116 results on '"Seumois, Grégory"'
Search Results
2. RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R
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Badrani, Jana H, Strohm, Allyssa N, Lacasa, Lee, Civello, Blake, Cavagnero, Kellen, Haung, Yung-An, Amadeo, Michael, Naji, Luay H, Lund, Sean J, Leng, Anthea, Kim, Hyojoung, Baum, Rachel E, Khorram, Naseem, Mondal, Monalisa, Seumois, Grégory, Pilotte, Julie, Vanderklish, Peter W, McGee, Heather M, and Doherty, Taylor A
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Asthma ,Lung ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Respiratory ,Allergens ,Animals ,Cytokines ,Immunity ,Innate ,Inflammation ,Interleukin-33 ,Lymphocytes ,Mice ,Pneumonia ,RNA-Binding Proteins ,Receptors ,Leukotriene - Abstract
Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.
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- 2022
3. Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity
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Herrera-De La Mata, Sara, Ramírez-Suástegui, Ciro, Mistry, Heena, Castañeda-Castro, Francisco Emmanuel, Kyyaly, Mohammad A., Simon, Hayley, Liang, Shu, Lau, Laurie, Barber, Clair, Mondal, Monalisa, Zhang, Hongmei, Arshad, Syed Hasan, Kurukulaaratchy, Ramesh J., Vijayanand, Pandurangan, and Seumois, Grégory
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- 2023
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4. Identification of cow milk epitopes to characterize and quantify disease-specific T cells in allergic children
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Lewis, Sloan A., Sutherland, Aaron, Soldevila, Ferran, Westernberg, Luise, Aoki, Minori, Frazier, April, Maiche, Synaida, Erlewyn-Lajeunesse, Mich, Arshad, Hasan, Leonard, Stephanie, Laubach, Susan, Dantzer, Jennifer A., Wood, Robert A., Sette, Alessandro, Seumois, Gregory, Vijayanand, Pandurangan, and Peters, Bjoern
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- 2023
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5. Transcriptome and chromatin landscape of iNKT cells are shaped by subset differentiation and antigen exposure.
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Murray, Mallory, Engel, Isaac, Seumois, Grégory, Herrera-De la Mata, Sara, Rosales, Sandy, Sethi, Ashu, Logandha Ramamoorthy Premlal, Ashmitaa, Seo, Goo-Young, Greenbaum, Jason, Vijayanand, Pandurangan, Scott-Browne, James, and Kronenberg, Mitchell
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Animals ,Cell Differentiation ,Chromatin ,Female ,Lung ,Lymphocyte Activation ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Natural Killer T-Cells ,T Follicular Helper Cells ,T-Lymphocyte Subsets ,Thymus Gland ,Transcriptome - Abstract
Invariant natural killer T cells (iNKT cells) differentiate into thymic and peripheral NKT1, NKT2 and NKT17 subsets. Here we use RNA-seq and ATAC-seq analyses and show iNKT subsets are similar, regardless of tissue location. Lung iNKT cell subsets possess the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. Following antigenic stimulation, iNKT cells undergo chromatin and transcriptional changes delineating two populations: one similar to follicular helper T cells and the other NK or effector like. Phenotypic analysis indicates these changes are observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to additional subsets.
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- 2021
6. Comprehensive Characterization of Difficult-to-Treat Asthma Reveals Near Absence of T2-Low Status
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Rupani, Hitasha, Kyyaly, Mohammed Aref, Azim, Adnan, Abadalkareen, Rana, Freeman, Anna, Dennison, Paddy, Howarth, Peter, Djukanovic, Ratko, Vijayanand, Pandurangan, Seumois, Gregory, Arshad, S. Hasan, Haitchi, Hans Michael, and Kurukulaaratchy, Ramesh J.
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- 2023
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7. Unconventional ST2- and CD127-negative lung ILC2 populations are induced by the fungal allergen Alternaria alternata
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Cavagnero, Kellen J, Badrani, Jana H, Naji, Luay H, Amadeo, Michael B, Shah, Veranca S, Gasparian, Suzanna, Pham, Alexa, Wang, Alice W, Seumois, Grégory, Croft, Michael, Broide, David H, and Doherty, Taylor A
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Biomedical and Clinical Sciences ,Immunology ,Allergens ,Alternaria ,Alternariosis ,Animals ,Antigens ,Fungal ,Cells ,Cultured ,Cytokines ,Disease Models ,Animal ,Humans ,Hypersensitivity ,Immunity ,Innate ,Interleukin-1 Receptor-Like 1 Protein ,Interleukin-7 Receptor alpha Subunit ,Lymphocyte Subsets ,Lymphocytes ,Mice ,Mice ,Knockout ,Th2 Cells ,Allergy - Abstract
We demonstrate that unconventional ST2- and CD127-negative ILC2 populations are present in mouse lung and are induced by Alternaria, suggesting commonly used ILC2 identification practices do not accurately enumerate the total burden of type 2 cytokine producing ILC2s.
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- 2019
8. Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared with Common β-Chain Cytokines IL-5 and GM-CSF
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Nelson, Ryan K, Brickner, Howard, Panwar, Bharat, Ramírez-Suástegui, Ciro, Herrera-de la Mata, Sara, Liu, Neiman, Diaz, Damaris, Alexander, Laura E Crotty, Ay, Ferhat, Vijayanand, Pandurangan, Seumois, Grégory, and Akuthota, Praveen
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Biotechnology ,Genetics ,Lung ,Clinical Research ,Asthma ,2.1 Biological and endogenous factors ,Aetiology ,Cytokines ,Down-Regulation ,Eosinophils ,Gene Expression ,Granulocyte-Macrophage Colony-Stimulating Factor ,Humans ,Interleukin-3 ,Interleukin-5 ,Signal Transduction ,Up-Regulation ,Immunology - Abstract
Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common β subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the β-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.
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- 2019
9. Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus–Specific CD8+ T Cells
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Grifoni, Alba, Costa-Ramos, Priscilla, Pham, John, Tian, Yuan, Rosales, Sandy L, Seumois, Grégory, Sidney, John, de Silva, Aruna D, Premkumar, Lakshmanane, Collins, Matthew H, Stone, Mars, Norris, Phillip J, Romero, Claudia ME, Durbin, Anna, Ricciardi, Michael J, Ledgerwood, Julie E, de Silva, Aravinda M, Busch, Michael, Peters, Bjoern, Vijayanand, Pandurangan, Harris, Eva, Falconar, Andrew K, Kallas, Esper, Weiskopf, Daniela, and Sette, Alessandro
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Prevention ,Clinical Research ,Biodefense ,Emerging Infectious Diseases ,Infectious Diseases ,Vaccine Related ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,Antigens ,Viral ,CD8-Positive T-Lymphocytes ,Cells ,Cultured ,Cytotoxicity ,Immunologic ,Epitopes ,T-Lymphocyte ,Gene Expression Profiling ,Granzymes ,Humans ,Immunoglobulins ,Immunophenotyping ,Interferon-gamma ,Receptors ,Tumor Necrosis Factor ,Tumor Necrosis Factor-alpha ,Zika Virus ,Zika Virus Infection ,Immunology - Abstract
Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8+ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8+ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8+ T cells are characterized by a polyfunctional IFN-γ signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8+ T cells responding to ZIKV infection.
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- 2018
10. Laser Capture Microscopy RNA Sequencing for Topological Mapping of Synovial Pathology During Rheumatoid Arthritis.
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Van Espen, Benjamin, Prideaux, E. Barton, Wilson, Andrew R., Machado, Camilla R. L., Sendo, Sho, Parker, James, Seumois, Grégory, Sacchetti, Cristiano, Belongia, Anna C., Perumal, Narayanan B., Vijayanand, Pandurangan, Linnik, Matthew D., Benschop, Robert J., Wang, Wei, Bottini, Nunzio, Firestein, Gary S., and Stanford, Stephanie M.
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RNA analysis ,RHEUMATOID arthritis ,SYNOVIAL fluid ,PAIRED comparisons (Mathematics) ,CELL cycle ,CELLULAR signal transduction ,GENE expression profiling ,MICROSCOPY ,STAINS & staining (Microscopy) ,FACTOR analysis ,SEQUENCE analysis ,PHENOTYPES - Abstract
Objective: Rheumatoid arthritis (RA) is an autoimmune disease in which the joint lining or synovium becomes highly inflamed and majorly contributes to disease progression. Understanding pathogenic processes in RA synovium is critical for identifying therapeutic targets. We performed laser capture microscopy (LCM) followed by RNA sequencing (LCM‐RNAseq) to study regional transcriptomes throughout RA synovium. Methods: Synovial lining, sublining, and vessel samples were captured by LCM from seven patients with RA and seven patients with osteoarthritis (OA). RNAseq was performed on RNA extracted from captured tissue. Principal component analysis was performed on the sample set by disease state. Differential expression analysis was performed between disease states based on log2 fold change and q value parameters. Pathway analysis was performed using the Reactome Pathway Database on differentially expressed genes among disease states. Significantly enriched pathways in each synovial region were selected based on the false discovery rate. Results: RA and OA transcriptomes were distinguishable by principal component analysis. Pairwise comparisons of synovial lining, sublining, and vessel samples between RA and OA revealed substantial differences in transcriptional patterns throughout the synovium. Hierarchical clustering of pathways based on significance revealed a pattern of association between biologic function and synovial topology. Analysis of pathways uniquely enriched in each region revealed distinct phenotypic abnormalities. As examples, RA lining samples were marked by anomalous immune cell signaling, RA sublining samples were marked by aberrant cell cycle, and RA vessel samples were marked by alterations in heme scavenging. Conclusion: LCM‐RNAseq confirms reported transcriptional differences between the RA synovium and the OA synovium and provides evidence supporting a relationship between synovial topology and molecular anomalies in RA. [ABSTRACT FROM AUTHOR]
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- 2024
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11. The Clinical Implications of Aspergillus Fumigatus Sensitization in Difficult-To-Treat Asthma Patients
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Mistry, Heena, Ajsivinac Soberanis, Hilda Maria, Kyyaly, Mohammad Aref, Azim, Adnan, Barber, Clair, Knight, Deborah, Newell, Colin, Haitchi, Hans Michael, Wilkinson, Tom, Howarth, Peter, Seumois, Grégory, Vijayanand, Pandurangan, Arshad, S. Hasan, and Kurukulaaratchy, Ramesh J.
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- 2021
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12. Allergen-specific IgG+ memory B cells are temporally linked to IgE memory responses
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Hoof, Ilka, Schulten, Veronique, Layhadi, Janice A., Stranzl, Thomas, Christensen, Lars H., Herrera de la Mata, Sara, Seumois, Grégory, Vijayanand, Pandurangan, Lundegaard, Claus, Niss, Kristoffer, Lund, Anders, Ahrenfeldt, Johanne, Holm, Jens, Steveling, Esther, Sharif, Hanisah, Durham, Stephen R., Peters, Björn, Shamji, Mohamed H., and Andersen, Peter S.
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- 2020
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13. Identification of a novel cis-regulatory element essential for immune tolerance
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LaFlam, Taylor N, Seumois, Grégory, Miller, Corey N, Lwin, Wint, Fasano, Kayla J, Waterfield, Michael, Proekt, Irina, Vijayanand, Pandurangan, and Anderson, Mark S
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Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Prevention ,Genetics ,Inflammatory and immune system ,Animals ,Base Sequence ,DNA ,Epithelial Cells ,HEK293 Cells ,Humans ,Immune Tolerance ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Microscopy ,Fluorescence ,Molecular Sequence Data ,NF-kappa B ,Protein Binding ,Regulatory Sequences ,Nucleic Acid ,Reverse Transcriptase Polymerase Chain Reaction ,Sequence Homology ,Nucleic Acid ,Thymus Gland ,Transcription Factors ,Transcriptome ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.
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- 2015
14. Single-cell analysis to understand the diversity of immune cell types that drive disease pathogenesis
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Seumois, Grégory and Vijayanand, Pandurangan
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- 2019
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15. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility.
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Seumois, Grégory, Chavez, Lukas, Gerasimova, Anna, Lienhard, Matthias, Omran, Nada, Kalinke, Lukas, Vedanayagam, Maria, Ganesan, Asha, Chawla, Ashu, Djukanović, Ratko, Peters, Bjoern, Rao, Anjana, Vijayanand, Pandurangan, and Ansel, Karl
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Adolescent ,Adult ,Aged ,Asthma ,Binding Sites ,Cell Differentiation ,Cells ,Cultured ,Core Binding Factor Alpha 3 Subunit ,DNA Methylation ,Epigenomics ,Female ,GATA3 Transcription Factor ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Histones ,Humans ,Immunologic Memory ,Male ,MicroRNAs ,Middle Aged ,Polymorphism ,Single Nucleotide ,Promoter Regions ,Genetic ,Protein Binding ,Sequence Analysis ,RNA ,T-Box Domain Proteins ,Th1 Cells ,Th2 Cells ,Young Adult - Abstract
A characteristic feature of asthma is the aberrant accumulation, differentiation or function of memory CD4(+) T cells that produce type 2 cytokines (TH2 cells). By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, we identified enhancers with known and potential roles in the normal differentiation of human TH1 cells and TH2 cells. We discovered disease-specific enhancers in T cells that differ between healthy and asthmatic individuals. Enhancers that gained the histone H3 Lys4 dimethyl (H3K4me2) mark during TH2 cell development showed the highest enrichment for asthma-associated single nucleotide polymorphisms (SNPs), which supported a pathogenic role for TH2 cells in asthma. In silico analysis of cell-specific enhancers revealed transcription factors, microRNAs and genes potentially linked to human TH2 cell differentiation. Our results establish the feasibility and utility of enhancer profiling in well-defined populations of specialized cell types involved in disease pathogenesis.
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- 2014
16. An integrated nano-scale approach to profile miRNAs in limited clinical samples.
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Seumois, Grégory, Vijayanand, Pandurangan, Eisley, Christopher J, Omran, Nada, Kalinke, Lukas, North, Mal, Ganesan, Asha P, Simpson, Laura J, Hunkapiller, Nathan, Moltzahn, Felix, Woodruff, Prescott G, Fahy, John V, Erle, David J, Djukanovic, Ratko, Blelloch, Robert, and Ansel, K Mark
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Lung ,Clinical Research ,Genetics ,Human Genome ,Biotechnology ,Asthma ,Aetiology ,2.1 Biological and endogenous factors ,Respiratory ,microRNA ,asthma ,helper T cell ,microfluidic ,qPCR arrays ,Clinical Sciences ,Immunology - Abstract
Profiling miRNA expression in cells that directly contribute to human disease pathogenesis is likely to aid the discovery of novel drug targets and biomarkers. However, tissue heterogeneity and the limited amount of human diseased tissue available for research purposes present fundamental difficulties that often constrain the scope and potential of such studies. We established a flow cytometry-based method for isolating pure populations of pathogenic T cells from bronchial biopsy samples of asthma patients, and optimized a high-throughput nano-scale qRT-PCR method capable of accurately measuring 96 miRNAs in as little as 100 cells. Comparison of circulating and airway T cells from healthy and asthmatic subjects revealed asthma-associated and tissue-specific miRNA expression patterns. These results establish the feasibility and utility of investigating miRNA expression in small populations of cells involved in asthma pathogenesis, and set a precedent for application of our nano-scale approach in other human diseases. The microarray data from this study (Figure 7) has been submitted to the NCBI Gene Expression Omnibus (GEO; http://ncbi.nlm.nih.gov/geo) under accession no. GSE31030.
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- 2012
17. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer
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Ganesan, Anusha-Preethi, Clarke, James, Wood, Oliver, Garrido-Martin, Eva M, Chee, Serena J, Mellows, Toby, Samaniego-Castruita, Daniela, Singh, Divya, Seumois, Grégory, Alzetani, Aiman, Woo, Edwin, Friedmann, Peter S, King, Emma V, Thomas, Gareth J, Sanchez-Elsner, Tilman, Vijayanand, Pandurangan, and Ottensmeier, Christian H
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- 2017
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18. Publisher Correction: Innate-like functions of natural killer T cell subsets result from highly divergent gene programs
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Engel, Isaac, Seumois, Grégory, Chavez, Lukas, Samaniego-Castruita, Daniela, White, Brandie, Chawla, Ashu, Mock, Dennis, Vijayanand, Pandurangan, and Kronenberg, Mitchell
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- 2019
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19. Innate-like functions of natural killer T cell subsets result from highly divergent gene programs
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Engel, Isaac, Seumois, Grégory, Chavez, Lukas, Samaniego-Castruita, Daniela, White, Brandie, Chawla, Ashu, Mock, Dennis, Vijayanand, Pandurangan, and Kronenberg, Mitchell
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- 2016
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20. Differential Recognition of Mycobacterium tuberculosis-Specific Epitopes as a Function of Tuberculosis Disease History
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Scriba, Thomas J., Carpenter, Chelsea, Pro, Sebastian Carrasco, Sidney, John, Musvosvi, Munyaradzi, Rozot, Virginie, Seumois, Grégory, Rosales, Sandy L., Vijayanand, Pandurangan, Goletti, Delia, Makgotlho, Edward, Hanekom, Willem, Hatherill, Mark, Peters, Bjoern, Sette, Alessandro, and Lindestam Arlehamn, Cecilia S.
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- 2017
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21. Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells
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Schulten, Véronique, Tripple, Victoria, Seumois, Grégory, Qian, Yu, Scheuermann, Richard H., Fu, Zheng, Locci, Michela, Rosales, Sandy, Vijayanand, Pandurangan, Sette, Alessandro, Alam, Rafeul, Crotty, Shane, and Peters, Bjoern
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- 2018
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22. Transcriptomics of Acute DENV-Specific CD8+ T Cells Does Not Support Qualitative Differences as Drivers of Disease Severity.
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Grifoni, Alba, Voic, Hannah, Yu, Esther Dawen, Mateus, Jose, Yan Fung, Kai Mei, Wang, Alice, Seumois, Grégory, De Silva, Aruna D., Tennekon, Rashika, Premawansa, Sunil, Premawansa, Gayani, Tippalagama, Rashmi, Wijewickrama, Ananda, Chawla, Ashu, Greenbaum, Jason, Peters, Bjoern, Pandurangan, Vijayanand, Weiskopf, Daniela, and Sette, Alessandro
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DENGUE hemorrhagic fever ,T cells ,CD8 antigen ,DENGUE ,DENGUE viruses - Abstract
While several lines of evidence suggest a protective role of T cells against disease associated with Dengue virus (DENV) infection, their potential contribution to immunopathology in the acute phase of DENV infection remains controversial, and it has been hypothesized that the more severe form of the disease (dengue hemorrhagic fever, DHF) is associated with altered T cell responses. To address this question, we determined the transcriptomic profiles of DENV-specific CD8+ T cells in a cohort of 40 hospitalized dengue patients with either a milder form of the disease (dengue fever, DF) or a more severe disease form (dengue hemorrhagic fever, DHF). We found multiple transcriptomic signatures, one associated with DENV-specific interferon-gamma responding cells and two other gene signatures, one specifically associated with the acute phase and the other with the early convalescent phase. Additionally, we found no differences in quantity and quality of DENV-specific CD8+ T cells based on disease severity. Taken together with previous findings that did not detect altered DENV-specific CD4 T cell responses, the current analysis argues against alteration in DENV-specific T cell responses as being a correlate of immunopathology. [ABSTRACT FROM AUTHOR]
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- 2022
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23. Single-cell eQTL analysis of activated T cell subsets reveals activation and cell type–dependent effects of disease-risk variants.
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Schmiedel, Benjamin J., Gonzalez-Colin, Cristian, Fajardo, Vicente, Rocha, Job, Madrigal, Ariel, Ramírez-Suástegui, Ciro, Bhattacharyya, Sourya, Simon, Hayley, Greenbaum, Jason A., Peters, Bjoern, Seumois, Grégory, Ay, Ferhat, Chandra, Vivek, and Vijayanand, Pandurangan
- Abstract
The impact of genetic variants on cells challenged in biologically relevant contexts has not been fully explored. Here, we activated CD4
+ T cells from 89 healthy donors and performed a single-cell RNA sequencing assay with >1 million cells to examine cell type–specific and activation-dependent effects of genetic variants. Single-cell expression quantitative trait loci (sc-eQTL) analysis of 19 distinct CD4+ T cell subsets showed that the expression of over 4000 genes is significantly associated with common genetic polymorphisms and that most of these genes show their most prominent effects in specific cell types. These genes included many that encode for molecules important for activation, differentiation, and effector functions of T cells. We also found new gene associations for disease-risk variants identified from genome-wide association studies and highlighted the cell types in which their effects are most prominent. We found that biological sex has a major influence on activation-dependent gene expression in CD4+ T cell subsets. Sex-biased transcripts were significantly enriched in several pathways that are essential for the initiation and execution of effector functions by CD4+ T cells like TCR signaling, cytokines, cytokine receptors, costimulatory, apoptosis, and cell-cell adhesion pathways. Overall, this DICE (Database of Immune Cell Expression, eQTLs, and Epigenomics) subproject highlights the power of sc-eQTL studies for simultaneously exploring the activation and cell type–dependent effects of common genetic variants on gene expression (https://dice-database.org). [ABSTRACT FROM AUTHOR]- Published
- 2022
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24. Interleukin-4 Production by Follicular Helper T Cells Requires the Conserved Il4 Enhancer Hypersensitivity Site V
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Vijayanand, Pandurangan, Seumois, Grégory, Simpson, Laura J., Abdul-Wajid, Sarah, Baumjohann, Dirk, Panduro, Marisella, Huang, Xiaozhu, Interlandi, Jeneen, Djuretic, Ivana M., Brown, Daniel R., Sharpe, Arlene H., Rao, Anjana, and Ansel, Mark K.
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- 2012
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25. Prosurvival activity for airway neutrophils in severe asthma
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Uddin, Mohib, Nong, Guangmin, Ward, Jonathan, Seumois, Grégory, Prince, Lynne R, Wilson, Susan J, Cornelius, Victoria, Dent, Gordon, and Djukanović, Ratko
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- 2010
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26. Pro-inflammatory properties for thiazolidinediones
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Desmet, Christophe, Warzée, Barbara, Gosset, Philippe, Mélotte, Dorothée, Rongvaux, Anthony, Gillet, Laurent, Fiévez, Laurence, Seumois, Grégory, Vanderplasschen, Alain, Staels, Bart, Lekeux, Pierre, and Bureau, Fabrice
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- 2005
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27. CD40 engagement enhances eosinophil survival through induction of cellular inhibitor of apoptosis protein 2 expression: Possible involvement in allergic inflammation
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Bureau, Fabrice, Seumois, Grégory, Jaspar, Fabrice, Vanderplasschen, Alain, Detry, Bruno, Pastoret, Paul-Pierre, Louis, Renaud, and Lekeux, Pierre
- Published
- 2002
28. Severely ill patients with COVID-19 display impaired exhaustion features in SARS-CoV-2–reactive CD8+ T cells.
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Kusnadi, Anthony, Ramírez-Suástegui, Ciro, Fajardo, Vicente, Chee, Serena J., Meckiff, Benjamin J., Simon, Hayley, Pelosi, Emanuela, Seumois, Grégory, Ay, Ferhat, Vijayanand, Pandurangan, and Ottensmeier, Christian H.
- Abstract
The molecular properties of CD8
+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified antigen-reactive T cell enrichment assay, from 39 patients with COVID-19 and 10 healthy participants. Patients with COVID-19 were segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was "exhausted" or "non-exhausted." SARS-CoV-2–reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in patients with COVID-19 experiencing mild compared with severe illness. In contrast, SARS-CoV-2–reactive cells in the dominant nonexhausted subset from patients with severe disease showed enrichment of transcripts linked to costimulation, prosurvival NF-κB signaling, and antiapoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy participants displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2–reactive cells from both patients with COVID-19 and healthy controls nonexposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. [ABSTRACT FROM AUTHOR]- Published
- 2021
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29. Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma.
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Seumois, Grégory, Ramírez-Suástegui, Ciro, Schmiedel, Benjamin J., Liang, Shu, Peters, Bjoern, Sette, Alessandro, and Vijayanand, Pandurangan
- Abstract
Finding a TRAIL to allergy control: House dust mites (HDMs) are a major source of aeroallergens that trigger human allergic responses including asthma. To characterize the heterogeneity of human CD4
+ T helper (TH ) cell responses to HDM antigens, Seumois et al. stimulated blood T cells with HDM peptides and isolated the freshly activated T cells for single-cell RNA sequencing. A TH subset expressing an interferon response gene signature (designated TH IFNR) and the cell death–inducing TRAIL ligand was more frequent in individuals without HDM allergy. This TRAIL+ TH IFNR subset may function to restrain allergic TH 2 responses. Individuals with both HDM allergy and asthma were enriched for interleukin-9–producing TH 2 cells. These findings provide a basis for designing more precise approaches to thwart pathogenic TH responses contributing to allergic asthma. CD4+ T helper (TH ) cells and regulatory T (Treg ) cells that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma. Until recently, direct, unbiased molecular analysis of allergen-reactive TH and Treg cells has not been possible. To better understand the diversity of these T cell subsets in allergy and asthma, we analyzed the single-cell transcriptome of ~50,000 house dust mite (HDM) allergen–reactive TH cells and Treg cells from asthmatics with HDM allergy and from three control groups: asthmatics without HDM allergy and nonasthmatics with and without HDM allergy. Our analyses show that HDM allergen–reactive TH and Treg cells are highly heterogeneous and certain subsets are quantitatively and qualitatively different in individuals with HDM-reactive asthma. The number of interleukin-9 (IL-9)–expressing HDM-reactive TH cells is greater in asthmatics with HDM allergy compared with nonasthmatics with HDM allergy, and this IL-9–expressing TH subset displays enhanced pathogenic properties. More HDM-reactive TH and Treg cells expressing the interferon response signature (TH IFNR and Treg IFNR) are present in asthmatics without HDM allergy compared with those with HDM allergy. In cells from these subsets (TH IFNR and Treg IFNR), expression of TNFSF10 was enriched; its product, tumor necrosis factor–related apoptosis-inducing ligand, dampens activation of TH cells. These findings suggest that the TH IFNR and Treg IFNR subsets may dampen allergic responses, which may help explain why only some people develop TH 2 responses to nearly ubiquitous allergens. [ABSTRACT FROM AUTHOR]- Published
- 2020
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30. Constitutive Activation of Natural Killer Cells in Primary Biliary Cholangitis.
- Author
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Hydes, Theresa J., Blunt, Matthew D., Naftel, Jennifer, Vallejo, Andres F., Seumois, Grégory, Wang, Alice, Vijayanand, Pandurangan, Polak, Marta E., and Khakoo, Salim I.
- Subjects
KILLER cells ,SJOGREN'S syndrome ,CHOLANGITIS ,CELL physiology - Abstract
Natural killer (NK) cells are innate immune cells that interface with the adaptive immune system to generate a pro-inflammatory immune environment. Primary Biliary Cholangitis (PBC) is a hepatic autoimmune disorder with extrahepatic associations including systemic sclerosis, Sjogren's syndrome and thyroiditis. Immunogenetic studies have identified polymorphisms of the IL-12/STAT4 pathway as being associated with PBC. As this pathway is important for NK cell function we investigated NK cells in PBC. Circulating NK cells from individuals with PBC were constitutively activated, with higher levels of CD49a and the liver-homing marker, CXCR6, compared to participants with non-autoimmune chronic liver disease and healthy controls. Stimulation with minimal amounts of IL-12 (0.005 ng/ml) led to significant upregulation of CXCR6 (p < 0.005), and enhanced IFNγ production (p < 0.02) on NK cells from PBC patients compared to individuals with non-autoimmune chronic liver disease, indicating dysregulation of the IL-12/STAT4 axis. In RNAseq studies, resting NK cells from PBC patients had a constitutively activated transcriptional profile and upregulation of genes associated with IL-12/STAT4 signaling and metabolic reprogramming. Consistent with these findings, resting NK cells from PBC patients expressed higher levels of pSTAT4 compared to control groups (p < 0.001 vs. healthy controls and p < 0.05 vs. liver disease controls). In conclusion NK cells in PBC are sensitive to minute quantities of IL-12 and have a "primed" phenotype. We therefore propose that peripheral priming of NK cells to express tissue-homing markers may contribute to the pathophysiology of PBC. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen.
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Havenar-Daughton, Colin, Sarkar, Anita, Kulp, Daniel W., Toy, Laura, Hu, Xiaozhen, Deresa, Isaiah, Kalyuzhniy, Oleksandr, Kaushik, Kirti, Upadhyay, Amit A., Menis, Sergey, Landais, Elise, Cao, Liwei, Diedrich, Jolene K., Kumar, Sonu, Schiffner, Torben, Reiss, Samantha M., Seumois, Grégory, Yates, John R., Paulson, James C., and Bosinger, Steven E.
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B cells ,IMMUNOGENETICS ,AIDS vaccination research ,GERM cells ,ANTIGENS - Abstract
Inspection of the naive B cell repertoire specific for an HIV vaccine immunogen provides actionable information for human vaccine design and advancement. Learning from naive B cells: Despite decades of intensive research, HIV vaccines are unable to generate broadly neutralizing antibodies that are likely necessary for protection. One vaccine candidate, eOD-GT8, was designed to bait naive B cells that may be capable of producing antibodies similar to VRC01, a potent CD4-binding site–targeting antibody with breadth. Havenar-Daughton et al. inspected the potential of human naive B cells to recognize eOD-GT8, and isolated B cells that used similar genes as those used to make VRC01. They also observed B cells with immunoglobulin genes similar to those used in other types of broadly neutralizing antibodies, some with a more conventional maturation path than VRC01. Their results suggest that vaccination of humans with eOD-GT8 has the potential to eventually induce CD4-binding site broadly neutralizing antibodies, which would be a major step forward in HIV vaccines. Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre–phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the envelope CD4-binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non–VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (K
D ) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement. [ABSTRACT FROM AUTHOR]- Published
- 2018
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32. Unique phenotypes and clonal expansions of human CD4 effector memory T cells re-expressing CD45RA.
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Yuan Tian, Babor, Mariana, Lane, Jerome, Schulten, Veronique, Patil, Veena S., Seumois, Grégory, Rosales, Sandy L., Burel, Julie, Zapardiel-Gonzalo, Jose, Vijayanand, Pandurangan, Weiskopf, Daniela, Sette, Alessandro, Peters, Bjoern, Tennekoon, Rashika N., De Silva, Aruna D., Zheng Fu, Greenbaum, Jason A., Picarda, Gaelle, Premawansa, Sunil, and Premawansa, Gayani
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PHENOTYPES ,T cells ,CLONE cells ,CD4 antigen ,DENGUE viruses - Abstract
The expression of CD45RA is generally associated with naive T cells. However, a subset of effector memory T cells re-expresses CD45RA (termed TEMRA) after antigenic stimulation with unknown molecular characteristics and functions. CD4 TEMRA cells have been implicated in protective immunity against pathogens such as dengue virus (DENV). Here we show that not only the frequency but also the phenotype of CD4 TEMRA cells are heterogeneous between individuals. These cells can be subdivided into two major subsets based on the expression of the adhesion G protein-coupled receptor GPR56, and GPR56
+ TEMRA cells display a transcriptional and proteomic program with cytotoxic features that is distinct from effector memory T cells. Moreover, GPR56+ TEMRA cells have higher levels of clonal expansion and contain the majority of virus-specific TEMRA cells. Overall, this study reveals the heterogeneity of CD4 TEMRA cells and provides insights into T-cell responses against DENV and other viral pathogens. [ABSTRACT FROM AUTHOR]- Published
- 2017
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33. Non-Atopic Individuals Exhibit a Distinct Immune Reactivity Patterns in Response to Timothy Grass Pollen in and out-of-Season
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Hinz, Denise, Seumois, Gregory, Greenbaum, Jason, White, Brandie, Schulten, Veronique M., Broide, David H., Sidney, John, Oseroff, Carla, Wambre, Erik R., James, Eddie A., Kwok, William W., Vijayanand, Pandurangan, Peters, Bjoern, and Sette, Alessandro
- Published
- 2016
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34. Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma.
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Seumois, Grégory, Zapardiel-Gonzalo, Jose, White, Brandie, Singh, Divya, Schulten, Veronique, Dillon, Myles, Hinz, Denize, Broide, David H., Sette, Alessandro, Peters, Bjoern, and Vijayanand, Pandurangan
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ASTHMA , *LUNG diseases , *INFLAMMATION , *RHINITIS - Abstract
Allergic asthma and rhinitis are two common chronic allergic diseases that affect the lungs and nose, respectively. Both diseases share clinical and pathological features characteristic of excessive allergen-induced type 2 inflammation, orchestrated by memory CD4+ T cells that produce type 2 cytokines (Th2 cells). However, a large majority of subjects with allergic rhinitis do not develop asthma, suggesting divergence in disease mechanisms. Because Th2 cells play a pathogenic role in both these diseases and are also present in healthy nonallergic subjects, we performed global transcriptional profiling to determine whether there are qualitative differences in Th2 cells from subjects with allergic asthma, rhinitis, and healthy controls. Th2 cells from asthmatic subjects expressed higher levels of several genes that promote their survival as well as alter their metabolic pathways to favor persistence at sites of allergic inflammation. In addition, genes that enhanced Th2 polarization and Th2 cytokine production were also upregulated in asthma. Several genes that oppose T cell activation were downregulated in asthma, suggesting enhanced activation potential of Th2 cells from asthmatic subjects. Many novel genes with poorly defined functions were also differentially expressed in asthma. Thus, our transcriptomic analysis of circulating Th2 cells has identified several molecules that are likely to confer pathogenic features to Th2 cells that are either unique or common to both asthma and rhinitis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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35. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility.
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Seumois, Grégory, Chavez, Lukas, Gerasimova, Anna, Lienhard, Matthias, Omran, Nada, Kalinke, Lukas, Vedanayagam, Maria, Ganesan, Asha Purnima V, Chawla, Ashu, Djukanović, Ratko, Ansel, K Mark, Peters, Bjoern, Rao, Anjana, and Vijayanand, Pandurangan
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EPIGENOMICS , *T cells , *CELL differentiation , *ASTHMA treatment , *DISEASE susceptibility , *GENE mapping - Abstract
A characteristic feature of asthma is the aberrant accumulation, differentiation or function of memory CD4+ T cells that produce type 2 cytokines (TH2 cells). By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, we identified enhancers with known and potential roles in the normal differentiation of human TH1 cells and TH2 cells. We discovered disease-specific enhancers in T cells that differ between healthy and asthmatic individuals. Enhancers that gained the histone H3 Lys4 dimethyl (H3K4me2) mark during TH2 cell development showed the highest enrichment for asthma-associated single nucleotide polymorphisms (SNPs), which supported a pathogenic role for TH2 cells in asthma. In silico analysis of cell-specific enhancers revealed transcription factors, microRNAs and genes potentially linked to human TH2 cell differentiation. Our results establish the feasibility and utility of enhancer profiling in well-defined populations of specialized cell types involved in disease pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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36. EGF-Induced Bronchial Epithelial Cells Drive Neutrophil Chemotactic and Anti-Apoptotic Activity in Asthma.
- Author
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Uddin, Mohib, Lau, Laurie C., Seumois, Grégory, Vijayanand, Pandurangan, Staples, Karl J., Bagmane, Dinesh, Cornelius, Victoria, Dorinsky, Paul, Davies, Donna E., and Djukanović, Ratko
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EPIDERMAL growth factor ,EPITHELIAL cells ,INTERLEUKIN-8 ,ASTHMA ,ASTHMATICS ,CELLULAR signal transduction - Abstract
Chronic damage and repair of the bronchial epithelium are features of asthma. We have previously reported that ex vivo stimulation of normal bronchial epithelial cells with epidermal growth factor (EGF), a key factor of epithelial repair, enhances the mechanisms of neutrophil accumulation, thereby promoting neutrophil defences during acute injury but potentially enhancing inflammation in chronic airway diseases. We have now sought to (i) determine whether this EGF-dependent pro-neutrophil activity is increased in asthma, where EGF and its epithelial receptor are over-expressed, and (ii) elucidate some of the mechanisms underlying this asthmatic epithelial-neutrophil interaction. Primary bronchial epithelial cells (PBEC) from healthy subjects, mild asthmatics and moderate-to-severe asthmatics (Mod/Sev) were stimulated with EGF, a model that mimics a repairing epithelium. Conditioned culture media (EGF-CM) were assessed for neutrophil chemotactic and anti-apoptotic activities and inflammatory mediator production. EGF induced the epithelium to produce soluble mediators with neutrophil chemotactic (p<0.001) and pro-survival (p = 0.021) activities which were related to the clinical severity of asthma (trend p = 0.010 and p = 0.009, respectively). This was associated with enhanced IL-6, IL-8, GM-CSF and TNF-α release, and cytokine-neutralising experiments using EGF-CM from Mod/Sev asthmatics demonstrated a role for GM-CSF in neutrophil survival (p<0.001). Pre-treatment of neutrophils with specific inhibitors of the myeloid-restricted class I phosphatidylinositol-3-OH kinase (PI(3)K) isoforms showed that the EGF-CM from Mod/Sev asthmatics depended on the γ (p<0.021) but not δ isoforms, while neutrophil survival required multiple class I PI(3)Ks. The EGF-induced chemotactic, but not pro-survival activity, involved RhoA signaling in neutrophils (p = 0.012). EGF whose activity is upregulated in asthma induces ex vivo the epithelium from asthmatic patients to produce pro-neutrophil activities; these are related to asthma severity and, in moderate-to-severe asthmatics, involves class IB PI(3)Kγ signaling, providing a potential therapeutic target for neutrophilic forms of asthma. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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37. Invariant Natural Killer T Cells in Asthma and Chronic Obstructive Pulmonary Disease.
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Vijayanand, Pandurangan, Seumois, Grégory, Pickard, Chris, Powell, Robert M., Angco, Gilbert, Sammut, David, Gadola, Stephan D., Friedmann, Peter S., and Djukanovic, Ratko
- Subjects
- *
T cells , *KILLER cells , *ASTHMA , *ASTHMATICS , *OBSTRUCTIVE lung diseases , *LUNG diseases , *BRONCHOALVEOLAR lavage , *AIRWAY (Anatomy) , *SPUTUM examination , *T cell receptors - Abstract
Background The number of type 2 helper CD4+ T cells is increased in the airways of persons with asthma. Whether the majority of these cells are class II major-histocompatibility-complex-restricted cells or are among the recently identified CD1d-restricted invariant natural killer T cells is a matter of controversy. We studied the frequency of invariant natural killer T cells in the airways of subjects with mild or moderately severe asthma to investigate the possibility of an association between the number of invariant natural killer T cells in the airway and disease severity. We also studied whether an increased number of these cells is a feature of chronic obstructive pulmonary disease (COPD). Methods We enumerated invariant natural killer T cells by flow cytometry with the use of CD1d tetramers loaded with α-galactosylceramide and antibodies specific to the invariant natural killer T-cell receptor in samples of bronchoalveolar-lavage fluid, induced sputum, and bronchial-biopsy specimens obtained from subjects with mild or moderately severe asthma, subjects with COPD, and healthy control subjects. Real-time polymerase-chain-reaction analysis was performed on bronchoalveolar-lavage cells for evidence of gene expression of the invariant natural killer T-cell receptor. Results Fewer than 2% of the T cells obtained from all subjects on airway biopsy, bronchoalveolar lavage, and sputum induction were invariant natural killer T cells, with no significant differences among the three groups of subjects. No expression of messenger RNA for the invariant natural killer T-cell-receptor domains Vα24 and Vβ11 was detected in bronchoalveolar-lavage cells from subjects with asthma. Conclusions Invariant natural killer T cells are found in low numbers in the airways of subjects with asthma, subjects with COPD, and controls. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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38. Molecular Signatures of Dengue Virus-Specific IL-10/IFN-γ Co-producing CD4 T Cells and Their Association with Dengue Disease.
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Tian, Yuan, Seumois, Grégory, De-Oliveira-Pinto, Luzia M., Mateus, Jose, Herrera-de la Mata, Sara, Kim, Cheryl, Hinz, Denise, Goonawardhana, N.D. Suraj, de Silva, Aruna D., Premawansa, Sunil, Premawansa, Gayani, Wijewickrama, Ananda, Balmaseda, Angel, Grifoni, Alba, Vijayanand, Pandurangan, Harris, Eva, Peters, Bjoern, Sette, Alessandro, and Weiskopf, Daniela
- Abstract
Dengue virus (DENV) can cause diseases ranging from dengue fever (DF) to more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Whether antiviral T cells contribute to the protection against or pathogenesis of severe disease is not well defined. Here, we identified antigen-specific IL-10
+ IFN-γ+ double-positive (DP) CD4 T cells during acute DENV infection. While the transcriptomic signatures of DP cells partially overlapped with those of cytotoxic and type 1 regulatory CD4 T cells, the majority of them were non-cytotoxic/Tr1 and included IL21 , IL22 , CD109 , and CCR1. Although we observed a higher frequency of DP cells in DHF, the transcriptomic profile of DP cells was similar in DF and DHF, suggesting that DHF is not associated with the altered phenotypic or functional attributes of DP cells. Overall, this study revealed a DENV-specific DP cell subset in patients with acute dengue disease and argues against altered DP cells as a determinant of DHF. • DENV-specific IL-10+ IFN-γ+ DP CD4 T cells are prominent during acute disease • Most DP cell DE genes are non-cytotoxic/Tr1 and include IL21 , IL22 , CD109 , and CCR1 • DP cells have similar gene expression in DF and DHF, despite higher frequency in DHF • Disease severity is not associated with altered DP cell phenotype or functionality Tian et al. identify and characterize antigen-specific IL-10+ IFN-γ+ double-positive (DP) CD4 T cells in acute dengue patients. DP cells display similar transcriptomic profiles in mild DF and severe DHF, despite their increased frequency in DHF, suggesting that DHF is not associated with the altered phenotype or functionality of DP cells. [ABSTRACT FROM AUTHOR]- Published
- 2019
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39. Recurrent group A Streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant TFH cells.
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Dan, Jennifer M., Havenar-Daughton, Colin, Kendric, Kayla, Al-kolla, Rita, Kaushik, Kirti, Rosales, Sandy L., Anderson, Ericka L., LaRock, Christopher N., Vijayanand, Pandurangan, Seumois, Grégory, Layfield, David, Cutress, Ramsey I., Ottensmeier, Christian H., Lindestam Arlehamn, Cecilia S., Sette, Alessandro, Nizet, Victor, Bothwell, Marcella, Brigger, Matthew, and Crotty, Shane
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STREPTOCOCCUS ,IMMUNOGLOBULINS ,ECTOPIC tissue ,TONSILLITIS ,TONSILLECTOMY - Abstract
Recurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to group A Streptococcus. Teasing apart tonsillitis: Although exposure to group A Streptococcus is prevalent, only some children develop recurrent tonsillitis, which can lead to tonsillectomy. To discern why some children are susceptible and others are resistant, Dan et al. examined tonsil samples from two cohorts. They found that children with a history of recurrent tonsillitis had smaller germinal centers and reduced antibacterial antibodies. Moreover, the T follicular helper cells from those subjects may actually have been cytotoxic toward B cells. Class II HLA analysis also identified protective and risk alleles. Together, these results reveal that altered adaptive immune responses to group A Streptococcus may differentiate those at risk of recurrent infection. "Strep throat" is highly prevalent among children, yet it is unknown why only some children develop recurrent tonsillitis (RT), a common indication for tonsillectomy. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric group A Streptococcus (GAS) RT and non-RT tonsils from two independent cohorts. GAS RT tonsils had smaller germinal centers, with an underrepresentation of GAS-specific CD4
+ germinal center T follicular helper (GC-TFH ) cells. RT children exhibited reduced antibody responses to an important GAS virulence factor, streptococcal pyrogenic exotoxin A (SpeA). Risk and protective human leukocyte antigen (HLA) class II alleles for RT were identified. Lastly, SpeA induced granzyme B production in GC-TFH cells from RT tonsils with the capacity to kill B cells and the potential to hobble the germinal center response. These observations suggest that RT is a multifactorial disease and that contributors to RT susceptibility include HLA class II differences, aberrant SpeA-activated GC-TFH cells, and lower SpeA antibody titers. [ABSTRACT FROM AUTHOR]- Published
- 2019
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40. 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.
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Schmiedel, Benjamin Joachim, Seumois, Grégory, Samaniego-Castruita, Daniela, Cayford, Justin, Schulten, Veronique, Chavez, Lukas, Ay, Ferhat, Sette, Alessandro, Peters, Bjoern, and Vijayanand, Pandurangan
- Published
- 2016
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41. Dengue-specific CD8+ T cell subsets display specialized transcriptomic and TCR profiles.
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Yuan Tian, Babor, Mariana, Lane, Jerome, Seumois, Grégory, Shu Liang, Suraj Goonawardhana, N. D., De Silva, Aruna D., Phillips, Elizabeth J., Mallal, Simon A., da Silva Antunes, Ricardo, Grifoni, Alba, Vijayanand, Pandurangan, Weiskopf, Daniela, Peters, Bjoern, Sette, Alessandro, Tian, Yuan, Liang, Shu, and Goonawardhana, N D Suraj
- Subjects
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T cells , *T cell receptors , *TRANSVERSE electromagnetic cells , *GENE expression profiling , *VACCINE effectiveness - Abstract
Accumulating evidence demonstrates that CD8+ T cells contribute to protection from severe dengue virus (DENV) disease and vaccine efficacy. Nevertheless, molecular programs associated with DENV-specific CD8+ T cell subsets have not been defined. Here, we studied the transcriptomic profiles of human DENV-specific CD8+ T cells isolated after stimulation with DENV epitopes from donors who had been infected with DENV multiple times and would therefore be expected to have significant levels of adaptive immunity. We found that DENV-specific CD8+ T cells mainly consisted of effector memory subsets, namely CD45RA-CCR7- effector memory (Tem) and CD45RA+CCR7- effector memory re-expressing CD45RA (Temra) cells, which enacted specific gene expression profiles upon stimulation with cognate antigens. DENV-specific CD8+ T cell subsets in general, and Temra cells in particular, were fully activated and polyfunctional, yet associated with relatively narrow transcriptional responses. Furthermore, we found that DENV-specific CD8+ Tem and Temra cells showed some unique T cell receptor features in terms of overlap and variable (V) gene usage. This study provides a transcriptomic definition of DENV-specific activated human CD8+ T cell subsets and defines a benchmark profile that vaccine-specific responses could aim to reproduce. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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42. Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus-Specific CD8+ T Cells.
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Grifoni, Alba, Pham, John, Yuan Tian, Rosales, Sandy L., Seumois, Grégory, Sidney, John, Vijayanand, Pandurangan, Weiskopf, Daniela, Peters, Bjoern, Sette, Alessandro, de Silva, Aruna D., Ricciardi, Michael J., Ledgerwood, Julie E., Harris, Eva, Costa-Ramos, Priscilla, Kallas, Esper, Premkumar, Lakshmanane, de Silva, Aravinda M., Collins, Matthew H., and Stone, Mars
- Abstract
Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8+ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8+ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKVspecific CD8+ T cells are characterized by a polyfunctional IFN-γ signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8+ T cells responding to ZIKV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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43. Th1/Th17 polarization persists following whole-cell pertussis vaccination despite repeated acellular boosters.
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da Silva Antunes, Ricardo, Babor, Mariana, Carpenter, Chelsea, Khalil, Natalie, Cortese, Mario, Mentzer, Alexander J., Seumois, Grégory, Petro, Christopher D., Purcell, Lisa A., Vijayanand, Pandurangan, Crotty, Shane, Pulendran, Bali, Peters, Bjoern, and Sette, Alessandro
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WHOOPING cough vaccines , *VACCINE effectiveness , *VACCINATION of children , *T cell differentiation , *CELL proliferation , *BORDETELLA pertussis , *CYTOKINES , *IMMUNITY , *IMMUNIZATION , *IMMUNOLOGY technique , *LYMPHOCYTES , *MEDICAL protocols , *T cells , *VACCINES , *BACTERIAL antibodies , *GENE expression profiling - Abstract
In the mid-1990s, whole-cell pertussis (wP) vaccines were associated with local and systemic adverse events that prompted their replacement with acellular pertussis (aP) vaccines in many high-income countries. In the past decade, rates of pertussis disease have increased in children receiving only aP vaccines. We compared the immune responses to aP boosters in individuals who received their initial doses with either wP or aP vaccines using activation-induced marker (AIM) assays. Specifically, we examined pertussis-specific memory CD4+ T cell responses ex vivo, highlighting a type 2/Th2 versus type 1/Th1 and Th17 differential polarization as a function of childhood vaccination. Remarkably, after a contemporary aP booster, cells from donors originally primed with aP were (a) associated with increased IL-4, IL-5, IL-13, IL-9, and TGF-β and decreased IFN-γ and IL-17 production, (b) defective in their ex vivo capacity to expand memory cells, and (c) less capable of proliferating in vitro. These differences appeared to be T cell specific, since equivalent increases of antibody titers and plasmablasts after aP boost were seen in both groups. In conclusion, our data suggest that there are long-lasting effects and differences in polarization and proliferation of T cell responses in adults originally vaccinated with aP compared with those that initially received wP, despite repeated acellular boosters. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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44. Transcriptomic Analysis of CD4+ T Cells Reveals Novel Immune Signatures of Latent Tuberculosis.
- Author
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Burel, Julie G., Arlehamn, Cecilia S. Lindestam, Khan, Nabeela, Seumois, Grégory, Greenbaum, Jason A., Taplitz, Randy, Gilman, Robert H., Mayuko Saito, Vijayanand, Pandurangan, Sette, Alessandro, and Peters, Bjoern
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CD4 lymphocyte count , *TUBERCULOSIS -- Immunological aspects , *PHENOTYPES , *COMMUNICABLE diseases ,TUBERCULOSIS transmission - Abstract
In the context of infectious diseases, cell population transcriptomics are useful to gain mechanistic insight into protective immune responses, which is not possible using traditional whole-blood approaches. In this study, we applied a cell population transcriptomics strategy to sorted memory CD4 T cells to define novel immune signatures of latent tuberculosis infection (LTBI) and gain insight into the phenotype of tuberculosis (TB)-specific CD4 T cells. We found a 74-gene signature that could discriminate between memory CD4 T cells from healthy latently Mycobacterium tuberculosis-infected subjects and noninfected controls. The gene signature presented a significant overlap with the gene signature of the Th1* (CCR6+CXCR3+CCR4-) subset of CD4 T cells, which contains the majority of TB-specific reactivity and is expanded in LTBI. In particular, three Th1* genes (ABCB1, c-KIT, and GPA33) were differentially expressed at the RNA and protein levels in memory CD4 T cells of LTBI subjects compared with controls. The 74-gene signature also highlighted novel phenotypic markers that further defined the CD4 T cell subset containing TB specificity. We found the majority of TB-specific epitope reactivity in the CD62L-GPA33- Th1* subset. Thus, by combining cell population transcriptomics and single-cell protein-profiling techniques, we identified a CD4 T cell immune signature of LTBI that provided novel insights into the phenotype of TB-specific CD4 T cells. The Journal of Immunology, 2018, 200: 3283-3290. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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45. Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19.
- Author
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Meckiff, Benjamin J., Ramírez-Suástegui, Ciro, Fajardo, Vicente, Chee, Serena J., Kusnadi, Anthony, Simon, Hayley, Eschweiler, Simon, Grifoni, Alba, Pelosi, Emanuela, Weiskopf, Daniela, Sette, Alessandro, Ay, Ferhat, Seumois, Grégory, Ottensmeier, Christian H., and Vijayanand, Pandurangan
- Subjects
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T cells , *COVID-19 , *SUPPRESSOR cells , *T helper cells , *CYTOTOXIC T cells , *CELL analysis , *SARS-CoV-2 - Abstract
The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper cells and cytotoxic T helper (T H) cells (CD4-CTLs) responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (T REG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic T FH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T H 1 and T H 17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities. • Single-cell transcriptomic analysis of >100,000 SARS-CoV-2-reactive CD4+ T cells • Strong cytotoxic T FH response in hospitalized patients early in the illness • Reduced proportions of regulatory CD4+ T cells in hospitalized patients • Substantial heterogeneity in the molecular profile of viral-reactive CD4+ T cells Analyses of CD4+ T cells from 40 COVID-19 patients show that hospitalization is associated with increased cytotoxic follicular helper cells and cytotoxic T helper cells and a reduction in regulatory T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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46. Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression.
- Author
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Schmiedel, Benjamin J., Singh, Divya, Madrigal, Ariel, Valdovino-Gonzalez, Alan G., White, Brandie M., Zapardiel-Gonzalo, Jose, Ha, Brendan, Altay, Gokmen, Greenbaum, Jason A., McVicker, Graham, Seumois, Grégory, Rao, Anjana, Kronenberg, Mitchell, Peters, Bjoern, and Vijayanand, Pandurangan
- Subjects
- *
GENETIC polymorphisms , *EPIGENOMICS , *PROTEIN expression , *GENE expression in mammals , *IMMUNOLOGY - Abstract
Summary While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune cell expression, expression quantitative trait loci [eQTLs], and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis -eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis -association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis (https://dice-database.org). Graphical Abstract Highlights • Cis -eQTLs for 12,254 unique genes were identified in 13 human immune cell types • 41% of eGenes showed strong cis -association with genotype in a single cell type • GWAS variants were linked to cell types where their effects are most pronounced • Biological sex was associated with major differences in immune cell gene expression Surveying gene expression and SNP genotypes across immune cell types from healthy humans reveals cis-eQTLs affecting over half of all expressed genes and demonstrates that variant effects often manifest in cell types other than those with highest gene expression. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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47. CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature.
- Author
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Singhania A, Dubelko P, Kuan R, Chronister WD, Muskat K, Das J, Phillips EJ, Mallal SA, Seumois G, Vijayanand P, Sette A, Lerm M, Peters B, and Lindestam Arlehamn C
- Subjects
- Adult, BCG Vaccine immunology, Gene Expression Regulation, Humans, Longitudinal Studies, Male, RNA-Seq, Th1 Cells metabolism, Th17 Cells metabolism, BCG Vaccine administration & dosage, CD4-Positive T-Lymphocytes metabolism, DNA Methylation, Gene Expression Profiling methods, Receptors, Antigen, T-Cell genetics, Receptors, CCR6 metabolism
- Abstract
Background: The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity., Methods: We investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool., Findings: Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects., Interpretation: The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies., Competing Interests: Declaration of Competing Interest The authors declare no competing interests, except for Dr. Phillips who reports grants from NHMRC Australia, grants from NIH, personal fees from Uptodate/Lexicomp, personal fees from Biocryst, from Patent for HLA-B*57:01 testing for abacavir HSR, personal fees and other from Biocryst, personal fees from Janssen, personal fees from Vertex, personal fees from Verve, other from Provisional patent pending for HLA-A*32:01 testing for Vancomycin hypersensitivity, personal fees from Regeneron, outside the submitted work; In addition, Dr. Phillips has a patent issued for HLA-B*57:01 testing for abacavir hypersensitivity to IIID Pty Ltd, where she acts as the co-director., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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48. Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8 + T cells.
- Author
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Kusnadi A, Ramírez-Suástegui C, Fajardo V, Chee SJ, Meckiff BJ, Simon H, Pelosi E, Seumois G, Ay F, Vijayanand P, and Ottensmeier CH
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Glycolysis immunology, Humans, Immunologic Memory immunology, Male, Middle Aged, NF-kappa B immunology, Signal Transduction immunology, Single-Cell Analysis methods, Young Adult, CD8-Positive T-Lymphocytes immunology, COVID-19 immunology, SARS-CoV-2 immunology
- Abstract
The molecular properties of CD8
+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2., (Copyright © 2021, American Association for the Advancement of Science.)- Published
- 2021
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49. A Semiautomated ChIP-Seq Procedure for Large-scale Epigenetic Studies.
- Author
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Cayford J, Herrera-da la Mata S, Schmiedel BJ, Chandra V, Vijayanand P, and Seumois G
- Subjects
- Chromatin genetics, Epigenesis, Genetic, Histone Code, Humans, Chromatin Immunoprecipitation Sequencing, Epigenomics methods
- Abstract
Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) is a powerful and widely used approach to profile chromatin DNA associated with specific histone modifications, such as H3K27ac, to help identify cis-regulatory DNA elements. The manual process to complete a ChIP-Seq is labor intensive, technically challenging, and often requires large-cell numbers (>100,000 cells). The method described here helps to overcome those challenges. A complete semiautomated, microscaled H3K27ac ChIP-Seq procedure including cell fixation, chromatin shearing, immunoprecipitation, and sequencing library preparation, for batch of 48 samples for cell number inputs less than 100,000 cells is described in detail. The semiautonomous platform reduces technical variability, improves signal-to-noise ratios, and drastically reduces labor. The system can thereby reduce costs by allowing for reduced reaction volumes, limiting the number of expensive reagents such as enzymes, magnetic beads, antibodies, and hands-on time required. These improvements to the ChIP-Seq method suit perfectly for large-scale epigenetic studies of clinical samples with limited cell numbers in a highly reproducible manner.
- Published
- 2020
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50. Correction: Quantitative and Qualitative Perturbations of CD8 + MAITs in Healthy Mycobacterium tuberculosis -Infected Individuals.
- Author
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Pomaznoy M, Kuan R, Lindvall M, Burel JG, Seumois G, Vijayanand P, Taplitz R, Gilman RH, Saito M, Lewinsohn DM, Sette A, Peters B, and Lindestam Arlehamn CS
- Published
- 2020
- Full Text
- View/download PDF
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