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1دورية أكاديمية
المؤلفون: Yan Zhang, Ada W.C. Yan, Lies Boelen, Linda Hadcocks, Arafa Salam, Daniel Padrosa Gispert, Loiza Spanos, Laura Mora Bitria, Neda Nemat-Gorgani, James A. Traherne, Chrissy Roberts, Danai Koftori, Graham P. Taylor, Daniel Forton, Paul J. Norman, Steven G.E. Marsh, Robert Busch, Derek C. Macallan, Becca Asquith
المصدر: The Journal of Clinical Investigation, Vol 133, Iss 12 (2023)
مصطلحات موضوعية: Immunology, Medicine
الوصف: BACKGROUND There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell–mediated control of chronic viral infection and that these results are consistent with an increase in the CD8+ T cell lifespan due to iKIR-ligand interactions. Here, we tested this prediction and investigated whether iKIRs affect T cell lifespan in humans in vivo.METHODS We used stable isotope labeling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections.RESULTS We showed that an individual’s iKIR-ligand genotype was a significant determinant of CD8+ T cell lifespan: in individuals with 2 iKIR-ligand gene pairs, memory CD8+ T cells survived, on average, for 125 days; in individuals with 4 iKIR-ligand gene pairs, the memory CD8+ T cell lifespan doubled to 250 days. Additionally, we showed that this survival advantage was independent of iKIR expression by the T cell of interest and, further, that the iKIR-ligand genotype altered the CD8+ and CD4+ T cell immune aging phenotype.CONCLUSIONS Together, these data reveal an unexpectedly large effect of iKIR genotype on T cell survival.FUNDING Wellcome Trust; Medical Research Council; EU Horizon 2020; EU FP7; Leukemia and Lymphoma Research; National Institute of Health Research (NIHR) Imperial Biomedical Research Centre; Imperial College Research Fellowship; National Institutes of Health; Jefferiss Trust.
وصف الملف: electronic resource
Relation: https://doaj.org/toc/1558-8238
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2دورية أكاديمية
المؤلفون: Daniel J Laydon, Vikram Sunkara, Lies Boelen, Charles R M Bangham, Becca Asquith
المصدر: PLoS Computational Biology, Vol 16, Iss 9, p e1007470 (2020)
مصطلحات موضوعية: Biology (General), QH301-705.5
الوصف: Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection. However, in light of recent high-throughput data on the abundance of HTLV-1 clones, and recent estimates of HTLV-1 clonal diversity that are substantially higher than previously thought (typically between 104 and 105 HTLV-1+ T cell clones in the body of an asymptomatic carrier or patient with HTLV-1-associated myelopathy/tropical spastic paraparesis), ongoing infectious spread during chronic infection remains possible. We estimate the ratio of infectious to mitotic spread using a hybrid model of deterministic and stochastic processes, fitted to previously published HTLV-1 clonal diversity estimates. We investigate the robustness of our estimates using three alternative estimators. We find that, contrary to previous belief, infectious spread persists during chronic infection, even after HTLV-1 proviral load has reached its set point, and we estimate that between 100 and 200 new HTLV-1 clones are created and killed every day. We find broad agreement between all estimators. The risk of HTLV-1-associated malignancy and inflammatory disease is strongly correlated with proviral load, which in turn is correlated with the number of HTLV-1-infected clones, which are created by de novo infection. Our results therefore imply that suppression of de novo infection may reduce the risk of malignant transformation.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Bisrat J Debebe, Lies Boelen, James C Lee, IAVI Protocol C Investigators, Chloe L Thio, Jacquie Astemborski, Gregory Kirk, Salim I Khakoo, Sharyne M Donfield, James J Goedert, Becca Asquith
المصدر: eLife, Vol 9 (2020)
مصطلحات موضوعية: HLA, GWAS, CD8 T cell, natural killer cell, disease association, immunogenetics, Medicine, Science, Biology (General), QH301-705.5
الوصف: Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of ‘protective’ or ‘detrimental’ CD8+ T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8+ T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn’s disease.
وصف الملف: electronic resource
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4دورية أكاديمية
المؤلفون: Juliette Griffié, Leigh Shlomovich, David J. Williamson, Michael Shannon, Jesse Aaron, Satya Khuon, Garth L. Burn, Lies Boelen, Ruby Peters, Andrew P. Cope, Edward A. K. Cohen, Patrick Rubin-Delanchy, Dylan M. Owen
المصدر: Scientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
الوصف: Abstract Single-molecule localisation microscopy (SMLM) allows the localisation of fluorophores with a precision of 10–30 nm, revealing the cell’s nanoscale architecture at the molecular level. Recently, SMLM has been extended to 3D, providing a unique insight into cellular machinery. Although cluster analysis techniques have been developed for 2D SMLM data sets, few have been applied to 3D. This lack of quantification tools can be explained by the relative novelty of imaging techniques such as interferometric photo-activated localisation microscopy (iPALM). Also, existing methods that could be extended to 3D SMLM are usually subject to user defined analysis parameters, which remains a major drawback. Here, we present a new open source cluster analysis method for 3D SMLM data, free of user definable parameters, relying on a model-based Bayesian approach which takes full account of the individual localisation precisions in all three dimensions. The accuracy and reliability of the method is validated using simulated data sets. This tool is then deployed on novel experimental data as a proof of concept, illustrating the recruitment of LAT to the T-cell immunological synapse in data acquired by iPALM providing ~10 nm isotropic resolution.
وصف الملف: electronic resource
Relation: https://doaj.org/toc/2045-2322
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5دورية أكاديمية
المؤلفون: Pedro Costa Del Amo, Julio Lahoz-Beneytez, Lies Boelen, Raya Ahmed, Kelly L Miners, Yan Zhang, Laureline Roger, Rhiannon E Jones, Silvia A Fuertes Marraco, Daniel E Speiser, Duncan M Baird, David A Price, Kristin Ladell, Derek Macallan, Becca Asquith
المصدر: PLoS Biology, Vol 16, Iss 6, p e2005523 (2018)
مصطلحات موضوعية: Biology (General), QH301-705.5
الوصف: Adaptive immunity relies on the generation and maintenance of memory T cells to provide protection against repeated antigen exposure. It has been hypothesised that a self-renewing population of T cells, named stem cell-like memory T (TSCM) cells, are responsible for maintaining memory. However, it is not clear if the dynamics of TSCM cells in vivo are compatible with this hypothesis. To address this issue, we investigated the dynamics of TSCM cells under physiological conditions in humans in vivo using a multidisciplinary approach that combines mathematical modelling, stable isotope labelling, telomere length analysis, and cross-sectional data from vaccine recipients. We show that, unexpectedly, the average longevity of a TSCM clone is very short (half-life < 1 year, degree of self-renewal = 430 days): far too short to constitute a stem cell population. However, we also find that the TSCM population is comprised of at least 2 kinetically distinct subpopulations that turn over at different rates. Whilst one subpopulation is rapidly replaced (half-life = 5 months) and explains the rapid average turnover of the bulk TSCM population, the half-life of the other TSCM subpopulation is approximately 9 years, consistent with the longevity of the recall response. We also show that this latter population exhibited a high degree of self-renewal, with a cell residing without dying or differentiating for 15% of our lifetime. Finally, although small, the population was not subject to excessive stochasticity. We conclude that the majority of TSCM cells are not stem cell-like but that there is a subpopulation of TSCM cells whose dynamics are compatible with their putative role in the maintenance of T cell memory.
وصف الملف: electronic resource
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6دورية أكاديمية
المؤلفون: Neil Arvin Bretaña, Lies Boelen, Rowena Bull, Suzy Teutsch, Peter A. White, Andrew R. Lloyd, Fabio Luciani
المصدر: Emerging Infectious Diseases, Vol 21, Iss 5, Pp 765-774 (2015)
مصطلحات موضوعية: hepatitis C virus, transmission, phylogenetics, clustering, injecting drug use, prisons, Medicine, Infectious and parasitic diseases, RC109-216
الوصف: Hepatitis C virus (HCV) is predominantly transmitted between persons who inject drugs. For this population, global prevalence of HCV infection is high and incarceration is common and an independent risk factor for HCV acquisition. To explore HCV transmission dynamics in incarcerated populations, we integrated virus sequences with risk behavior and spatiotemporal data and analyzed transmission clusters among prisoners in Australia. We detected 3 clusters of recent HCV transmission consisting of 4 likely in-custody transmission events involving source/recipient pairs located in the same prison at the same time. Of these 4 events, 3 were associated with drug injecting and equipment sharing. Despite a large population of prisoners with chronic HCV, recent transmission events were identified in the prison setting. This ongoing HCV transmission among high-risk prisoners argues for expansion of prevention programs to reduce HCV transmission in prisons.
وصف الملف: electronic resource
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7دورية أكاديمية
المؤلفون: Marjet Elemans, Lies Boelen, Michael Rasmussen, Søren Buus, Becca Asquith
المصدر: PLoS Pathogens, Vol 13, Iss 6, p e1006361 (2017)
مصطلحات موضوعية: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
الوصف: The observation, by Alter et al., of the enrichment of NK cell "escape" variants in individuals carrying certain Killer-cell Immunoglobulin-like Receptor (KIR) genes is compelling evidence that natural killer (NK) cells exert selection pressure on HIV-1. Alter et al hypothesise that variant peptide, in complex with HLA class I molecules binds KIR receptors and either increases NK cell inhibition or decreases NK cell activation compared to wild type peptide thus leading to virus escape from the NK cell response. According to this hypothesis, in order for NK cells to select for an escape variant, an individual must carry both the KIR and an HLA ligand that binds the variant peptide. In this study we estimate the proportion of the population that is capable of selecting for escape variants and use both epidemiological modelling and a model-free approach to investigate whether this proportion explains the observed variant enrichment. We found that the fraction of individuals within whom the variant would have a selective advantage was low and was unable to explain the high degree of enrichment observed. We conclude that whilst Alter et al's data is consistent with selection pressure, the mechanism that they postulate is unlikely. The importance of this work is two-fold. Firstly, it forces a re-evaluation of some of the clearest evidence that NK cells exert a protective effect in HIV-1 infection. Secondly, it implies that there is a significant aspect of immunology that is not understood: it is possible that KIRs bind much more widely than was previously appreciated; that a gene in linkage with the KIR genes is responsible for considerable peptide-dependent selection or that variant peptides are indirectly impacting KIR ligation.
وصف الملف: electronic resource
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8دورية أكاديمية
المؤلفون: Lies Boelen, Patrick K O'Neill, Kathryn J Quigley, Catherine J Reynolds, Bernard Maillere, John H Robinson, Ganjana Lertmemongkolchai, Daniel M Altmann, Rosemary J Boyton, Becca Asquith
المصدر: PLoS Computational Biology, Vol 12, Iss 3, p e1004796 (2016)
مصطلحات موضوعية: Biology (General), QH301-705.5
الوصف: Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual's HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3-14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.
وصف الملف: electronic resource
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9دورية أكاديمية
المؤلفون: Lies Boelen, Suzy Teutsch, David P Wilson, Kate Dolan, Greg J Dore, Andrew R Lloyd, Fabio Luciani, HITS investigators
المصدر: PLoS ONE, Vol 9, Iss 7, p e100749 (2014)
الوصف: BackgroundShared injecting apparatus during drug use is the premier risk factor for hepatitis C virus (HCV) transmission.AimsTo estimate the per-event probability of HCV infection during a sharing event, and the transmission probability of HCV from contaminated injecting apparatus.MethodsEstimates were obtained using a maximum likelihood method with estimated IDU and sharing events obtained from behavioural data.SettingsCohort study in multiple correction centres in New South Wales, Australia.ParticipantsSubjects (N = 500) with a lifetime history of injecting drug use (IDU) who were followed up between 2005 and 2012. During follow-up, interviews for risk behaviours were taken and blood sampling (HCV-antibody and RNA testing) was performed.MeasurementsSelf-reported frequencies of injecting drugs and sharing events, as well as other risk behaviours and details on the nature of injecting events.FindingsThe best estimate of the per-event probability of infection was 0.57% (CI: 0.32-1.05%). A sensitivity analysis on the likely effect of under-reporting of sharing of the injecting apparatus indicated that the per event infection probability may be as low as 0.17% (95% CI: 0.11%-0.25%). The transmission probability was similarly shown to range up to 6%, dependent on the presumed prevalence of the virus in injecting equipment.ConclusionsThe transmission probability of HCV during a sharing event is small. Hence, strategies to reduce the frequency and sharing of injecting equipment are required, as well as interventions focused on decreasing the per event risk.
وصف الملف: electronic resource
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10دورية أكاديمية
المؤلفون: John Y. Ng, Lies Boelen, Jason W. H. Wong
المصدر: Open Biology, Vol 3, Iss 2 (2013)
مصطلحات موضوعية: 3-nitrotyrosine, bioinformatics, secondary structure, post-translational modification conservation, phosphotyrosine, Biology (General), QH301-705.5
الوصف: Protein 3-nitrotyrosine is a post-translational modification that commonly arises from the nitration of tyrosine residues. This modification has been detected under a wide range of pathological conditions and has been shown to alter protein function. Whether 3-nitrotyrosine is important in normal cellular processes or is likely to affect specific biological pathways remains unclear. Using GPS-YNO2, a recently described 3-nitrotyrosine prediction algorithm, a set of predictions for nitrated residues in the human proteome was generated. In total, 9.27 per cent of the proteome was predicted to be nitratable (27 922/301 091). By matching the predictions against a set of curated and experimentally validated 3-nitrotyrosine sites in human proteins, it was found that GPS-YNO2 is able to predict 73.1 per cent (404/553) of these sites. Furthermore, of these sites, 42 have been shown to be nitrated endogenously, with 85.7 per cent (36/42) of these predicted to be nitrated. This demonstrates the feasibility of using the predicted dataset for a whole proteome analysis. A comprehensive bioinformatics analysis was subsequently performed on predicted and all experimentally validated nitrated tyrosine. This found mild but specific biophysical constraints that affect the susceptibility of tyrosine to nitration, and these may play a role in increasing the likelihood of 3-nitrotyrosine to affect processes, including phosphorylation and DNA binding. Furthermore, examining the evolutionary conservation of predicted 3-nitrotyrosine showed that, relative to non-nitrated tyrosine residues, 3-nitrotyrosine residues are generally less conserved. This suggests that, at least in the majority of cases, 3-nitrotyrosine is likely to have a deleterious effect on protein function and less likely to be important in normal cellular function.
وصف الملف: electronic resource
Relation: https://doaj.org/toc/2046-2441
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