{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:08:30Z","timestamp":1790341710751,"version":"4.1.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T00:00:00Z","timestamp":1704240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022656","name":"Centre Hospitalier Universitaire de N\u00eemes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022656","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>As about 10% of patients with COVID-19 present sequelae, it is important to better understand the physiopathology of so-called long COVID.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>To this aim, we recruited 29 patients hospitalized for SARS-CoV-2 infection and, by Luminex<jats:sup>\u00ae<\/jats:sup>, quantified 19 soluble factors in their plasma and in the supernatant of their peripheral blood mononuclear cells, including inflammatory and anti-inflammatory cytokines and chemokines, Th1\/Th2\/Th17 cytokines, and endothelium activation markers. We also measured their T4, T8 and NK differentiation, activation, exhaustion and senescence, T cell apoptosis, and monocyte subpopulations by flow cytometry. We compared these markers between participants who developed long COVID or not one year later.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>None of these markers was predictive for sequelae, except programmed T4 cell death. T4 lymphocytes from participants who later presented long COVID were more apoptotic in culture than those of sequelae-free participants at Month 12 (36.9 \u00b1 14.7 vs. 24.2 \u00b1 9.0%, p\u00a0= 0.016).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our observation raises the hypothesis that T4 cell death during the acute phase of SARS-CoV-2 infection might pave the way for long COVID. Mechanistically, T4 lymphopenia might favor phenomena that could cause sequelae, including SARS-CoV-2 persistence, reactivation of other viruses, autoimmunity and immune dysregulation. In this scenario, inhibiting T cell apoptosis, for instance, by caspase inhibitors, could prevent long COVID.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1335352","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:43:27Z","timestamp":1704257007000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["T4 apoptosis in the acute phase of SARS-CoV-2 infection predicts long COVID"],"prefix":"10.3389","volume":"14","author":[{"given":"Renaud","family":"Cezar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Kundura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Andr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Lozano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Muller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Yves","family":"Lefrant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Roger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-G\u00e9raud","family":"Claret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Duvnjak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Loubet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Sotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tu-Ahn","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Estaquier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Corbeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.28568","article-title":"Short-term and long-term rates of postacute sequelae of SARS-coV-2 infection: A systematic review","volume":"4","author":"Groff","year":"2021","journal-title":"JAMA Netw Open"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.12603","article-title":"Persistent symptoms in patients after acute COVID-19","volume":"324","author":"Carfi","year":"2020","journal-title":"JAMA"},{"key":"B3","unstructured":""},{"key":"B4","unstructured":""},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.11417","article-title":"Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: A systematic review","volume":"4","author":"Nasserie","year":"2021","journal-title":"JAMA Netw Open"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.30476\/ijms.2021.92080.2326","article-title":"Risk factors associated with long COVID syndrome: A retrospective study","volume":"46","author":"Asadi-Pooya","year":"2021","journal-title":"Iran J Med Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2023.0750","article-title":"Risk factors associated with post-COVID-19 condition: A systematic review and meta-analysis","volume":"183","author":"Tsampasian","year":"2023","journal-title":"JAMA Intern Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2424","article-title":"Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers","volume":"33","author":"Yong","year":"2023","journal-title":"Rev Med Virol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1038\/s41467-023-37368-1","article-title":"Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8(+)beta7 integrin(+) T cells and anti-SARS-CoV-2 IgA response","volume":"14","author":"Santa Cruz","year":"2023","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s40249-023-01086-z","article-title":"Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis","volume":"12","author":"Yin","year":"2023","journal-title":"Infect Dis Poverty"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010359","article-title":"SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2","volume":"18","author":"Littlefield","year":"2022","journal-title":"PloS Pathog"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djac057","article-title":"COVID-19 sequelae and the host proinflammatory response: an analysis from the onCovid registry","volume":"114","author":"Cortellini","year":"2022","journal-title":"J Natl Cancer Inst"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200003","article-title":"Plasma markers of neurologic injury and inflammation in people with self-reported neurologic postacute sequelae of SARS-coV-2 infection","volume":"9","author":"Peluso","year":"2022","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01113-x","article-title":"Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection","volume":"23","author":"Phetsouphanh","year":"2022","journal-title":"Nat Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.cell.2022.01.014","article-title":"Multiple early factors anticipate post-acute COVID-19 sequelae","volume":"185","author":"Su","year":"2022","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.700782","article-title":"Immune-based prediction of COVID-19 severity and chronicity decoded using machine learning","volume":"12","author":"Patterson","year":"2021","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01599-21","article-title":"Immunological profiling of COVID-19 patients with pulmonary sequelae","volume":"12","author":"Wu","year":"2021","journal-title":"mBio"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1038\/s41418-022-00936-x","article-title":"T cell apoptosis characterizes severe Covid-19 disease","volume":"29","author":"Andre","year":"2022","journal-title":"Cell Death Differ"},{"key":"B19","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/j.jaci.2022.06.020","article-title":"Angiotensin II induces reactive oxygen species, DNA damage, and T cell apoptosis in severe COVID-19","volume":"150","author":"Kundura","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"7942","DOI":"10.3390\/ijms22157942","article-title":"The role of P-selectin in COVID-19 coagulopathy: an updated review","volume":"22","author":"Agrati","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"102885","DOI":"10.1016\/j.ebiom.2020.102885","article-title":"Reappearance of effector T cells is associated with recovery from COVID-19","volume":"57","author":"Odak","year":"2020","journal-title":"EBioMedicine"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2020.05.106","article-title":"Aberrant hyperactivation of cytotoxic T-cell as a potential determinant of COVID-19 severity","volume":"97","author":"Kang","year":"2020","journal-title":"Int J Infect Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"9764002","DOI":"10.1155\/2022\/9764002","article-title":"Upregulation of PD-1 expression and high sPD-L1 levels associated with COVID-19 severity","volume":"2022","author":"Beserra","year":"2022","journal-title":"J Immunol Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"102964","DOI":"10.1016\/j.ebiom.2020.102964","article-title":"Monocyte activation in systemic Covid-19 infection: Assay and rationale","volume":"59","author":"Martinez","year":"2020","journal-title":"EBioMedicine"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2020.12.010","article-title":"Dynamic changes in monocytes subsets in COVID-19 patients","volume":"82","author":"Qin","year":"2021","journal-title":"Hum Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/s41419-022-05190-0","article-title":"Low quantity and quality of anti-spike humoral response is linked to CD4 T-cell apoptosis in COVID-19 patients","volume":"13","author":"Andre","year":"2022","journal-title":"Cell Death Dis"},{"key":"B27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00296-020-04636-y","article-title":"Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic","volume":"41","author":"Soy","year":"2021","journal-title":"Rheumatol Int"},{"key":"B28","doi-asserted-by":"publisher","first-page":"10458","DOI":"10.3390\/ijms241310458","article-title":"Laboratory findings and biomarkers in long COVID: what do we know so far? Insights into epidemiology, pathogenesis, therapeutic perspectives and challenges","volume":"24","author":"Tsilingiris","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1038\/s41577-023-00904-7","article-title":"The immunology of long COVID","volume":"23","author":"Altmann","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12016-022-08942-0","article-title":"Autoimmunity in primary immunodeficiencies (PID)","volume":"65","author":"Padron","year":"2023","journal-title":"Clin Rev Allergy Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature01323","article-title":"Inflammation in atherosclerosis","volume":"420","author":"Libby","year":"2002","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3390\/biomedicines11020294","article-title":"Crosstalk between gut microbiota and host immunity: impact on inflammation and immunotherapy","volume":"11","author":"Campbell","year":"2023","journal-title":"Biomedicines"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2023.06.002","article-title":"Physiological role of cytokines in the regulation of mammalian metabolism","volume":"44","author":"de Baat","year":"2023","journal-title":"Trends Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1206741","article-title":"Innate immune system regulation of nuclear hormone receptors in metabolic diseases","volume":"82","author":"Chow","year":"2007","journal-title":"J Leukoc Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1335352\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:43:31Z","timestamp":1704257011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1335352\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,3]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2023.1335352"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1335352","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,3]]},"article-number":"1335352"}}