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Xue Z, Wu L, Tian R, Gao B, Zhao Y, He B, Sun D, Zhao B, Li Y, Zhu K, Wang L, Yao J, Liu W, Lu L. Integrative mapping of human CD8 + T cells in inflammation and cancer. Nat Methods 2025; 22:435-445. [PMID: 39614111 DOI: 10.1038/s41592-024-02530-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/16/2024] [Indexed: 12/01/2024]
Abstract
CD8+ T cells exhibit remarkable phenotypic diversity in inflammation and cancer. However, a comprehensive understanding of their clonal landscape and dynamics remains elusive. Here we introduce scAtlasVAE, a deep-learning-based model for the integration of large-scale single-cell RNA sequencing data and cross-atlas comparisons. scAtlasVAE has enabled us to construct an extensive human CD8+ T cell atlas, comprising 1,151,678 cells from 961 samples across 68 studies and 42 disease conditions, with paired T cell receptor information. Through incorporating information in T cell receptor clonal expansion and sharing, we have successfully established connections between distinct cell subtypes and shed light on their phenotypic and functional transitions. Notably, our approach characterizes three distinct exhausted T cell subtypes and reveals diverse transcriptome and clonal sharing patterns in autoimmune and immune-related adverse event inflammation. Furthermore, scAtlasVAE facilitates the automatic annotation of CD8+ T cell subtypes in query single-cell RNA sequencing datasets, enabling unbiased and scalable analyses. In conclusion, our work presents a comprehensive single-cell reference and computational framework for CD8+ T cell research.
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Affiliation(s)
- Ziwei Xue
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
- Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China
| | - Lize Wu
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China
- Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ruonan Tian
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China
| | - Bing Gao
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Zhao
- AI Lab, Tencent, Shenzhen, China
| | - Bing He
- AI Lab, Tencent, Shenzhen, China
| | - Di Sun
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingkang Zhao
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
- Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Yicheng Li
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China
- Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Kaixiang Zhu
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lie Wang
- Bone Marrow Transplantation Center and Institute of Immunology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | - Wanlu Liu
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China.
- Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China.
- Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, China.
| | - Linrong Lu
- Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University, University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China.
- Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China.
- Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Xia J, Xiao Y, Gui G, Gong S, Wang H, Li X, Yan R, Fan J. Insights into cytomegalovirus-associated T cell receptors in recipients following allogeneic hematopoietic stem cell transplantation. Virol J 2024; 21:236. [PMID: 39350155 PMCID: PMC11443867 DOI: 10.1186/s12985-024-02511-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/18/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) reactivation is a serious problem in recipients of allogeneic hematopoietic stem cell transplantation. Long-term latency depends on specific T cell immune reconstitution, which identifies various pathogens by T cell receptors (TCRs). However, the mechanisms underlying the selection of CMV-specific TCRs in recipients after transplantation remain unclear. METHODS Using high-throughput sequencing and bioinformatics analysis, the T cell immune repertoire of seven CMV reactivated recipients (CRRs) were analyzed and compared to those of seven CMV non-activated recipients (CNRs) at an early stage after transplant. RESULTS The counts of unique complementarity-determining region 3 (CDR3) were significantly higher in CNRs than in CRRs. The CDR3 clones in the CNRs exhibit higher homogeneity compared to the CRRs. With regard to T cell receptor β-chain variable region (TRBV) and joint region (TRBJ) genotypes, significant differences were observed in the frequencies of TRBV6, BV23, and BV7-8 between the two groups. In addition to TRBV29-1/BJ1-2, TRBV2/BJ2-2, and TRBV12-4/BJ1-5, 11 V-J combinations had significantly different expression levels between CRRs and CNRs. CONCLUSIONS The differences in TCR diversity, TRBV segments, and TRBV-BJ combinations observed between CNRs and CRRs might be associated with post-transplant CMV reactivation and could serve as a foundation for further research.
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Affiliation(s)
- Jintao Xia
- Department of Clinical Laboratory, Department of "A", Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310053, China
| | - Yingjun Xiao
- The Third Affiliated Hospital of Zhejiang, Chinese Medical University, Zhongshan Hospital of Zhejiang Province, Hangzhou, China
| | - Genyong Gui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 31006, China
| | - Shengnan Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 31006, China
| | - Huiqi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 31006, China
| | - Xuejie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 31006, China
| | - Ren Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 31006, China
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 31006, China.
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Li Y, Ji L, Zhang Y, Zhang J, Reuben A, Zeng H, Huang Q, Wei Q, Tan S, Xia X, Li W, Zhang J, Tian P. The combination of tumor mutational burden and T-cell receptor repertoire predicts the response to immunotherapy in patients with advanced non-small cell lung cancer. MedComm (Beijing) 2024; 5:e604. [PMID: 38840771 PMCID: PMC11151154 DOI: 10.1002/mco2.604] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/27/2024] [Accepted: 05/01/2024] [Indexed: 06/07/2024] Open
Abstract
Tumor mutational burden (TMB) and T-cell receptor (TCR) might predict the response to immunotherapy in patients with non-small cell lung cancer (NSCLC). However, the predictive value of the combination of TMB and TCR was not clear. Targeted DNA and TCR sequencing were performed on tumor biopsy specimens. We combined TMB and TCR diversity into a TMB-and-TCR (TMR) score using logistic regression. In total, 38 patients with advanced NSCLC were divided into a discovery set (n = 17) and validation set (n = 21). A higher TMR score was associated with better response and longer progression-free survival to immunotherapy in both the discovery set and validation set. The performance of TMR score was confirmed in the two external validation cohorts of 225 NSCLC patients and 306 NSCLC patients. Tumors with higher TMR scores were more likely to combine with LRP1B gene mutation (p = 0.027) and top 1% CDR3 sequences (p = 0.001). Furthermore, LRP1B allele frequency was negatively correlated with the top 1% CDR3 sequences (r = -0.55, p = 0.033) and positively correlated with tumor shrinkage (r = 0.68, p = 0.007). The TMR score could serve as a potential predictive biomarker for the response to immunotherapy in advanced NSCLC.
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Affiliation(s)
- Yalun Li
- Department of Pulmonary and Critical Care MedicineState Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital of Sichuan University, Precision Medicine Key Laboratory of Sichuan ProvinceChengduSichuanChina
- Lung Cancer Center/Lung Cancer InstituteWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Liyan Ji
- Geneplus‐Beijing InstituteBeijingChina
| | | | - Jiexin Zhang
- Departments of Bioinformatics and Computational BiologyUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Alexandre Reuben
- Department of Thoracic/Head and Neck Medical OncologyUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Hao Zeng
- Department of Pulmonary and Critical Care MedicineWest China Hospital, West China School of Medicine, Sichuan UniversityChengduSichuanChina
| | - Qin Huang
- Department of Pulmonary and Critical Care MedicineWest China Hospital, West China School of Medicine, Sichuan UniversityChengduSichuanChina
| | - Qi Wei
- Department of Pulmonary and Critical Care MedicineWest China Hospital, West China School of Medicine, Sichuan UniversityChengduSichuanChina
| | - Sihan Tan
- Department of Pulmonary and Critical Care MedicineWest China Hospital, West China School of Medicine, Sichuan UniversityChengduSichuanChina
| | | | - Weimin Li
- Department of Pulmonary and Critical Care MedicineState Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital of Sichuan University, Precision Medicine Key Laboratory of Sichuan ProvinceChengduSichuanChina
| | - Jianjun Zhang
- Department of Thoracic/Head and Neck Medical OncologyUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
- Department of Genomic MedicineUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
- Lung Cancer Genomics ProgramUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
- Lung Cancer Interception ProgramUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Panwen Tian
- Department of Pulmonary and Critical Care MedicineState Key Laboratory of Respiratory Health and MultimorbidityWest China Hospital of Sichuan University, Precision Medicine Key Laboratory of Sichuan ProvinceChengduSichuanChina
- Lung Cancer Center/Lung Cancer InstituteWest China Hospital, Sichuan UniversityChengduSichuanChina
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Jiao W, Martinez M, Muntnich CB, Zuber J, Parks C, Obradovic A, Tian G, Wang Z, Long KD, Waffarn E, Frangaj K, Jones R, Gorur A, Shonts B, Rogers K, Lv G, Velasco M, Ravella S, Weiner J, Kato T, Shen Y, Fu J, Sykes M. Dynamic establishment of recipient resident memory T cell repertoire after human intestinal transplantation. EBioMedicine 2024; 101:105028. [PMID: 38422982 PMCID: PMC10944178 DOI: 10.1016/j.ebiom.2024.105028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 01/19/2024] [Accepted: 02/06/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Understanding formation of the human tissue resident memory T cell (TRM) repertoire requires longitudinal access to human non-lymphoid tissues. METHODS By applying flow cytometry and next generation sequencing to serial blood, lymphoid tissue, and gut samples from 16 intestinal transplantation (ITx) patients, we assessed the origin, distribution, and specificity of human TRMs at phenotypic and clonal levels. FINDINGS Donor age ≥1 year and blood T cell macrochimerism (peak level ≥4%) were associated with delayed establishment of stable recipient TRM repertoires in the transplanted ileum. T cell receptor (TCR) overlap between paired gut and blood repertoires from ITx patients was significantly greater than that in healthy controls, demonstrating increased gut-blood crosstalk after ITx. Crosstalk with the circulating pool remained high for years of follow-up. TCR sequences identifiable in pre-Tx recipient gut but not those in lymphoid tissues alone were more likely to populate post-Tx ileal allografts. Clones detected in both pre-Tx gut and lymphoid tissue had distinct transcriptional profiles from those identifiable in only one tissue. Recipient T cells were distributed widely throughout the gut, including allograft and native colon, which had substantial repertoire overlap. Both alloreactive and microbe-reactive recipient T cells persisted in transplanted ileum, contributing to the TRM repertoire. INTERPRETATION Our studies reveal human intestinal TRM repertoire establishment from the circulation, preferentially involving lymphoid tissue counterparts of recipient intestinal T cell clones, including TRMs. We have described the temporal and spatial dynamics of this active crosstalk between the circulating pool and the intestinal TRM pool. FUNDING This study was funded by the National Institute of Allergy and Infectious Diseases (NIAID) P01 grant AI106697.
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Affiliation(s)
- Wenyu Jiao
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States; Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Jilin, China
| | - Mercedes Martinez
- Department of Pediatrics, Columbia University, New York, NY, United States
| | - Constanza Bay Muntnich
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Julien Zuber
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Christopher Parks
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Aleksandar Obradovic
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Guangyao Tian
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Jilin, China
| | - Zicheng Wang
- Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, NY, United States
| | - Katherine D Long
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Elizabeth Waffarn
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Kristjana Frangaj
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Rebecca Jones
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Alaka Gorur
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Brittany Shonts
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Kortney Rogers
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Jilin, China
| | - Monica Velasco
- School of Nursing, Columbia University, New York, NY, United States
| | - Shilpa Ravella
- Department of Medicine, Columbia University, New York, NY, United States
| | - Joshua Weiner
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States; Department of Surgery, Columbia University, New York, NY, United States
| | - Tomoaki Kato
- Department of Surgery, Columbia University, New York, NY, United States
| | - Yufeng Shen
- Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, NY, United States
| | - Jianing Fu
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States.
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States; Department of Surgery, Columbia University, New York, NY, United States; Department of Microbiology & Immunology, Columbia University, New York, NY, United States.
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Yerigeri K, Buhtoiarov I. Pediatric-type follicular lymphoma in a Crohn's disease patient receiving anti-α4β7-integrin therapy: A case report. World J Gastroenterol 2023; 29:5865-5871. [PMID: 38074918 PMCID: PMC10701312 DOI: 10.3748/wjg.v29.i43.5865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/15/2023] [Accepted: 11/09/2023] [Indexed: 11/20/2023] Open
Abstract
BACKGROUND Patients with autoimmune conditions receiving immunosuppressants are at risk of non-Hodgkin lymphomas (NHL). Vedolizumab (anti-α4β7-integrin antibody), a treatment-of-choice for Crohn's disease (CD), reduces inflammatory lymphocyte trafficking into the intestinal mucosa. This effect is believed to be confined to the colon. CASE SUMMARY We report the case of a CD patient on vedolizumab for five years who developed pediatric-type follicular lymphoma. Work-up prior to therapy revealed a reduction in circulating T-lymphocytes and their suppressed response to mitogens. Rituximab, cyclophosphamide, vincristine, and prednisone chemo-immunotherapy resulted in durable lymphoma remission, and vedolizumab treatment was continued. While the patient's T-lymphocyte population and immunoglobulin production recovered, the T-lymphocyte mitogen response remained suppressed. CONCLUSION This patient's NHL may be linked to receiving anti-α4β7 therapy. Further research could be beneficial to determine if proactive surveillance for NHL and other systemic diseases is indicated in patients on vedolizumab.
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Affiliation(s)
- Keval Yerigeri
- Internal Medicine-Pediatrics, Case Western Reserve University/MetroHealth, Cleveland, OH 44109, United States
| | - Ilia Buhtoiarov
- Pediatric Hematology/Oncology and Bone Marrow Transplantation, Cleveland Clinic Children’s, Cleveland, OH 44106, United States
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Di Lollo V, Canciello A, Peserico A, Orsini M, Russo V, Cerveró-Varona A, Dufrusine B, El Khatib M, Curini V, Mauro A, Berardinelli P, Tournier C, Ancora M, Cammà C, Dainese E, Mincarelli LF, Barboni B. Unveiling the immunomodulatory shift: Epithelial-mesenchymal transition Alters immune mechanisms of amniotic epithelial cells. iScience 2023; 26:107582. [PMID: 37680464 PMCID: PMC10481295 DOI: 10.1016/j.isci.2023.107582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 06/01/2023] [Accepted: 08/04/2023] [Indexed: 09/09/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) changes cell phenotype by affecting immune properties of amniotic epithelial cells (AECs). The present study shows how the response to lipopolysaccharide of cells collected pre- (eAECs) and post-EMT (mAECs) induces changes in their transcriptomics profile. In fact, eAECs mainly upregulate genes involved in antigen-presenting response, whereas mAECs over-express soluble inflammatory mediator transcripts. Consistently, network analysis identifies CIITA and Nrf2 as main drivers of eAECs and mAECs immune response, respectively. As a consequence, the depletion of CIITA and Nrf2 impairs the ability of eAECs and mAECs to inhibit lymphocyte proliferation or macrophage-dependent IL-6 release, thus confirming their involvement in regulating immune response. Deciphering the mechanisms controlling the immune function of AECs pre- and post-EMT represents a step forward in understanding key physiological events wherein these cells are involved (pregnancy and labor). Moreover, controlling the immunomodulatory properties of eAECs and mAECs may be essential in developing potential strategies for regenerative medicine applications.
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Affiliation(s)
- Valeria Di Lollo
- National Reference Center for Whole Genome Sequencing of Microbial Pathogens: Database and Bioinformatic Analysis, Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise, Campo Boario, 64100 Teramo, Italy
| | - Angelo Canciello
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Alessia Peserico
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Massimiliano Orsini
- National Reference Center for Whole Genome Sequencing of Microbial Pathogens: Database and Bioinformatic Analysis, Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise, Campo Boario, 64100 Teramo, Italy
- Istituto Zooprofilattico Sperimentale delle Venezie, Department of Microbiology, Viale dell’Università 10, 35020 Legnaro (PD), Italy
| | - Valentina Russo
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Adrián Cerveró-Varona
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Beatrice Dufrusine
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Mohammad El Khatib
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Valentina Curini
- National Reference Center for Whole Genome Sequencing of Microbial Pathogens: Database and Bioinformatic Analysis, Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise, Campo Boario, 64100 Teramo, Italy
| | - Annunziata Mauro
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Paolo Berardinelli
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Cathy Tournier
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
| | - Massimo Ancora
- National Reference Center for Whole Genome Sequencing of Microbial Pathogens: Database and Bioinformatic Analysis, Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise, Campo Boario, 64100 Teramo, Italy
| | - Cesare Cammà
- National Reference Center for Whole Genome Sequencing of Microbial Pathogens: Database and Bioinformatic Analysis, Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise, Campo Boario, 64100 Teramo, Italy
| | - Enrico Dainese
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
| | - Luana Fiorella Mincarelli
- National Reference Center for Whole Genome Sequencing of Microbial Pathogens: Database and Bioinformatic Analysis, Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise, Campo Boario, 64100 Teramo, Italy
| | - Barbara Barboni
- Department of Biosciences and Technology for Food, Agriculture and Environment, University of Teramo, Via Balzarini 1, 64100 Teramo, Italy
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Zahmatkesh A, Sohouli MH, Hosseini SME, Rohani P. The role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in the diagnosis and severity of inflammatory bowel disease in children. Eur J Pediatr 2023; 182:4263-4270. [PMID: 37458815 DOI: 10.1007/s00431-023-05110-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/05/2023] [Accepted: 07/08/2023] [Indexed: 10/14/2023]
Abstract
Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are simple and inexpensive inflammatory biomarkers that reflect systemic inflammation based on complete blood count values. In this study, we investigate the role of these biomarkers in the diagnosis and severity of pediatric inflammatory bowel disease (IBD). We analyzed 73 pediatric patients with IBD with a retrospective study design who underwent measurement of fecal calprotectin (FC) and endoscopy and 67 age- and sex-matched healthy controls. NLR and PLR were compared between the patients and healthy controls. We also plotted the ROC diagrams separately for markers to obtain the optimal point and a suitable cutoff point. We enrolled 73 pediatric patients less than 18 years of age with IBD, 40 subjects with UC and 33 with CD and 67 healthy subjects as control group with median age of 9.00 ± 4.61 in all subjects. Furthermore, the mean score of PCDAI or PUCAI in the all subjects was 19.26 ± 16.31. In the ROC curve, the optimal cutoff value for NLR and PLR for detecting IBD was 2.04 (sensitivity 82.1%; specificity 82.9%) and 103 (sensitivity 67.9%; specificity 71.4%). Also, the optimal cutoff values for NLR and PLR for differentiating IBD severity (remission vs. active disease) were 2.94 (sensitivity 77.8%; specificity 50.0%) and 157 (sensitivity 88.9%; specificity 54.5%), respectively. CONCLUSION Our findings indicate the role of easy and non-invasive markers such as NLR and PLR in order to diagnose the disease in the initial examinations as well as the severity of the disease. WHAT IS KNOWN • NLR and PLR are simple and inexpensive inflammatory biomarkers that reflect systemic inflammation based on complete blood count values. WHAT IS NEW • In this study, we investigate the role of these biomarkers in the diagnosis and severity of pediatric IBD. • Our findings indicate the role of NLR and PLR in order to diagnose the disease in the initial examinations as well as the severity of the disease.
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Affiliation(s)
- Arefeh Zahmatkesh
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Pediatrics Gastroenterology, Department of Pediatrics, School of Medicine Childrens Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
| | | | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Pediatrics Gastroenterology, Department of Pediatrics, School of Medicine Childrens Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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DeWolf S, Elhanati Y, Nichols K, Waters NR, Nguyen CL, Slingerland JB, Rodriguez N, Lyudovyk O, Giardina PA, Kousa AI, Andrlová H, Ceglia N, Fei T, Kappagantula R, Li Y, Aleynick N, Baez P, Murali R, Hayashi A, Lee N, Gipson B, Rangesa M, Katsamakis Z, Dai A, Blouin AG, Arcila M, Masilionis I, Chaligne R, Ponce DM, Landau HJ, Politikos I, Tamari R, Hanash AM, Jenq RR, Giralt SA, Markey KA, Zhang Y, Perales MA, Socci ND, Greenbaum BD, Iacobuzio-Donahue CA, Hollmann TJ, van den Brink MR, Peled JU. Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse. Sci Transl Med 2023; 15:eabq0476. [PMID: 37494469 PMCID: PMC10758167 DOI: 10.1126/scitranslmed.abq0476] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/06/2023] [Indexed: 07/28/2023]
Abstract
T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.
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Affiliation(s)
- Susan DeWolf
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yuval Elhanati
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Katherine Nichols
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nicholas R. Waters
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chi L. Nguyen
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John B. Slingerland
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Natasia Rodriguez
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Olga Lyudovyk
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paul A. Giardina
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anastasia I. Kousa
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hana Andrlová
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nick Ceglia
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Teng Fei
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rajya Kappagantula
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center; New York, NY, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yanyun Li
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nathan Aleynick
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Priscilla Baez
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rajmohan Murali
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Akimasa Hayashi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Pathology, Kyorin University, Mitaka City, Tokyo, Japan
| | - Nicole Lee
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Brianna Gipson
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Madhumitha Rangesa
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zoe Katsamakis
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anqi Dai
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amanda G. Blouin
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Arcila
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ignas Masilionis
- Program for Computational and System Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronan Chaligne
- Program for Computational and System Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Doris M. Ponce
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Heather J. Landau
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Ioannis Politikos
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Roni Tamari
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Alan M. Hanash
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Robert R. Jenq
- Departments of Genomic Medicine and Stem Cell Transplantation Cellular Therapy, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sergio A. Giralt
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Kate A. Markey
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Medical Oncology, University of Washington; Seattle, WA, USA
| | - Yanming Zhang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Miguel-Angel Perales
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Nicholas D. Socci
- Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benjamin D. Greenbaum
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA
| | | | - Travis J. Hollmann
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Bristol Myers Squibb, Lawrenceville, NJ 08540
| | - Marcel R.M. van den Brink
- Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Jonathan U. Peled
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
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9
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Chasman DA, Welch Schwartz R, Vazquez J, Chavarria M, Jenkins ET, Lopez GE, Tyler CT, Stanic AK, Ong IM. Proteogenomic and V(D)J Analysis of Human Decidual T Cells Highlights Unique Transcriptional Programming and Clonal Distribution. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:154-162. [PMID: 37195197 PMCID: PMC10330249 DOI: 10.4049/jimmunol.2200061] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/25/2023] [Indexed: 05/18/2023]
Abstract
Immunological tolerance toward the semiallogeneic fetus is one of many maternal adaptations required for a successful pregnancy. T cells are major players of the adaptive immune system and balance tolerance and protection at the maternal-fetal interface; however, their repertoire and subset programming are still poorly understood. Using emerging single-cell RNA sequencing technologies, we simultaneously obtained transcript, limited protein, and receptor repertoire at the single-cell level, from decidual and matched maternal peripheral human T cells. The decidua maintains a tissue-specific distribution of T cell subsets compared with the periphery. We find that decidual T cells maintain a unique transcriptome programming, characterized by restraint of inflammatory pathways by overexpression of negative regulators (DUSP, TNFAIP3, ZFP36) and expression of PD-1, CTLA-4, TIGIT, and LAG3 in some CD8 clusters. Finally, analyzing TCR clonotypes demonstrated decreased diversity in specific decidual T cell populations. Overall, our data demonstrate the power of multiomics analysis in revealing regulation of fetal-maternal immune coexistence.
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Affiliation(s)
- Deborah A. Chasman
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
| | - Rene Welch Schwartz
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI
| | - Jessica Vazquez
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Melina Chavarria
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Eryne T. Jenkins
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Gladys E. Lopez
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Chanel T. Tyler
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Aleksandar K. Stanic
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Irene M. Ong
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI
- Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI
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10
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Egozi A, Olaloye O, Werner L, Silva T, McCourt B, Pierce RW, An X, Wang F, Chen K, Pober JS, Shouval D, Itzkovitz S, Konnikova L. Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis. PLoS Biol 2023; 21:e3002124. [PMID: 37205711 PMCID: PMC10234541 DOI: 10.1371/journal.pbio.3002124] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 06/01/2023] [Accepted: 04/13/2023] [Indexed: 05/21/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a gastrointestinal complication of premature infants with high rates of morbidity and mortality. A comprehensive view of the cellular changes and aberrant interactions that underlie NEC is lacking. This study aimed at filling in this gap. We combine single-cell RNA sequencing (scRNAseq), T-cell receptor beta (TCRβ) analysis, bulk transcriptomics, and imaging to characterize cell identities, interactions, and zonal changes in NEC. We find an abundance of proinflammatory macrophages, fibroblasts, endothelial cells as well as T cells that exhibit increased TCRβ clonal expansion. Villus tip epithelial cells are reduced in NEC and the remaining epithelial cells up-regulate proinflammatory genes. We establish a detailed map of aberrant epithelial-mesenchymal-immune interactions that are associated with inflammation in NEC mucosa. Our analyses highlight the cellular dysregulations of NEC-associated intestinal tissue and identify potential targets for biomarker discovery and therapeutics.
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Affiliation(s)
- Adi Egozi
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Oluwabunmi Olaloye
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Lael Werner
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel, affiliated to the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tatiana Silva
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Blake McCourt
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Richard W. Pierce
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, United States of America
- Program in Human and Translational Immunology, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Xiaojing An
- Department of Medicine, University of Pittsburgh Medical Center Montefiore Hospital, Pittsburgh, Pennsylvania, United States of America
| | - Fujing Wang
- Department of Medicine, University of Pittsburgh Medical Center Montefiore Hospital, Pittsburgh, Pennsylvania, United States of America
| | - Kong Chen
- Department of Medicine, University of Pittsburgh Medical Center Montefiore Hospital, Pittsburgh, Pennsylvania, United States of America
| | - Jordan S. Pober
- Program in Human and Translational Immunology, Yale School of Medicine, New Haven, Connecticut, United States of America
- Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Dror Shouval
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel, affiliated to the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shalev Itzkovitz
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Liza Konnikova
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, United States of America
- Program in Human and Translational Immunology, Yale School of Medicine, New Haven, Connecticut, United States of America
- Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
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11
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Morita A, Imagawa K, Tagawa M, Sakamoto N, Takada H. Case report: Immunological characteristics of de novo ulcerative colitis in a child post COVID-19. Front Immunol 2023; 14:1107808. [PMID: 36875135 PMCID: PMC9978098 DOI: 10.3389/fimmu.2023.1107808] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/07/2023] [Indexed: 02/18/2023] Open
Abstract
The pathological mechanisms of de novo inflammatory bowel disease (IBD) following SARS-CoV-2 infection are unknown. However, cases of coexisting IBD and multisystem inflammatory syndrome in children (MIS-C), which occurs 2-6 weeks after SARS-CoV-2 infection, have been reported, suggesting a shared underlying dysfunction of immune responses. Herein, we conducted the immunological analyses of a Japanese patient with de novo ulcerative colitis following SARS-CoV-2 infection based on the pathological hypothesis of MIS-C. Her serum level of lipopolysaccharide-binding protein, a microbial translocation marker, was elevated with T cell activation and skewed T cell receptor repertoire. The dynamics of activated CD8+ T cells, including T cells expressing the gut-homing marker α4β7, and serum anti-SARS-CoV-2 spike IgG antibody titer reflected her clinical symptoms. These findings suggest that SARS-CoV-2 infection may trigger the de novo occurrence of ulcerative colitis by impairing intestinal barrier function, T cell activation with a skewed T cell receptor repertoire, and increasing levels of anti-SARS-CoV-2 spike IgG antibodies. Further research is needed to clarify the association between the functional role of the SARS-CoV-2 spike protein as a superantigen and ulcerative colitis.
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Affiliation(s)
- Atsushi Morita
- Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.,Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Manabu Tagawa
- Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.,Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Noriaki Sakamoto
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hidetoshi Takada
- Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.,Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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12
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Safra M, Werner L, Peres A, Polak P, Salamon N, Schvimer M, Weiss B, Barshack I, Shouval DS, Yaari G. A somatic hypermutation-based machine learning model stratifies individuals with Crohn's disease and controls. Genome Res 2023; 33:71-79. [PMID: 36526432 PMCID: PMC9977146 DOI: 10.1101/gr.276683.122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
Crohn's disease (CD) is a chronic relapsing-remitting inflammatory disorder of the gastrointestinal tract that is characterized by altered innate and adaptive immune function. Although massively parallel sequencing studies of the T cell receptor repertoire identified oligoclonal expansion of unique clones, much less is known about the B cell receptor (BCR) repertoire in CD. Here, we present a novel BCR repertoire sequencing data set from ileal biopsies from pediatric patients with CD and controls, and identify CD-specific somatic hypermutation (SHM) patterns, revealed by a machine learning (ML) algorithm trained on BCR repertoire sequences. Moreover, ML classification of a different data set from blood samples of adults with CD versus controls identified that V gene usage, clusters, or mutation frequencies yielded excellent results in classifying the disease (F1 > 90%). In summary, we show that an ML algorithm enables the classification of CD based on unique BCR repertoire features with high accuracy.
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Affiliation(s)
- Modi Safra
- The Alexander Kofkin Faculty of Engineering, Bar Ilan University, 5290002, Ramat Gan, Israel
- Bar Ilan Institute of Nanotechnology and Advanced Materials, Bar Ilan University, 5290002, Ramat Gan, Israel
| | - Lael Werner
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva 4920235, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ayelet Peres
- The Alexander Kofkin Faculty of Engineering, Bar Ilan University, 5290002, Ramat Gan, Israel
- Bar Ilan Institute of Nanotechnology and Advanced Materials, Bar Ilan University, 5290002, Ramat Gan, Israel
| | - Pazit Polak
- The Alexander Kofkin Faculty of Engineering, Bar Ilan University, 5290002, Ramat Gan, Israel
- Bar Ilan Institute of Nanotechnology and Advanced Materials, Bar Ilan University, 5290002, Ramat Gan, Israel
| | - Naomi Salamon
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel
| | - Michael Schvimer
- Institute of Pathology, Sheba Medical Center, Ramat Gan 5262100, Israel
| | - Batia Weiss
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan 5262100, Israel
| | - Iris Barshack
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Institute of Pathology, Sheba Medical Center, Ramat Gan 5262100, Israel
| | - Dror S Shouval
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva 4920235, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Gur Yaari
- The Alexander Kofkin Faculty of Engineering, Bar Ilan University, 5290002, Ramat Gan, Israel
- Bar Ilan Institute of Nanotechnology and Advanced Materials, Bar Ilan University, 5290002, Ramat Gan, Israel
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13
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Frimpong A, Ofori MF, Degoot AM, Kusi KA, Gershom B, Quartey J, Kyei-Baafour E, Nguyen N, Ndifon W. Perturbations in the T cell receptor β repertoire during malaria infection in children: A preliminary study. Front Immunol 2022; 13:971392. [PMID: 36311775 PMCID: PMC9606469 DOI: 10.3389/fimmu.2022.971392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 09/22/2022] [Indexed: 11/13/2022] Open
Abstract
The changes occurring in the T cell repertoire during clinical malaria infection in children remain unknown. In this study, we undertook the first detailed comparative study of the T cell repertoire in African children with and without clinical malaria to test the hypothesis that clonotypic expansions that occur during P. falciparum infection will contribute to the generation of a T cell repertoire that is unique to each disease state. We profiled the complementarity-determining region 3 (CDR3) of the TCRβ chain sequences from children with Plasmodium falciparum infections (asymptomatic, uncomplicated and severe malaria) and compared these with sequences from healthy children. Interestingly, we discovered that children with symptomatic malaria have a lower TCR diversity and frequency of shared (or “public”) TCR sequences compared to asymptomatic children. Also, TCR diversity was inversely associated with parasitemia. Furthermore, by clustering TCR sequences based on their predicted antigen specificities, we identified a specificity cluster, with a 4-mer amino acid motif, that is overrepresented in the asymptomatic group compared to the diseased groups. Further investigations into this finding may help in delineating important antigenic targets for vaccine and therapeutic development. The results show that the T cell repertoire in children is altered during malaria, suggesting that exposure to P. falciparum antigens disrupts the adaptive immune response, which is an underlying feature of the disease.
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Affiliation(s)
- Augustina Frimpong
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell, and Molecular Biology, University of Ghana, Accra, Ghana
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
- African Institute for Mathematical Sciences, Accra, Ghana
- *Correspondence: Wilfred Ndifon, ; Augustina Frimpong,
| | - Michael Fokuo Ofori
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell, and Molecular Biology, University of Ghana, Accra, Ghana
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Abdoelnaser M. Degoot
- Research Department, African Institute for Mathematical Sciences, Next Einstein Initiative, Kigali, Rwanda
| | - Kwadwo Asamoah Kusi
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell, and Molecular Biology, University of Ghana, Accra, Ghana
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Buri Gershom
- African Institute for Mathematical Sciences, Cape Town, South Africa
| | - Jacob Quartey
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Eric Kyei-Baafour
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana
| | | | - Wilfred Ndifon
- Research Department, African Institute for Mathematical Sciences, Next Einstein Initiative, Kigali, Rwanda
- African Institute for Mathematical Sciences, Cape Town, South Africa
- *Correspondence: Wilfred Ndifon, ; Augustina Frimpong,
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14
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Song R, Jia X, Zhao J, Du P, Zhang JA. T cell receptor revision and immune repertoire changes in autoimmune diseases. Int Rev Immunol 2021; 41:517-533. [PMID: 34243694 DOI: 10.1080/08830185.2021.1929954] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Autoimmune disease (AID) is a condition in which the immune system breaks down and starts to attack the body. Some common AIDs include systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus and so forth. The changes in T-cell receptor (TCR) repertoire have been found in several autoimmune diseases, and may be responsible for the breakdown of peripheral immune tolerance. In this review, we discussed the processes of TCR revision in peripheral immune environment, the changes in TCR repertoire that occurred in various AIDs, and the specifically expanded T cell clones. We hope our discussion can provide insights for the future studies, helping with the discovery of disease biomarkers and expanding the strategies of immune-targeted therapy. HighlightsRestricted TCR repertoire and biased TCR-usage are found in a variety of AIDs.TCR repertoire shows tissue specificity in a variety of AID diseases.The relationship between TCR repertoire diversity and disease activity is still controversial in AIDs.Dominant TCR clonotypes may help to discover new disease biomarkers and expand the strategies of immune-targeted therapy.
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Affiliation(s)
- Ronghua Song
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Xi Jia
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Jing Zhao
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Peng Du
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Jin-An Zhang
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
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15
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Wanjalla CN, McDonnell WJ, Ram R, Chopra A, Gangula R, Leary S, Mashayekhi M, Simmons JD, Warren CM, Bailin S, Gabriel CL, Guo L, Furch BD, Lima MC, Woodward BO, Hannah L, Pilkinton MA, Fuller DT, Kawai K, Virmani R, Finn AV, Hasty AH, Mallal SA, Kalams SA, Koethe JR. Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells. CELL REPORTS MEDICINE 2021; 2:100205. [PMID: 33665640 PMCID: PMC7897802 DOI: 10.1016/j.xcrm.2021.100205] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 09/22/2020] [Accepted: 01/21/2021] [Indexed: 12/11/2022]
Abstract
Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV.
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Affiliation(s)
- Celestine N Wanjalla
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wyatt J McDonnell
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA.,Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA.,10x Genomics, Pleasanton, CA, USA
| | - Ramesh Ram
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
| | - Rama Gangula
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Shay Leary
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
| | - Mona Mashayekhi
- Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Joshua D Simmons
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christian M Warren
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Samuel Bailin
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Curtis L Gabriel
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University, Nashville, TN, USA
| | - Liang Guo
- CVPath Institute, Gaithersburg, MD, USA
| | - Briana D Furch
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Morgan C Lima
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Beverly O Woodward
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - LaToya Hannah
- Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mark A Pilkinton
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | | | | | | | - Alyssa H Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.,Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Simon A Mallal
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA.,VANTAGE, Vanderbilt University Medical Center, Nashville, TN, USA.,Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
| | - Spyros A Kalams
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - John R Koethe
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA.,Tennessee Center for AIDS Research, Vanderbilt University Medical Center, Nashville, TN, USA.,Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
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16
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Gamliel A, Werner L, Pinsker M, Salamon N, Weiss B, Shouval DS. Circulating α4β7 + Memory T Cells in Pediatric IBD Patients Express a Polyclonal T Cell Receptor Repertoire. Clin Exp Gastroenterol 2020; 13:439-447. [PMID: 33061522 PMCID: PMC7537844 DOI: 10.2147/ceg.s271565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 08/21/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The integrin α4β7 is highly expressed on activated T cells and is thought to direct homing of lymphocytes to the intestine. Since ulcerative colitis (UC) and Crohn's disease (CD) are characterized by mucosal oligoclonal T cells' expansion, we aimed to assess whether similar repertoire features are identified in circulating gut-specific memory T cells. METHODS Memory CD3+ T cells were isolated from blood samples of control subjects and patients with active UC or CD and then FACS-sorted into α4β7+ and α4β7- populations. DNA was extracted from each subset and subjected to next-generation sequencing of the TCRβ. Different repertoire characteristics were compared between α4β7+ and α4β7- subsets for each subject, and between groups. RESULTS The percentages of memory T cells and α4β7+ cells were comparable between groups. α4β7+ memory T cells displayed a polyclonal distribution, in control subjects and in UC or CD patients, with similar indices of diversity. Strikingly, the clonal overlap between α4β7+ and α4β7- T cells for each subject in all three groups was high, ranging between 20%-50%. We were unable to identify shared T cell clones that were specific to one of the groups. CONCLUSION α4β7+ memory T cells exhibited a polyclonal repertoire in both control subjects and patients with active inflammatory bowel disease, with high rates of overlap with α4β7- memory T cells. Our study, along with additional recent reports, may suggest that the suppression of intestinal inflammation by vedolizumab is independent of the drug's effect on T cell migration to the gut.
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Affiliation(s)
- Adir Gamliel
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lael Werner
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Marina Pinsker
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel
- Institute of Nanotechnology and Advanced Materials, Bar Ilan University, Ramat Gan, Israel
| | - Naomi Salamon
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel
| | - Batia Weiss
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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17
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Soto C, Bombardi RG, Kozhevnikov M, Sinkovits RS, Chen EC, Branchizio A, Kose N, Day SB, Pilkinton M, Gujral M, Mallal S, Crowe JE. High Frequency of Shared Clonotypes in Human T Cell Receptor Repertoires. Cell Rep 2020; 32:107882. [PMID: 32668251 PMCID: PMC7433715 DOI: 10.1016/j.celrep.2020.107882] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/18/2020] [Accepted: 06/16/2020] [Indexed: 01/30/2023] Open
Abstract
The collection of T cell receptors (TCRs) generated by somatic recombination is large but unknown. We generate large TCR repertoire datasets as a resource to facilitate detailed studies of the role of TCR clonotypes and repertoires in health and disease. We estimate the size of individual human recombined and expressed TCRs by sequence analysis and determine the extent of sharing between individual repertoires. Our experiments reveal that each blood sample contains between 5 million and 21 million TCR clonotypes. Three individuals share 8% of TCRβ- or 11% of TCRα-chain clonotypes. Sorting by T cell phenotypes in four individuals shows that 5% of naive CD4+ and 3.5% of naive CD8+ subsets share their TCRβ clonotypes, whereas memory CD4+ and CD8+ subsets share 2.3% and 0.4% of their clonotypes, respectively. We identify the sequences of these shared TCR clonotypes that are of interest for studies of human T cell biology.
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Affiliation(s)
- Cinque Soto
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Robin G Bombardi
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Morgan Kozhevnikov
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Robert S Sinkovits
- San Diego Supercomputer Center, University of California, San Diego, San Diego, CA 92093, USA
| | - Elaine C Chen
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
| | - Andre Branchizio
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Nurgun Kose
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Samuel B Day
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mark Pilkinton
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Madhusudan Gujral
- San Diego Supercomputer Center, University of California, San Diego, San Diego, CA 92093, USA
| | - Simon Mallal
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - James E Crowe
- The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
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18
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Kakuta Y, Nakano T, Naito T, Watanabe K, Izumiyama Y, Okamoto D, Ichikawa R, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Naitoh T, Kinouchi Y, Unno M, Masamune A. Repertoire analysis of memory T-cell receptors in Japanese patients with inflammatory bowel disease. JGH OPEN 2020; 4:624-631. [PMID: 32782948 PMCID: PMC7411559 DOI: 10.1002/jgh3.12305] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 01/11/2020] [Indexed: 01/07/2023]
Abstract
Background and Aim The T‐cell receptor (TCR) repertoire was assessed in response to various antigens and was considered to be associated with the pathogenesis of inflammatory bowel disease (IBD). Thus, we performed TCR repertoire analysis to examine the pathology of IBD from changes in the TCR repertoire of memory T cells in the intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) of patients with IBD. Methods LPMCs in the surgical specimens and PBMCs were isolated from 12 patients with IBD (5 patients with ulcerative colitis [UC] and 7 patients with Crohn's disease [CD]). PBMCs were collected from 10 healthy individuals as controls. Comprehensive TCR sequence analyses of adaptor‐ligation polymerase chain reaction (PCR) products were performed using MiSeq. Results The diversity of TCR‐α and TCR‐β in PBMCs was significantly lower in patients with IBD than that in controls (P = 0.00084 and 0.0013, respectively). Comparisons of TCR diversity in LPMCs and PBMCs between CD and UC showed that the diversity in LPMC was not affected by diseases, whereas that in PBMCs was significantly lower in CD than in UC (P = 0.045 and 0.049, respectively). Some TCR clones may have shown a specific increase or decrease in CD and UC, and many clones were common to both LPMCs and PBMCs in the same patients. Conclusion The diversity of TCR clones in LPMCs and PBMCs in patients with IBD was significantly lower than that of PBMCs in controls. TCR diversity in PBMCs was particularly low in patients with CD.
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Affiliation(s)
- Yoichi Kakuta
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Takeru Nakano
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Takeo Naito
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Kazuhiro Watanabe
- Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
| | - Yasuhiro Izumiyama
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Daisuke Okamoto
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Ryo Ichikawa
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Rintaro Moroi
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Masatake Kuroha
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Yoshitake Kanazawa
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Tomoya Kimura
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Hisashi Shiga
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
| | - Takeshi Naitoh
- Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
| | - Yoshitaka Kinouchi
- Student Health Care Center, Institute for Excellence in Higher Education Tohoku University Sendai Japan
| | - Michiaki Unno
- Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
| | - Atsushi Masamune
- Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan
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19
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Werner L, Lee YN, Rechavi E, Lev A, Yerushalmi B, Ling G, Shah N, Uhlig HH, Weiss B, Somech R, Snapper SB, Shouval DS. Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD. Front Immunol 2020; 11:109. [PMID: 32117262 PMCID: PMC7017840 DOI: 10.3389/fimmu.2020.00109] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/15/2020] [Indexed: 01/04/2023] Open
Abstract
Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns. We aimed to characterize TCR and BCR features in peripheral blood of patients with deleterious IL10 signaling defects. DNA was isolated from blood of seven patients with IL10R mutations and one with an IL10 mutation, along with eight controls, and subjected to next generation sequencing of TRB and IgH loci. A significant increase in clonality was observed in both TCR and BCR repertoires in circulating lymphocytes of IL10/IL10R-deficient patients, but to a much greater extent in T cells. Furthermore, short CDR3β length and altered hydrophobicity were demonstrated in T cells of patients, but not in B cells, secondary to lower rates of insertions of nucleotides, but not deletions, at the V-, D-, or J-junctions. We were unable to observe specific T or B clones that were limited only to the patients or among controls. Moreover, the expanded T cells clones were unique to each patient. In conclusion, next generation sequencing of the TCR and BCR is a powerful tool for characterizing the adaptive immune cell phenotype and function in immune-mediated disorders. The oligoclonality observed among IL10/IL10R-deficient patients may suggest specialization of unique clones that likely have a role in mediating tissue damage. Nevertheless, the lack of shared clones between patients provides another piece of evidence that the adaptive immune response in IBD is not triggered against common antigens. Additional studies are required to define the specific antigens that interact with the expanded IL10/IL10R-deficient clones.
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Affiliation(s)
- Lael Werner
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yu Nee Lee
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel
| | - Erez Rechavi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel
| | - Atar Lev
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel
| | - Baruch Yerushalmi
- Pediatric Gastroenterology Unit, Soroka University Medical Center, Ben Gurion University of the Negev, Be'er Sheva, Israel
| | - Galina Ling
- Pediatric Gastroenterology Unit, Soroka University Medical Center, Ben Gurion University of the Negev, Be'er Sheva, Israel
| | - Neil Shah
- Department of Gastroenterology, Great Ormond Street Hospital, London, United Kingdom
| | - Holm H Uhlig
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.,Department of Pediatrics, University of Oxford, Oxford, United Kingdom.,NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Batia Weiss
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Raz Somech
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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20
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Stras SF, Werner L, Toothaker JM, Olaloye OO, Oldham AL, McCourt CC, Lee YN, Rechavi E, Shouval DS, Konnikova L. Maturation of the Human Intestinal Immune System Occurs Early in Fetal Development. Dev Cell 2019; 51:357-373.e5. [PMID: 31607651 DOI: 10.1016/j.devcel.2019.09.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 06/16/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023]
Abstract
There are limited data on fetal and early life development of human intestinal immunity. Using mass cytometry (CyTOF) and next-generation sequencing of B and T cell receptor (BCR and TCR) repertoires, we demonstrate complex intestinal immunity from 16 weeks' gestational age (GA). Both BCR and TCR repertoires are diverse with CDRH and CDR3β length increasing with advancing GA. The difference-from-germline, CDR insertions and/or deletions, similarly occur in utero for TCR but not BCR, suggesting earlier mucosal T than B cell maturity. Innate immunity is dominated by macrophages, dendritic cells (DCs), innate lymphoid cells (ILCs), and natural killer (NK) cells. Follicular and transitional B cells are enriched in fetuses while CD69+IgM+ B cells are abundant in infants. Both CD4+ and CD8+ T cells are abundant, capable of secreting cytokines and are phenotypically of the tissue resident memory state in utero. Our data provide the foundation for a 2nd trimester and infant intestinal immune atlas and suggest that a complex innate and adaptive immune landscape exists significantly earlier than previously reported.
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Affiliation(s)
- Stephanie F Stras
- Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Lael Werner
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Jessica M Toothaker
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Oluwabunmi O Olaloye
- Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Austin L Oldham
- Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Collin C McCourt
- Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Yu Nee Lee
- Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Erez Rechavi
- Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
| | - Liza Konnikova
- Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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