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CD4+T follicular helper (Tfh) cells in human tonsil and blood are clonally convergent, but divergent from non-Tfh CD4+cells
ABSTRACTT follicular helper (Tfh) cells are fundamental for B cell selection and antibody maturation in germinal centers. Circulating Tfh (cTfh) cells constitute a minor proportion of the CD4+T cells in peripheral blood, but their clonotypic relationship to Tfh populations resident in lymph nodes and the extent to which they differ from non-Tfh CD4+cells has been unclear. Using donor-matched blood and tonsil samples we investigated T cell receptor (TCR) sharing between tonsillar Tfh cells and peripheral Tfh and non-Tfh cell populations. TCR transcript sequencing revealed considerable clonal overlap between peripheral and tonsillar Tfh cell subsets as well as a clear distinction between Tfh and non-Tfh cells. Furthermore, influenza-specific cTfh cell clones derived from blood could be found in the repertoire of tonsillar Tfh cells. Therefore, human blood samples can be used to gain insight into the specificity of Tfh responses occurring in lymphoid tissues, provided cTfh subsets are studied.
CD4+ T Follicular Helper Cells in Human Tonsils and Blood Are Clonally Convergent but Divergent from Non-Tfh CD4+ Cells
© 2019 The Authors T follicular helper (Tfh) cells are fundamental for B cell selection and antibody maturation in germinal centers. Circulating Tfh (cTfh) cells constitute a minor proportion of the CD4+ T cells in peripheral blood, but their clonotypic relationship to Tfh populations resident in lymph nodes and the extent to which they differ from non-Tfh CD4+ cells have been unclear. Using donor-matched blood and tonsil samples, we investigate T cell receptor (TCR) sharing between tonsillar Tfh cells and peripheral Tfh and non-Tfh cell populations. TCR transcript sequencing reveals considerable clonal overlap between peripheral and tonsillar Tfh cell subsets as well as a clear distinction between Tfh and non-Tfh cells. Furthermore, influenza-specific cTfh cell clones derived from blood can be found in the repertoire of tonsillar Tfh cells. Therefore, human blood samples can be used to gain insight into the specificity of Tfh responses occurring in lymphoid tissues, provided that cTfh subsets are studied.
Corrigendum: Elucidation of the Signatures of Proteasome-Catalysed Peptide Splicing.
[This corrects the article DOI: 10.3389/fimmu.2020.563800.].
The Importance of Cellular Immune Response to HIV: Implications for Antibody Production and Vaccine Design.
Despite many years from the discovery of human immunodeficiency virus (HIV), a prophylactic vaccine against HIV is still needed. The failure of most of the vaccine clinical trials in the field has different causes, mainly due by the difficulties to identify the correct antigen able to prime the optimal B cell lineage and then make the series of somatic mutations necessary to generate broadly neutralizing antibodies (bNAbs). B cells are responsible for the bNAbs production; however, their function is strongly influenced by the presence of a population of CD4+ T lymphocytes, mainly present in the lymphoid organs, the T follicular helper cells (Tfh). In this review, the importance of the contribution of Tfh cells in HIV response is highlighted and future therapy perspectives based on these observations are described. The advanced technology available nowadays and the wide knowledge built over the past years for HIV may eventually create the best scenario for the generation of an effective vaccine.
Digital pathology transformation in a supraregional germ cell tumour network
Background: In this article we share our experience of creating a digital pathology (DP) supraregional germ cell tumour service, including full digitisation of the central laboratory. Methods: DP infrastructure (Philips) was deployed across our hospital network to allow full central digitisation with partial digitisation of two peripheral sites in the supraregional testis germ cell tumour network. We used a survey-based approach to capture the quantitative and qualitative experiences of the multidisciplinary teams involved. Results: The deployment enabled case sharing for the purposes of diagnostic reporting, second opinion, and supraregional review. DP was seen as a positive step forward for the departments involved, and for the wider germ cell tumour network, and was completed without significant issues. Whilst there were challenges, the transition to DP was regarded as worthwhile, and examples of benefits to patients are already recognised. Conclusion: Pathology networks, including highly specialised services, such as in this study, are ideally suited to be digitised. We highlight many of the benefits but also the challenges that must be overcome for such clinical transformation. Overall, from the survey, the change was seen as universally positive for our service and highlights the importance of engagement of the whole team to achieve success.
An immunodominant NP105–113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease
AbstractNP105–113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105–113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105–113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105–113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105–113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
Discordant diagnostic criteria for pneumonia in COPD trials: a review
Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients’ pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence.
Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation
Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions.
PolypGen: A multi-center polyp detection and segmentation dataset for generalisability assessment
Polyps in the colon are widely known as cancer precursors identified by colonoscopy either related to diagnostic work-up for symptoms, colorectal cancer screening or systematic surveillance of certain diseases. Whilst most polyps are benign, the number, size and the surface structure of the polyp are tightly linked to the risk of colon cancer. There exists a high missed detection rate and incomplete removal of colon polyps due to the variable nature, difficulties to delineate the abnormality, high recurrence rates and the anatomical topography of the colon. In the past, several methods have been built to automate polyp detection and segmentation. However, the key issue of most methods is that they have not been tested rigorously on a large multi-center purpose-built dataset. Thus, these methods may not generalise to different population datasets as they overfit to a specific population and endoscopic surveillance. To this extent, we have curated a dataset from 6 different centers incorporating more than 300 patients. The dataset includes both single frame and sequence data with 3446 annotated polyp labels with precise delineation of polyp boundaries verified by six senior gastroenterologists. To our knowledge, this is the most comprehensive detection and pixel-level segmentation dataset curated by a team of computational scientists and expert gastroenterologists. This dataset has been originated as the part of the Endocv2021 challenge aimed at addressing generalisability in polyp detection and segmentation. In this paper, we provide comprehensive insight into data construction and annotation strategies, annotation quality assurance and technical validation for our extended EndoCV2021 dataset which we refer to as PolypGen.