{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:14:33Z","timestamp":1787026473078,"version":"build-2736575974"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"DOI":"10.3389\/fimmu.2020.589380","type":"journal-article","created":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T05:00:52Z","timestamp":1602133252000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":151,"title":["T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis"],"prefix":"10.3389","volume":"11","author":[{"given":"Bahire","family":"Kalfaoglu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Almeida-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanidapa Adele","family":"Tye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yorifumi","family":"Satou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-32-9717-3_8","article-title":"Stimulatory and Inhibitory Co-signals in Autoimmunity","volume":"1189","author":"Okazaki","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/cei.13194","article-title":"From stability to dynamics: understanding molecular mechanisms of regulatory T cells through Foxp3 transcriptional dynamics","volume":"197","author":"Bending","year":"2018","journal-title":"Clin Exp Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02232-10","article-title":"Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response","volume":"85","author":"Glowacka","year":"2011","journal-title":"J Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes","volume":"26","author":"Sungnak","year":"2020","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antiviral Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.molcel.2020.04.022","article-title":"A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells","volume":"78","author":"Hoffmann","year":"2020","journal-title":"Mol Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nature07210","article-title":"T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance","volume":"455","author":"Pesu","year":"2008","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-09-3824","article-title":"Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma","volume":"108","author":"Pesu","year":"2006","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401629","article-title":"Proprotein convertase FURIN constrains Th2 differentiation and is critical for host resistance against Toxoplasma gondii","volume":"193","author":"Oksanen","year":"2014","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137244","article-title":"Clinical and immunological features of severe and moderate coronavirus disease 2019","volume":"130","author":"Chen","year":"2020","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30121-1","article-title":"Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia","volume":"2","author":"McGonagle","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1101\/2020.02.18.20024364","article-title":"Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)","volume":"11","author":"Diao","year":"2020","journal-title":"medRxiv"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1986.tb01496.x","article-title":"Structure and function of the interleukin 2 receptor: affinity conversion model","volume":"92","author":"Shimizu","year":"1986","journal-title":"Immunol Rev"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/ni1008-1091","article-title":"The Immunological Genome Project: networks of gene expression in immune cells","volume":"9","author":"Heng","year":"2008","journal-title":"Nat Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2016.19","article-title":"Promoter H3K4 methylation dynamically reinforces activation-induced pathways in human CD4 T cells","volume":"17","author":"LaMere","year":"2016","journal-title":"Genes Immun"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS: A J Integr Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01444","article-title":"Elucidating T Cell Activation-Dependent Mechanisms for Bifurcation of Regulatory and Effector T Cell Differentiation by Multidimensional and Single-Cell Analysis","volume":"9","author":"Bradley","year":"2018","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.79.12.7658-7663.2005","article-title":"Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Immune Response to Influenza Virus Infection in Mice","volume":"79","author":"Ishikawa","year":"2005","journal-title":"J Virol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2011.08.008","article-title":"TNF Superfamily Networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14)","volume":"23","author":"Ware","year":"2011","journal-title":"Curr Opin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02255-16","article-title":"The Measles Virus Receptor SLAMF1 Can Mediate Particle Endocytosis","volume":"91","author":"Gon\u00e7alves-Carneiro","year":"2017","journal-title":"J Virol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.69","article-title":"CD161intCD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut","volume":"9","author":"Fergusson","year":"2016","journal-title":"Mucosal Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201711048","article-title":"A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo","volume":"217","author":"Bending","year":"2018","journal-title":"J Cell Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/icb.2015.65","article-title":"Controversies concerning thymus-derived regulatory T cells: fundamental issues and a new perspective","volume":"94","author":"Ono","year":"2016","journal-title":"Immunol Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.016","article-title":"Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response","volume":"39","author":"Bailey-Bucktrout","year":"2013","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.012","article-title":"Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells","volume":"36","author":"Miyao","year":"2012","journal-title":"Immunity"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2008.03037.x","article-title":"Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells","volume":"127","author":"O\u2019Malley","year":"2009","journal-title":"Immunology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature06878","article-title":"TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function","volume":"453","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.immuni.2009.03.019","article-title":"Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor","volume":"30","author":"Miyara","year":"2009","journal-title":"Immunity"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2019.00207","article-title":"The PD-1\/PD-L1 Axis and Virus Infections: A Delicate Balance","volume":"9","author":"Sch\u00f6nrich","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070104","article-title":"Interleukin-10 production by effector T cells: Th1 cells show self control","volume":"204","author":"Trinchieri","year":"2007","journal-title":"J Exp Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.12.001","article-title":"The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases","volume":"49","author":"Roncarolo","year":"2018","journal-title":"Immunity"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601045","article-title":"IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo","volume":"198","author":"Brockmann","year":"2017","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.9.5771","article-title":"IL-10: The Master Regulator of Immunity to Infection","volume":"180","author":"Couper","year":"2008","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1111\/imm.13178","article-title":"Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes","volume":"160","author":"Ono","year":"2020","journal-title":"Immunology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nature05673","article-title":"Foxp3 controls regulatory T-cell function by interacting with AML1\/Runx1","volume":"446","author":"Ono","year":"2007","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899013","article-title":"A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme","volume":"37","author":"Bending","year":"2018","journal-title":"EMBO J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2020.0994","article-title":"Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China","volume":"180","author":"Wu","year":"2020","journal-title":"JAMA Internal Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2020.154244","article-title":"Letter to the Editor: Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease","volume":"108","author":"Zheng","year":"2020","journal-title":"Metabolism"},{"key":"B43","doi-asserted-by":"publisher","first-page":"598","DOI":"10.2119\/molmed.2011.00471","article-title":"Statins induce the accumulation of regulatory T cells in atherosclerotic plaque","volume":"18","author":"Meng","year":"2012","journal-title":"Mol Med (Cambridge Mass.)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2012.03.016","article-title":"Regulatory T cells and IL-10 levels are reduced in patients with vulnerable coronary plaques","volume":"222","author":"George","year":"2012","journal-title":"Atherosclerosis"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0196","article-title":"Drug Insight: the role of leptin in human physiology and pathophysiology\u2014emerging clinical applications","volume":"2","author":"Brennan","year":"2006","journal-title":"Nat Clin Pract Endocrinol Metab"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.01.011","article-title":"A Key Role of Leptin in the Control of Regulatory T Cell Proliferation","volume":"26","author":"De Rosa","year":"2007","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601118","article-title":"Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them","volume":"197","author":"Visperas","year":"2016","journal-title":"J Immunol (Baltimore Md 1950)"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.005","article-title":"Metabolic Pathways in Immune Cell Activation and Quiescence","volume":"38","author":"Pearce","year":"2013","journal-title":"Immunity"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646663","article-title":"Sugars and fat \u2013 A healthy way to generate functional regulatory T cells","volume":"46","author":"Gabriel","year":"2016","journal-title":"Eur J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.07.033","article-title":"Control of T(H)17\/T(reg) balance by hypoxia-inducible factor 1","volume":"146","author":"Dang","year":"2011","journal-title":"Cell"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav7062","article-title":"Restriction of PD-1 function by cis-PD-L1\/CD80 interactions is required for optimal T cell responses","volume":"364","author":"Sugiura","year":"2019","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02423-13","article-title":"Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection","volume":"87","author":"McNally","year":"2013","journal-title":"J Virol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1086\/499275","article-title":"Expression of Programmed Death\u20131 Ligand (PD-L) 1, PD-L2, B7-H3, and Inducible Costimulator Ligand on Human Respiratory Tract Epithelial Cells and Regulation by Respiratory Syncytial Virus and Type 1 and 2 Cytokines","volume":"193","author":"Stanciu","year":"2006","journal-title":"J Infect Dis"},{"key":"B54","doi-asserted-by":"publisher","first-page":"606.e601","DOI":"10.1016\/j.cell.2009.07.020","article-title":"SnapShot: effector and memory T cell differentiation","volume":"138","author":"Pipkin","year":"2009","journal-title":"Cell"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202541","article-title":"Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease","volume":"190","author":"Furmanski","year":"2013","journal-title":"J Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0800601","article-title":"Foxp3-Deficient Regulatory T Cells Do Not Revert into Conventional Effector CD4+ T Cells but Constitute a Unique Cell Subset","volume":"183","author":"Kuczma","year":"2009","journal-title":"J Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2009.02268.x","article-title":"CD25 Shedding by Human Natural Occurring CD4+CD25+ Regulatory T Cells does not Inhibit the Action of IL-2","volume":"70","author":"Pedersen","year":"2009","journal-title":"Scand J Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-019-03685-z","article-title":"Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy","volume":"98","author":"Jiang","year":"2019","journal-title":"Ann Hematol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fimmu.2020.589380\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T02:39:16Z","timestamp":1602815956000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fimmu.2020.589380\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,8]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2020.589380"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.589380","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.05.26.115923","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,8]]},"article-number":"589380"}}