12 results
Search Results
2. Self-supervised deep clustering of single-cell RNA-seq data to hierarchically detect rare cell populations.
- Author
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Lei, Tianyuan, Chen, Ruoyu, Zhang, Shaoqiang, and Chen, Yong
- Subjects
DEEP learning ,CELL populations ,KILLER cells ,CYTOTOXIC T cells ,RNA sequencing ,MONOCYTES ,HIERARCHICAL clustering (Cluster analysis) ,T cells - Abstract
Single-cell RNA sequencing (scRNA-seq) is a widely used technique for characterizing individual cells and studying gene expression at the single-cell level. Clustering plays a vital role in grouping similar cells together for various downstream analyses. However, the high sparsity and dimensionality of large scRNA-seq data pose challenges to clustering performance. Although several deep learning-based clustering algorithms have been proposed, most existing clustering methods have limitations in capturing the precise distribution types of the data or fully utilizing the relationships between cells, leaving a considerable scope for improving the clustering performance, particularly in detecting rare cell populations from large scRNA-seq data. We introduce DeepScena, a novel single-cell hierarchical clustering tool that fully incorporates nonlinear dimension reduction, negative binomial-based convolutional autoencoder for data fitting, and a self-supervision model for cell similarity enhancement. In comprehensive evaluation using multiple large-scale scRNA-seq datasets, DeepScena consistently outperformed seven popular clustering tools in terms of accuracy. Notably, DeepScena exhibits high proficiency in identifying rare cell populations within large datasets that contain large numbers of clusters. When applied to scRNA-seq data of multiple myeloma cells, DeepScena successfully identified not only previously labeled large cell types but also subpopulations in CD14 monocytes, T cells and natural killer cells, respectively. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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3. Dissecting T-cell heterogeneity in esophageal squamous cell carcinoma reveals the potential role of LAIR2 in antitumor immunity.
- Author
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Wang, Ping, Zhuang, Weitao, Zheng, Zhuojun, Zhang, Liyun, Zhang, Xu, and Chen, Qingyun
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MONONUCLEAR leukocytes ,CYTOTOXIC T cells ,SQUAMOUS cell carcinoma ,T-cell exhaustion ,ESOPHAGEAL cancer ,REGULATORY T cells - Abstract
Esophageal squamous cell carcinoma (ESCC), one of the most commonly diagnosed and lethal malignant diseases, has a complex tumor ecosystem. An obvious requirement for T-cell-mediated tumor control is the infiltration of tumor-reactive T cells into the tumor. Here, we obtained detailed T-cell compositions in both ESCC tumors and matched peripheral blood mononuclear cells (PBMCs) at single-cell resolution. We demonstrated that T cells in tumors and PBMCs had different compositions and functional states. ESCC tumors were rich in Treg and exhausted T cells but poor in cytotoxic and naïve T cells compared with PBMCs. The exhausted T cells showed higher exhausted signature in tumors than in PBMCs, while the cytotoxic T cells exhibited higher cytotoxic signature in PBMCs than in tumors. Our data indicated an immunosuppressive status and a defect at the level of T-cell priming in the tumor microenvironment. Leukocyte-associated Ig-like receptor-2 (LAIR2), a soluble collagen receptor that prevents the binding of human leukocyte-associated Ig-like receptor-1 (LAIR1) to collagens, was predominantly expressed in proliferating CD8
+ T and Treg cells in tumors but in cytotoxic cells in PBMCs. LAIR2 could inhibit tumor metastasis, invasion, and collagen deposition via suppressing transforming growth factor-β signaling. These findings revealed differential T-cell populations in tumors and PBMCs and provided convincing evidence that LAIR2 acted as a tumor suppressor. Esophageal squamous cell carcinoma (ESCC), one of the most commonly diagnosed and lethal malignant diseases, has a complex tumor ecosystem. An obvious requirement for T-cell-mediated tumor control is the infiltration of tumor-reactive T cells into the tumor. Here, we obtained detailed T-cell compositions in both ESCC tumors and matched peripheral blood mononuclear cells (PBMCs) at single-cell resolution. We demonstrated that T cells in tumors and PBMCs had different compositions and functional states. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
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4. Novel plasma and brain proteins that are implicated in multiple sclerosis.
- Author
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Lin, Xin, Yang, Yuanhao, Gresle, Melissa, Cuellar-Partida, Gabriel, Han, Xikun, Stankovich, Jim, Group, AusLong, Simpson-Yap, Steve, Fuh-Ngwa, Valery, Charlesworth, Jac, Burdon, Kathryn P, Butzkueven, Helmut, Taylor, Bruce V, Zhou, Yuan, and AusLong/Ausimmune Investigators Group Steve Simpson-Yap
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BLOOD proteins ,MULTIPLE sclerosis ,KILLER cells ,CYTOTOXIC T cells ,GENOME-wide association studies - Abstract
Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls; dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls; dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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5. Manufacture and Characterization of Good Manufacturing Practice-Compliant SARS-COV-2 Cytotoxic T Lymphocytes.
- Author
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Chu, Yaya, Milner, Jordan, Lamb, Margaret, Maryamchik, Elena, Rigot, Olivia, Ayello, Janet, Harrison, Lauren, Shaw, Rosemarie, Behbehani, Gregory K, Mardis, Elaine R, Miller, Katherine, Venkata, Lakshmi Prakruthi Rao, Chang, Hsiaochi, Lee, Dean, Rosenthal, Elana, Kadauke, Stephan, Bunin, Nancy, Talano, Julie-An, Johnson, Bryon, and Wang, Yongping
- Subjects
CYTOTOXIC T cells ,SARS-CoV-2 ,MONONUCLEAR leukocytes ,TUMOR necrosis factors ,COVID-19 - Abstract
Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2–vCTLs generated from convalescent COVID-19 donors using the CliniMACS Cytokine Capture System (CCS). Methods Donor screening was done by stimulation of convalescent COVID-19 donor peripheral blood mononuclear cells with viral peptides and identification of interferonγ (IFN-γ)
+ CD4 and CD8 T cells using flow cytometry. Clinical-grade SARS-CoV-2–vCTLs were manufactured using the CliniMACS CCS. The enriched SARS-CoV-2–vCTLs were characterized by T-cell receptor sequencing, mass cytometry, and transcriptome analysis. Results Of the convalescent donor blood samples, 93% passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T cells that were 79% (standard error of the mean 21%) IFN-γ+ T cells. SARS-CoV-2–vCTLs displayed a highly diverse T-cell receptor repertoire with enhancement of both memory CD8 and CD4 T cells, especially in CD8 TEM, CD4 TCM , and CD4 TEMRA cell subsets. SARS-CoV-2–vCTLs were polyfunctional with increased gene expression in T-cell function, interleukin, pathogen defense, and tumor necrosis factor superfamily pathways. Conclusions Highly functional SARS-CoV-2–vCTLs can be rapidly generated by direct cytokine enrichment (12 hours) from convalescent donors. Clinical Trials Registration NCT04896606. [ABSTRACT FROM AUTHOR]- Published
- 2023
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6. T cell activation and IFNγ modulate organ dysfunction in LPS‐mediated inflammation.
- Author
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Taylor, Matthew D., Fernandes, Tiago D., Yaipen, Omar, Higgins, Cassidy E., Capone, Christine A., Leisman, Daniel E., Nedeljkovic‐Kurepa, Ana, Abraham, Mabel N., Brewer, Mariana R., and Deutschman, Clifford S.
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CYTOTOXIC T cells ,T cells ,DENDRITIC cells - Abstract
LPS challenge is used to model inflammation‐induced organ dysfunction. The effects of T cell activation on LPS‐mediated organ dysfunction and immune responses are unknown. We studied these interactions through in vivo administration of anti‐CD3ε (CD3) T cell activating antibody and LPS. Mortality in response to high‐dose LPS (LPSHi; 600 μg) was 60%; similar mortality was observed with a 10‐fold reduction in LPS dose (LPSLo; 60 μg) when administered with CD3 (CD3LPSLo). LPSHi and CD3LPSLo cohorts suffered severe organ dysfunction. CD3LPSLo led to increased IFNγ and IL12p70 produced by T cells and dendritic cells (cDCs) respectively. CD3LPSLo caused cDC expression of CD40 and MHCII and prevented PD1 expression in response to CD3. These interactions led to the generation of CD4 and CD8 cytolytic T cells. CD3LPSLo responded to IFNγ or IL12p40 blockade, in contrast to LPSHi. The combination of TCR activation and LPS (CD3LPSLo) dysregulated T cell activation and increased LPS‐associated organ dysfunction and mortality through T cell and cDC interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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7. Bacillus Calmette-Guerin (BCG) induces superior anti-tumour responses by Vδ2+ T cells compared with the aminobisphosphonate drug zoledronic acid.
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Fenn, J, Ridgley, L A, White, A, Sarfas, C, Dennis, M, Dalgleish, A, Reljic, R, Sharpe, S, and Bodman-Smith, M
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T cells ,ZOLEDRONIC acid ,CELLULAR recognition ,CYTOTOXIC T cells ,CELL populations - Abstract
Vδ2
+ T cells can recognize malignantly transformed cells as well as those infected with mycobacteria. This cross-reactivity supports the idea of using mycobacteria to manipulate Vδ2+ T cells in cancer immunotherapy. To date, therapeutic interventions using Vδ2+ T cells in cancer have involved expanding these cells in or ex vivo using zoledronic acid (ZA). Here, we show that the mycobacterium Bacillus Calmette–Guérin (BCG) also causes Vδ2+ T-cell expansion in vitro and that resulting Vδ2+ cell populations are cytotoxic toward tumour cell lines. We show that both ZA and BCG-expanded Vδ2+ cells effectively killed both Daudi and THP-1 cells. THP-1 cell killing by both ZA and BCG-expanded Vδ2+ cells was enhanced by treatment of targets cells with ZA. Although no difference in cytotoxic activity between ZA- and BCG-expanded Vδ2+ cells was observed, BCG-expanded cells degranulated more and produced a more diverse range of cytokines upon tumour cell recognition compared to ZA-expanded cells. ZA-expanded Vδ2+ cells were shown to upregulate exhaustion marker CD57 to a greater extent than BCG-expanded Vδ2+ cells. Furthermore, ZA expansion was associated with upregulation of inhibitory markers PD-1 and TIM3 in a dose-dependent manner whereas PD-1 expression was not increased following expansion using BCG. Intradermal BCG vaccination of rhesus macaques caused in vivo expansion of Vδ2+ cells. In combination with the aforementioned in vitro data, this finding suggests that BCG treatment could induce expansion of Vδ2+ T cells with enhanced anti-tumour potential compared to ZA treatment and that either ZA or BCG could be used intratumourally as a means to potentiate stronger anti-tumour Vδ2+ T-cell responses. Vd2+ gamma-delta T cells have been shown in vitroto elicit potent cytolytic responses toward tumour cells, suggesting the potential for these responses to be manipulated in cancer immunotherapy. We show that heat-killed Bacillus Calmette-Guerin (HKBCG) promotes the expansion of Vd2+ T cells both in vitroand in vivo. These HKBCG-expanded cells exhibited enhanced degranulation and cytokine production in tumour cells compared to cells expanded using bisphosphonates. [ABSTRACT FROM AUTHOR]- Published
- 2022
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8. Patho-immunological mechanisms of vitiligo: the role of the innate and adaptive immunities and environmental stress factors.
- Author
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Faraj, Safa, Kemp, Elizabeth Helen, and Gawkrodger, David John
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PSYCHONEUROIMMUNOLOGY ,VITILIGO ,NATURAL immunity ,CHROMATOPHORES ,EMOTIONAL trauma ,ANTIGEN presentation - Abstract
Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Regeneration of antigen-specific T cells by using induced pluripotent stem cell (iPSC) technology.
- Author
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Kawamoto, Hiroshi, Masuda, Kyoko, and Nagano, Seiji
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INDUCED pluripotent stem cells ,T cells ,CYTOTOXIC T cells ,REGENERATION (Biology) ,ACUTE myeloid leukemia - Abstract
In currently ongoing adoptive T-cell therapies, T cells collected from the patient are given back to the patient after ex vivo cell activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period. Although such strategies have been shown to be effective in some types of cancer, there remain issues to be solved; these methods (i) are time-consuming, (ii) are costly and (iii) it is difficult to guarantee the quality because the products depend on patient-derived T cells. To address these issues, several groups including ours have developed methods in which cytotoxic cells are mass-produced by using induced pluripotent stem cell (iPSC) technology. For the regeneration of T cells, the basic idea is as follows: iPSCs produced from T cells inherit rearranged TCR genes, and thus all regenerated T cells should express the same TCR. Based on this idea, various types of T cells have been regenerated, including conventional cytotoxic T lymphocytes (CTLs), γδT cells, NKT cells and mucosal-associated invariant T (MAIT) cells. On the other hand, any cytotoxic cells can be used as the base cells into which CAR is introduced, and thus iPSC-derived NK cells have been developed. To apply the iPSC-based cell therapy in an allogeneic setting, the authors' group developed a method in which non-T-cell-derived iPSCs are transduced with exogenous TCR genes (TCR-iPSC method). This approach is being prepared for a clinical trial to be realized in Kyoto University Hospital, in which acute myeloid leukemia patients will be treated by the regenerated WT1 antigen-specific CTLs. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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10. Novel actors on the stage of cardiac dysfunction induced by anti-PD1 oncological treatments.
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Varricchi, Gilda, Galdiero, Maria Rosaria, and Tocchetti, Carlo G
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CARDIOTOXICITY ,IMMUNE checkpoint inhibitors ,MONOCLONAL antibodies ,PROGRAMMED death-ligand 1 ,CYTOTOXIC T cells - Abstract
An editorial is presented on targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Topics include cancer immunotherapies with monoclonal antibodies (mAbs) against immune checkpoints and programmed death 1 (PD1) improving antineoplastic treatments; and causing autoimmune myocarditis with lymphocytic infiltration of cytotoxic T cells suggesting molecules having a major role in preventing autoimmunity.
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- 2022
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11. Interview with Dr Kazuo Sugamura.
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INTERLEUKIN-2 ,CYTOTOXIC T cells ,INDIGENOUS peoples of South America ,COVID-19 - Published
- 2021
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12. Interview with Dr Toshio Hirano.
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CLINICAL immunology ,COVID-19 ,CYTOLOGY ,CYTOTOXIC T cells ,B cells ,SYSTEMIC lupus erythematosus - Published
- 2021
- Full Text
- View/download PDF
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