional hierarchies exist among NK cells bearing different allotypes of one KIR for its ligand in a manner correlated with inhibitory capacity. Finally, cis-interactions between KIR and HLA contribute to NK licensing, indicating that human NK education is at least partly determined by molecules intrinsic to the cell itself. These findings of differential NK licensing among KIR3DL1-Bw4 allotype combinations now provide the biological basis for the clinical findings of variable HIV control among patients with different KIR3DL1-Bw4 allotype combinations. Disclosures: No relevant conflicts of interest to declare.

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Marra, John, Juan Du, Jimmy Hwang, Jeffrey L. Wolf, Thomas G. Martin, and Jeffrey M. Venstrom. "KIR and HLA Genotypes Influence Clinical Outcome in Multiple Myeloma Patients Treated with SAR650984 (Anti-CD38) in Combination with Lenalidomide and Dexamethasone." Blood 124, no. 21 (December 6, 2014): 2126. http://dx.doi.org/10.1182/blood.v124.21.2126.2126.

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Abstract SAR650984 (SAR) is a humanized IgG1 monoclonal antibody that binds selectively to the human CD38 receptor. TCD11863 (TCD) is a phase Ib trial evaluating the combination of SAR with lenalidomide (LEN) and dexamethasone (Dex) in relapsed/refractory multiple myeloma (RRMM) [NCT01749969]. Because natural killer (NK) cells contribute to antibody-dependent cellular cytotoxicity, we hypothesized that immunogenetic factors contributing to NK cell function would influence clinical activity among RRMM patients treated with SAR/LEN/Dex. We therefore prospectively performed KIR and HLA class I genotyping on 31 RRMM patients enrolled in TCD. We used the typing data to stratify patients based on predicted differences in KIR3DL1, HLA-Bw4 receptor-ligand binding affinities. We used the Kaplan-Meier method to estimate probabilities of progression-free survival (PFS) and time to progression (TTP) among all 31 treated patients, with the log-rank test to evaluate differences in survival distributions based on patient KIR and HLA genotype status, the cox proportional hazard model to examine the association of the hazard of failure with genotype status, and the Fischer's exact test to compare overall response rates (ORR) among 28 evaluable patients. P-values are provided for exploratory purpose, since the study was not powered for formal comparison of efficacy variables by genotype subgroup. Of the 31 patients, 12 had a high-affinity KIR3DL1,HLA-B Bw4-80Ile compound genotype (including 3 with both HLA-A and HLA-BBw4-80Ile), and 19 lacked the KIR3DL1,HLA-B Bw4-80Ile genotype, with 7 of these 19 patients possessing a low-affinity KIR3DL1, HLA-Bw4-80Thr genotype (including 1 with HLA-ABw4-80Ile), 7 with a missing ligand or receptor genotype, and 5 with a KIR3DL1, HLA-ABw4-80Ile genotype not containing other HLA-B Bw4 alleles. Presence of a high-affinity KIR3DL1,HLA-B Bw4-80Ile genotype (n=12, 10 evaluable for ORR) was associated with high ORR and prolonged TTP and PFS relative to patients lacking KIR3DL1,HLA-B Bw4-80Ile (n=19, 18 evaluable for ORR; 90% ORR vs. 56%, P=0.10; TTP HR 0.11, [95% CI] 0.08-0.68, P<0.01; PFS HR 0.22, [95% CI] 0.05-0.98, P=0.03). The benefit of KIR3DL1,HLA-B Bw4-80Ile varied with gene dose, such that the proportion of patients remaining on treatment increased with increasing copy number of HLA-B Bw4-80Ile from 0 (n=19) to 1 (n=8) to 2 (n=4) copies, with 21% remaining on treatment at 6 months vs. 50% vs. 100% (TTP P=0.02). Because HLA-A Bw4-80Ile ligands bind KIR3DL1 with different strength and specificity than HLA-B Bw4-80Ile ligands, we separated patients with KIR3DL1, HLA-ABw4-80Ile from patients with KIR3DL1, HLA-BBw4-80Ile and found a specific association of prolonged PFS among patients with a pure high-affinity KIR3DL1,HLA-B Bw4-80Ile genotype (n=9; 7 patients remain on treatment at 6 months, 2 AEs), compared with patients with a pure KIR3DL1, HLA-A Bw4-80Ile genotype (n=5; 2 on treatment at 6 months, 3 PDs), a KIR3DL1, HLA-ABw4-80Ile genotype containing other HLA-B Bw4 alleles (n=4), a pure low-affinity KIR3DL1, HLA-Bw4-80Thr genotype (n=6; 2 on treatment at 6 months, 3 PDs, and 1 AE), and a missing KIR3DL1 ligand or receptor genotype (n=7; 3 on treatment at 6 months, 3 PDs, and 1 AE) [PFS P=0.02]. While the number of prior therapies (2-4 vs. 5-7 vs. 8-12, P=0.02) and ISS stage at the start of treatment (stage I to III, P<0.01) also influenced PFS, possession of KIR3DL1,HLA-B Bw4-80Ile was associated with prolonged PFS within each of these subgroups. In summary, a KIR3DL1, HLA-B Bw4-80Ile genotype predictive of high-affinity NK cell receptor-ligand interactions and potent NK cell licensing correlated with increased ORR and PFS among patients treated with SAR/LEN/Dex, although the small sample size requires validation in future studies. Disclosures Martin: Sanofi: Research Funding. Venstrom:Sanofi Oncology: Research Funding.

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Grifoni, Alba, Atanas Patronov, Carla Montesano, Vittorio Colizzi, and Massimo Amicosante. "Structural Differences in KIR3DL1 and LILRB1 Interaction with HLA-B and the Loading Peptide Polymorphisms: In Silico Evidences." Computational Biology Journal 2015 (November 16, 2015): 1–10. http://dx.doi.org/10.1155/2015/427217.

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KIR3DL1 and LILRB1 interact with HLA class I. Using KIR3DL1/HLA-B interaction to set up the procedure, structural immune-informatics approaches have been performed in LILRB1/HLA-B alleles’ combination also considering the contribution of the HLA bound peptide. All KIR3DL1 alleles interact strongly with HLA-B alleles carrying Bw4 epitope and negative charged amino acid residues in peptide position P8 disrupt KIR3DL1 binding. HLA-B alleles carrying Ile 194 show a higher strength of interaction with LILRB1 in all the analyzed haplotypes. Finally, we hypothesize a contribution of the amino acid at position 1 of the HLA bound peptide in the modulation of HLA-B/LILRB1 interaction.

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Shaffer, Brian C., Jean-Benoit Le Luduec, Soo Park, Sean Devlin, Anne Archer, Eric Davis, Candice Cooper, et al. "Prospective KIR genotype evaluation of hematopoietic cell donors is feasible with potential to benefit patients with AML." Blood Advances 5, no. 7 (April 12, 2021): 2003–11. http://dx.doi.org/10.1182/bloodadvances.2020002701.

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Abstract Donor KIR and recipient HLA combinations that minimize inhibition and favor activation of the NK repertoire are associated with improved outcomes after allogeneic hematopoietic cell transplantation (HCT) in patients with myeloid neoplasia. We prospectively evaluated a weighted donor ranking algorithm designed to prioritize HLA-compatible unrelated donors (URDs) with weak inhibitory KIR3DL1/HLA-Bw4 interaction, followed by donors with nontolerized activating KIR2DS1, and finally those with KIR centromeric B haplotype. During donor evaluation, we performed KIR genotyping and ranked 2079 URDs for 527 subjects with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Among all patients, 394 (75%) had at least 1 KIR-advantageous donor, and 263 (50%) underwent HCT. In patients with AML, KIR3DL1 weak inhibition provided protection from relapse. Compared with KIR3DL1-Weak Inhibiting donors, KIR3DL1-Noninteracting donors were associated with increased risk of relapse (HR, 2.97; 95% CI, 1.33-6.64; P = .008) and inferior event-free survival (EFS; HR, 2.14; 95% CI, 1.16-3.95; P = .015). KIR3DL1-Strong Inhibiting donors were associated with HR, 1.65 (95% CI, 0.66-4.08; P = .25) for AML relapse and HR, 1.6 (95% CI, 0.81-3.17; P = .1) for EFS when compared with the use of KIR3DL1-weak inhibiting donors. Donor KIR2DS1/HLA-C1 status and centromeric KIR haplotype-B content were not associated with decreased risk of AML relapse. There was no benefit to KIR-based donor selection in patients with MDS. This study demonstrates that donor KIR typing is feasible, and prioritization of donors with certain KIR3DL1 genotypes may confer a protection from relapse after HCT in patients with AML.

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Geng, Jie, and Malini Raghavan. "CD8αα homodimers function as a coreceptor for KIR3DL1." Proceedings of the National Academy of Sciences 116, no. 36 (August 16, 2019): 17951–56. http://dx.doi.org/10.1073/pnas.1905943116.

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Cluster of differentiation 8 (CD8) is a cell surface glycoprotein, which is expressed as 2 forms, αα homodimer or αβ heterodimer. Peptide-loaded major histocompatibility complex class I (pMHC-I) molecules are major ligands for both forms of CD8. CD8αβ is a coreceptor for the T cell receptor (TCR) and binds to the same cognate pMHC-I as the TCR, thus enabling or augmenting T cell responses. The function of CD8αα homodimers is largely unknown. While CD8αβ heterodimer is expressed exclusively on CD8+ T cells, the CD8αα homodimer is present in subsets of T cells and human natural killer (NK) cells. Here, we report that the CD8αα homodimer functions as a coreceptor for KIR3DL1, an inhibitory receptor of NK cells that is specific for certain MHC-I allotypes. CD8αα enhances binding of pMHC-I to KIR3DL1, increases KIR3DL1 clustering at the immunological synapse, and augments KIR3DL1-mediated inhibition of NK cell activation. Additionally, interactions between pMHC-I and CD8αα homodimers regulate KIR3DL1+ NK cell education. Together, these findings reveal another dimension to the modulation of NK cell activity.

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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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Graciano-Machuca, Omar, Anabell Alvarado-Navarro, María Guadalupe Ramírez-Dueñas, Delfina Guadalupe Villanueva-Quintero, Erandi Enif Velarde-de la Cruz, Andrea Carolina Machado-Sulbarán, Margarita Montoya-Buelna, and Pedro Ernesto Sánchez-Hernández. "Diversity of KIR/HLA Genotypes and Their Association with Psoriasis Vulgaris in the Western Mexican Population." Genes 11, no. 3 (March 22, 2020): 338. http://dx.doi.org/10.3390/genes11030338.

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NK and some T cell functions are regulated by the interaction between KIR and HLA molecules. Several studies have shown an association between activating KIR genes and the development of autoimmune diseases, including psoriasis vulgaris (PsV). Our objective was to determine the association between KIR/HLA genes and genotypes with PsV in the Western mestizo Mexican population. One hundred subjects diagnosed with PsV (SP) and 108 healthy subjects (HS) were genotyped for 14 KIR genes, HLA-Bw4, HLA-C1, and HLA-C2 by PCR-single specific primer (SSP). Positive associations of the KIR3DS1 gene (odds ratio (OR) 1.959, p = 0.021), G11 genotype (OR 19.940, p = 0.008), and KIR3DS1/HLA-ABw4 (OR 2.265, p = 0.009) were found with susceptibility to PsV. In contrast, the G1 genotype (OR 0.448, p = 0.031) and KIR3DL1/HLA-Bw4Ile80 (OR 0.522, p = 0.022) were negatively associated with susceptibility to this disease. These results suggest an implication of the KIR3DS1/HLA-ABw4 genotype in PsV pathology.

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van der Ploeg, Kattria, Jean-Benoît Le Luduec, Philip A. Stevenson, Soo Park, Ted A. Gooley, Effie W. Petersdorf, Brian C. Shaffer, and Katharine C. Hsu. "HLA-A alleles influencing NK cell function impact AML relapse following allogeneic hematopoietic cell transplantation." Blood Advances 4, no. 19 (October 13, 2020): 4955–64. http://dx.doi.org/10.1182/bloodadvances.2020002086.

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Abstract HLA-B allotypes exhibiting the Bw4 epitope trigger variable inhibitory signaling of KIR3DL1 receptor types, where strong inhibitory HLA-B and KIR3DL1 allele combinations are associated with increased risk for relapse of acute myelogenous leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). Several HLA-A allotypes also exhibit the Bw4 epitope. Studies with natural killer (NK) cell clones have demonstrated NK inhibition via KIR3DL1 by HLA-A Bw4+ allotypes, but did not delineate strengths of inhibition or hierarchies of NK education. Using primary NK cells from healthy donors, we demonstrate that HLA-A*23, HLA-A*24, and HLA-A*32 proteins are expressed at different densities and exhibit different capacities to educate and inhibit KIR3DL1-expressing NK cells in vitro. Among the HLA-A Bw4+ allotypes, HLA-A*24 and HLA-A*32 demonstrate the strongest inhibitory capacity. To determine if HLA-A allotypes with strong inhibitory capacity have similar negative impact in allogeneic HCT as HLA-B Bw4+ allotypes, we performed a retrospective analysis of 1729 patients with AML who received an allogeneic HCT from a 9/10 or 10/10 HLA allele-matched unrelated donor. Examination of the donor-recipient pairs whose Bw4 epitope was exclusively contributed from HLA-A*24 and A*32 allotypes revealed that patients with HLA-A*24 who received an allograft from a KIR3DL1+ donor experienced a higher risk of disease relapse (hazard ratio, 1.65; 95% confidence interval, 1.17-2.32; P = .004) when compared with patients without a Bw4 epitope. These findings indicate that despite weak affinity interactions with KIR3DL1, common HLA-A allotypes with the Bw4 epitope can interact with KIR3DL1+ donor NK cells with clinically meaningful impact and provide additional insight to donor NK alloreactivity in HLA-matched HCT.

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Ravet, Sophie, Daniel Scott-Algara, Elodie Bonnet, Hung Khiem Tran, Ton Tran, Ngai Nguyen, Lien Xuan Truong, et al. "Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals." Blood 109, no. 10 (February 1, 2007): 4296–305. http://dx.doi.org/10.1182/blood-2006-08-040238.

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Abstract We have previously associated high natural killer (NK)–cell activity and protection against HIV-1 infection in Vietnamese exposed uninfected intravascular drug users (EUs). Considering that activating and inhibitory signals sensed by NK-cell receptors regulate NK-cell activation, we performed phenotypic and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) transcript analyses of the NK-cell receptor (NKR) repertoire in 25 EUs, 19 HIV+ intravenous drug users, and 26 uninfected blood donors. Although NK-cell activation was not linked to a unique NKR repertoire in EUs, various patterns consistent with NK-cell activation were detected in EUs: high KIR3DS1/KIR3DL1 ratio associated with down-regulated KIR3DL1 transcript levels, KIR2DL3+ low-affinity receptor expansion associated to group HLA-C1 ligand in 2DS2−/2DL2− EUs, enhanced NKG2C/NKG2A ratio, and increased CD69 expression. Remarkably, EUs exhibited high constitutive degranulation activity in the absence of exogenous stimulation, as shown by the CD107a assay. Furthermore, CD161 expression was increased within the CD107a+ NK-cell compartment. Our results suggest that in response to viral exposition, particular genetic or regulated features of the NKR repertoire of EUs contribute to their high constitutive NK-cell potential. This might allow NK cells to generate a more rapid and effective immune response to HIV-1, thereby contributing to prevention toward infection.

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Sorgho, Pegdwendé Abel, Florencia Wendkuuni Djigma, Jeremy James Martinson, Albert Théophane Yonli, Bolni Marius Nagalo, Tégwindé Rebeca Compaore, Birama Diarra, et al. "Role of Killer cell immunoglobulin-like receptors (KIR) genes in stages of HIV-1 infection among patients from Burkina Faso." Biomolecular Concepts 10, no. 1 (December 19, 2019): 226–36. http://dx.doi.org/10.1515/bmc-2019-0024.

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AbstractObjectivesA cluster of specialized KIR genes of specialized KIR genes has been shown to be associated with susceptibility or resistance to viral infections in humans. Therefore, this pilot study, this pilot investigation sought to determine the frequencies of KIR genes human immunodeficiency virus type 1( HIV-1) patients and establish their potential clinical involvement in disease progression and staging.MethodsHIV-1 infected and healthy individuals were selected for this study. Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and anti-HIV-1/2 antibody/ antigen were screened using a 4th generation ELISA assay (Cobas e 411 Analyzer, Roche Diagnostics GmbH Mannheim, Germany). SSP-PCR was used to evaluate the frequencies of KIR genes. CD4+ T counts and HIV-1 viral load were measured in patients using respectively BD FACSCount and Abbott m2000rt instruments.ResultsWe found a significant association between the frequencies of KIR2DL2 (OR=4.41; p < 0.001), KIR2DS2 (OR=4.76; p < 0.001), KIR2DS3 (OR=2.27; p=0.004), KIR2DS4 (OR=1.76; p=0.026), KIR3DS1 (OR=2.43; p=0.016) and HIV-1 infection; whilst the KIR3DL1 gene (OR= 0.39; p < 0.001) was associated with protection against HIV-1 infection. HIV-1 replication was found to be associated with the presence of KIR2DS2 (OR=6.08, p = 0.024). In contrary the pseudogene KIR2DP1 (OR=0.39; p=0.026) were linked to a protective status with the highest number of lymphocyte T CD4 counts.ConclusionOur data showed that KIR2DL2, KIR2DS2, KIR2DS3, KIR2DS4, and KIR3DS1 were significantly associated with HIV-1 infection whereas KIR3DL1 was associated with protection against HIV-1 infection. Further investigations are needed to fully comprehend the clinical significance of KIR genes in HIV disease progression.

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Stern, Martin, Loredana Ruggeri, Marusca Capanni, Antonella Mancusi, and Andrea Velardi. "Human leukocyte antigens A23, A24, and A32 but not A25 are ligands for KIR3DL1." Blood 112, no. 3 (August 1, 2008): 708–10. http://dx.doi.org/10.1182/blood-2008-02-137521.

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Abstract Inhibitory killer cell immunoglobulin receptors (KIR) bind to major histocompatibility complex antigens. Concise knowledge of KIR ligands allows prediction of natural killer (NK)–cell alloreactivity after hematopoietic stem cell transplantation. KIR3DL1 binds to the Bw4 epitope on HLA-B antigens. Although the same epitope is also found on 4 HLA-A antigens (HLA-A23/24/25/32), these are not currently regarded as KIR3DL1 ligands. We show that expression of HLA A*2301, A*2402, or A*3201 but not HLA A*2501 protects target cells from lysis by KIR3DL1+ NK cells. KIR3DL1+ NK cells from donors expressing the Bw4 epitope on an HLA-A antigen only are fully functional and capable of lysing Bw4− target cells. HLA A25 differs at amino acid 90, close to the serologic Bw4 epitope, from A23/24/32 and from Bw4+ HLA-B antigens. These data suggest that HLA-A antigens should be taken into consideration when assessing the potential for NK alloreactivity after hematopoietic stem cell transplantation.

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Gagne, Katia, Catherine Willem, Nolwenn Legrand, Zakia Djaoud, Gaëlle David, Pauline Rettman, Céline Bressollette-Bodin, et al. "Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK-cell repertoire in the French population." European Journal of Immunology 43, no. 4 (March 4, 2013): 1085–98. http://dx.doi.org/10.1002/eji.201243007.

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Díaz-Peña, Roberto, Jose Ramón Vidal-Castiñeira, Rebeca Alonso-Arias, Beatriz Suarez-Alvarez, Jose Luis Vicario, Rafael Solana, Eduardo Collantes, Antonio López-Vázquez, Jesús Martínez-Borra, and Carlos López-Larrea. "Association of the KIR3DS1*013 and KIR3DL1*004 alleles with susceptibility to ankylosing spondylitis." Arthritis & Rheumatism 62, no. 4 (January 21, 2010): 1000–1006. http://dx.doi.org/10.1002/art.27332.

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Gao, Xiaojiang, Darlene Marti, Pete Karacki, Pat Martin, and Mary Canrrington. "Characterization of KIR3DL1/3DS1 subtypes." Human Immunology 64, no. 10 (October 2003): S13. http://dx.doi.org/10.1016/j.humimm.2003.08.020.

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Saunders, Philippa M., Bruce J. MacLachlan, Phillip Pymm, Patricia T. Illing, Yuanchen Deng, Shu Cheng Wong, Clare V. L. Oates, et al. "The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function." Proceedings of the National Academy of Sciences 117, no. 21 (May 13, 2020): 11636–47. http://dx.doi.org/10.1073/pnas.1920570117.

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Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

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Boudreau, Jeanette E., Fabio Giglio, Ted A. Gooley, Philip A. Stevenson, Jean-Benoît Le Luduec, Brian C. Shaffer, Raja Rajalingam, et al. "KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation." Journal of Clinical Oncology 35, no. 20 (July 10, 2017): 2268–78. http://dx.doi.org/10.1200/jco.2016.70.7059.

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Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells—upregulated in the post-HCT environment—signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.

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Zipperlen, Katrin, Maureen Gallant, Staci Stapleton, John Heath, Lisa Barrett, and Michael Grant. "Protective genotypes in HIV infection reflect superior function of KIR3DS1 + over KIR3DL1 + CD8 + T cells." Immunology & Cell Biology 93, no. 1 (August 12, 2014): 67–76. http://dx.doi.org/10.1038/icb.2014.68.

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Umemura, Takeji, Satoru Joshita, Hiromi Saito, Shun-ichi Wakabayashi, Hiroyuki Kobayashi, Yuki Yamashita, Ayumi Sugiura, Tomoo Yamazaki, and Masao Ota. "Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients." Cancers 13, no. 13 (June 29, 2021): 3267. http://dx.doi.org/10.3390/cancers13133267.

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Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.

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Thomas, Rasmi, Eriko Yamada, Galit Alter, Maureen P. Martin, Arman A. Bashirova, Paul J. Norman, Marcus Altfeld, et al. "Novel KIR3DL1 Alleles and Their Expression Levels on NK Cells: Convergent Evolution of KIR3DL1 Phenotype Variation?" Journal of Immunology 180, no. 10 (May 3, 2008): 6743–50. http://dx.doi.org/10.4049/jimmunol.180.10.6743.

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Pugh, Jason, Neda Nemat-Gorgani, Zakia Djaoud, Lisbeth A. Guethlein, Paul J. Norman, and Peter Parham. "In vitro education of human natural killer cells by KIR3DL1." Life Science Alliance 2, no. 6 (November 13, 2019): e201900434. http://dx.doi.org/10.26508/lsa.201900434.

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During development, NK cells are “educated” to respond aggressively to cells with low surface expression of HLA class I, a hallmark of malignant and infected cells. The mechanism of education involves interactions between inhibitory killer immunoglobulin–like receptors (KIRs) and specific HLA epitopes, but the details of this process are unknown. Because of the genetic diversity of HLA class I genes, most people have NK cells that are incompletely educated, representing an untapped source of human immunity. We demonstrate how mature peripheral KIR3DL1+ human NK cells can be educated in vitro. To accomplish this, we trained NK cells expressing the inhibitory KIR3DL1 receptor by co-culturing them with target cells that expressed its ligand, Bw4+HLA-B. After this training, KIR3DL1+ NK cells increased their inflammatory and lytic responses toward target cells lacking Bw4+HLA-B, as though they had been educated in vivo. By varying the conditions of this basic protocol, we provide mechanistic and translational insights into the process NK cell education.

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Guerini, Franca Rosa, Sergio Lo Caputo, Andrea Gori, Alessandra Bandera, Francesco Mazzotta, Alessia Uglietti, Milena Zanzottera, Renato Maserati, and Mario Clerici. "Under Representation of the Inhibitory KIR3DL1 Molecule and the KIR3DL1+/BW4+ Complex in HIV Exposed Seronegative Individuals." Journal of Infectious Diseases 203, no. 9 (May 1, 2011): 1235–39. http://dx.doi.org/10.1093/infdis/jir020.

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40

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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Belle, I., L. Hou, M. Chen, N. K. Steiner, J. Ng, and C. K. Hurley. "Investigation of killer cell immunoglobulin-like receptor gene diversity in KIR3DL1 and KIR3DS1 in a transplant population." Tissue Antigens 71, no. 5 (May 2008): 434–39. http://dx.doi.org/10.1111/j.1399-0039.2008.01017.x.

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Zvyagin, Ivan V., Ilgar Z. Mamedov, Olga V. Britanova, Dmitriy B. Staroverov, Evgeni L. Nasonov, Anna G. Bochkova, Anna V. Chkalina, et al. "Contribution of functional KIR3DL1 to ankylosing spondylitis." Cellular & Molecular Immunology 7, no. 6 (September 6, 2010): 471–76. http://dx.doi.org/10.1038/cmi.2010.42.

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Ahn, R. S., H. Moslehi, M. P. Martin, M. Abad-Santos, A. M. Bowcock, M. Carrington, and W. Liao. "Inhibitory KIR3DL1 alleles are associated with psoriasis." British Journal of Dermatology 174, no. 2 (November 17, 2015): 449–51. http://dx.doi.org/10.1111/bjd.14081.

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Wong, Shu Cheng, Philippa M. Saunders, Phillip Pymm, Jamie Rossjohn, Julian P. Vivian, and Andrew G. Brooks. "OR26 BW4 + HLA class I and KIR3DL1 allotypic pairing influences licensing and effector function of KIR3DL1 + NK cells." Human Immunology 78 (September 2017): 25. http://dx.doi.org/10.1016/j.humimm.2017.06.032.

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Giglio, Fabio, Ted A. Gooley, Jeffrey M. Venstrom, Meighan M. Gallagher, LiHua Hou, Carolyn K. Hurley, Tatiana Lebedeva, et al. "Donor KIR3DL1 and HLA-B Allotypes Control Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation." Blood 120, no. 21 (November 16, 2012): 349. http://dx.doi.org/10.1182/blood.v120.21.349.349.

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Abstract Abstract 349 Natural killer (NK) cells are vital in the control of viral infection and malignancy, in particular AML. Affinity strength between NK receptors and their HLA ligands control both NK effector function and degree of NK inhibition. Differences in binding affinity between allotypes of the NK receptor KIR3DL1 and allotypes of its ligand HLA-Bw4 depend on the expression levels of the receptor and the amino acid residue at position 80 in the ligand. Because receptor-ligand affinities are associated with differences in HIV control, we hypothesized that different affinities between donor KIR3DL1 and donor-recipient HLA-Bw4 allotypes would impact the risk for AML relapse following allogeneic hematopoietic stem cell transplantation (HCT). Methods: We evaluated 299 AML patients who underwent allogeneic HCT from an unrelated donor between 1995 and 2002. Clinical data, HLA allotyping, and donor DNA were provided by the CIBMTR. KIR3DL1 allotyping was executed using PCR- and sequence-based methods. Donors were segregated into those with high-, low- and null expressing KIR3DL1 allele groups [3DL1-H (n=130), 3DL1-L (n=69), 3DL1-N (n=82)] and HLA-B allele groups (Bw6/Bw6, Bw4-I80, Bw4-T80). 3DL1-N genotypes are predictive of poor surface expression and were analyzed separately. Patients and donors were matched at 9 or 10 HLA loci in all cases, with only 3 donor-patient pairs mismatched for HLA-Bw4 ligands. Affinity cohorts were compared using Cox regression for the time-to-event outcomes of relapse and overall mortality (OM). Kaplan-Meier estimates of overall survival and cumulative incidence estimates of relapse were obtained. Results: Recipients of 3DL1-H and 3DL1-L donors were analyzed for high and low-affinity associations with post-HCT AML relapse. Among patients with a 3DL1-H donor, those transplanted from donors with the low-affinity KIR/HLA allotype combination 3DL1-H/Bw4-T80 had lower risk of relapse when compared to those with the high-affinity 3DL1-H/Bw4-I80 combination (HR 0.22; p=.003, Table) and even moreso when compared to the extra-high affinity combinations of 3DL1-H with Bw4-I80-B*2702 or B*57 (HR 0.10; p<.001). Among patients with 3DL1-L donors, those with the low-affinity KIR-HLA combination 3DL1-L/Bw4-I80 were associated with lower relapse in patients when compared to those with the high-affinity 3DL1-L/Bw4-T80 combination (HR 0.21; P=.009). Among the combined patient groups, low-affinity combinations were strongly associated with lower relapse (HR 0.24; P<.001; FigA) and lower mortality (HR 0.62; P=.03; FigB) in patients compared to the high-affinity combinations. Lack of HLA-Bw4 ligand (HLA-Bw6/Bw6) provided intermediate protection from AML relapse compared to patients in the high-affinity group (HR 0.39; P= .002; Fig 1A). Donor 3DL1-N genotypes, predictive of poor receptor expression on the NK cell surface, were not associated with HCT outcome. Conclusions: Protection from relapse of AML after unrelated HCT is associated with the affinity between donor KIR3DL1 and HLA-Bw4, ranging from the highly protective low-affinity donor KIR3DL1/HLA-Bw4 allotype combinations to the susceptible and “super-susceptible” effects of high- and extra-high affinity KIR/HLA combinations. These data support the consideration of KIR and HLA allotype combinations in stem cell donor selection algorithms to minimize the risk of AML relapse following HCT. Because >95% of donors are positive for KIR3DL1 and 69% of patients are positive for HLA-Bw4, incorporation of KIR3DL1/HLA-Bw4 allotypes in donor selection algorithms is a highly relevant and feasible goal. Disclosures: No relevant conflicts of interest to declare.

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Fang, Xinchen, Xiaoyu Zhu, Baolin Tang, Kaidi Song, Kaidi Song, Wen Yao, Xiang Wan, Huilan Liu, Zimin Sun, and Jun Peng. "DONOR KIR3DL1/RECEPTOR HLA-BW4-80I COMBINATION REDUCES ACUTE LEUKEMIA RELAPSE AFTER UMBILICAL CORD BLOOD TRANSPLANTATION WITHOUT IN VITRO T-CELL DEPLETION." Mediterranean Journal of Hematology and Infectious Diseases 13, no. 1 (December 31, 2020): e2021005. http://dx.doi.org/10.4084/mjhid.2021.005.

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Background: Donor natural killer (NK) cell alloreactivity in umbilical cord bone marrow transplantation (UCBT) can lead to leukemic relapse. However, NK cell function is calibrated by interaction with human leukocyte antigens (HLAs). This study aimed to investigate graft-resistant leukemia after transplantation and compared specific genotypes of killer immunoglobulin-like receptors (KIRs) in donors and human leukocyte antigen ligands in patients. Methods: We retrospectively analyzed 232 patients with acute leukemia from a single center. Patients had undergone UCBT with myeloablative conditioning and without anti-thymocyte globulin. We identified the KIR genotypes of cord blood donors using polymerase chain reaction with sequence-specific primers. All of the donors contained KIR3DL1. Results: The patients were divided into three groups according to the HLA-B locus. The donor KIR3DL1 and recipient HLA-Bw4-80I combination was predictive of being highly educated, and was associated with a lower relapse (P = 0.006) and better overall survival (probability of relapse = 0.13, P < 0.001) than the uneducated group. We found no significant increase in the incidence of acute or chronic graft-versus-host disease. Conclusions: Our data suggest that the donor KIR3DL1/receptor and HLA-Bw4-80I combination in UCBT results in stronger graft-versus-leukemia effects and improved outcomes in patients with acute leukemia.

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Liberatore, Concetta, Marusca Capanni, Nicola Albi, Isabella Volpi, Elena Urbani, Loredana Ruggeri, Amedea Mencarelli, Francesco Grignani, and Andrea Velardi. "Natural Killer Cell–mediated Lysis of Autologous Cells Modified by Gene Therapy." Journal of Experimental Medicine 189, no. 12 (June 21, 1999): 1855–62. http://dx.doi.org/10.1084/jem.189.12.1855.

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This study investigated the role of natural killer (NK) cells as effectors of an immune response against autologous cells modified by gene therapy. T lymphocytes were transduced with LXSN, a retroviral vector adopted for human gene therapy that carries the selectable marker gene neo, and the autologous NK response was evaluated. We found that (i) infection with LXSN makes cells susceptible to autologous NK cell–mediated lysis; (ii) expression of the neo gene is responsible for conferring susceptibility to lysis; (iii) lysis of neo-expressing cells is clonally distributed and mediated only by NK clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory receptor; and (iv) the targets are cells from HLA-Bw4+ individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recognition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutations preventing translation of two of the four potentially nonprotective peptides reduced KIR3DL1+ NK clone–mediated autologous lysis. Thus, individuals expressing Bw4 alleles possess an NK repertoire with the potential to eliminate autologous cells modified by gene therapy. By demonstrating that NK cells can selectively detect the expression of heterologous genes, these observations provide a general model of the NK cell–mediated control of viral infections.

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Foley, Bree A., Dianne De Santis, Els Van Beelen, Louise J. Lathbury, Frank T. Christiansen, and Campbell S. Witt. "The reactivity of Bw4+ HLA-B and HLA-A alleles with KIR3DL1: implications for patient and donor suitability for haploidentical stem cell transplantations." Blood 112, no. 2 (July 15, 2008): 435–43. http://dx.doi.org/10.1182/blood-2008-01-132902.

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Abstract Natural killer (NK)–cell alloreactivity can be exploited in haploidentical hematopoietic stem cell transplantation (HSCT). NK cells from donors whose HLA type includes Bw4, a public epitope present on a subset of HLA-B alleles, can be alloreactive toward recipients whose cells lack Bw4. Serologically detectable epitopes related to Bw4 also exist on a subset of HLA-A alleles, but the interaction of these alleles with KIR3DL1 is controversial. We therefore undertook a systematic analysis of the ability of most common HLA-B alleles and HLA-A alleles with Bw4 serologic reactivity to protect target cells from lysis by KIR3DL1-dependent NK cells. All Bw4− HLA-B alleles failed to protect target cells from lysis. All Bw4+ HLA-B alleles with the exception of HLA-B*1301 and -B*1302 protected targets from lysis. HLA-A*2402 and HLA-A*3201 unequivocally protected target cells from lysis, whereas HLA-A*2501 and HLA-A*2301 provided only weak protection from lysis. KIR3DL1-dependent alloreactive NK clones were identified in donors with HLA-A*2402 but not in donors with HLA-B*1301 or -B*1302. These findings clarify the HLA types that donors and recipients need in haploidentical HSCT and other NK allotherapies in order to benefit from NK alloreactivity.

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Yawata, Nobuyo, Mariko Shirane, Kaing Woon, Xinru Lim, Hidenori Tanaka, Yoh-Ichi Kawano, Makoto Yawata, Soon-Phaik Chee, Jay Siak, and Koh-Hei Sonoda. "Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals." International Journal of Molecular Sciences 22, no. 7 (March 31, 2021): 3623. http://dx.doi.org/10.3390/ijms22073623.

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Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.

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Kreutzkamp, Barbara. "alloSCT bei AML: KIR3DL1/HLA-B-Status ausschlaggebend." Im Focus Onkologie 21, no. 4 (April 2018): 74. http://dx.doi.org/10.1007/s15015-018-3920-3.

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Journal articles on the topic 'KIR3DL1'

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