{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T11:12:52Z","timestamp":1783941172134,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Laborat\u00f3rio de Investiga\u00e7\u00e3o M\u00e9dica","doi-asserted-by":"publisher","award":["2019\/22448-0"],"award-info":[{"award-number":["2019\/22448-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Laborat\u00f3rio de Investiga\u00e7\u00e3o M\u00e9dica","doi-asserted-by":"publisher","award":["2019\/25119-7"],"award-info":[{"award-number":["2019\/25119-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The viral infection can evolve asymptomatically or can generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia based on the severity of symptoms in patients affected with COVID-19 is frequent. However, the profiles of CD4+ and CD8+ T cells regarding cytotoxicity and antiviral factor expression have not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study was to evaluate the phenotypic and functional profile of T lymphocytes in patients with moderate and severe\/critical COVID-19. During the pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe\/critical cases). Notwithstanding lymphopenia, we observed an increase in the expression of CD28, a co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T lymphocytes as well as an increase in the frequency of CD4+ T cells, CD8+ T cells, and NK cells that express the immunological checkpoint protein PD-1 in patients with a severe\/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T cells was already observed at the baseline level and scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T lymphocytes decreased the cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed by t-SNE, there were CD4+ T-cytotoxic and CD8+ T with low granzyme production, evidencing their dysfunction in severe\/critical conditions. In addition, purified CD8+ T lymphocytes from patients with severe COVID-19 showed increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and, curiously, had reduced expression of TNF-\u03b1. The cytotoxic profile of CD4+ T cells may compensate for the dysfunction\/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T cells and CD8+ T cells in the severity of acute COVID-19 infection.<\/jats:p>","DOI":"10.3390\/cells11213359","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T12:29:45Z","timestamp":1666700985000},"page":"3359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Generation of Cytotoxic T Cells and Dysfunctional CD8 T Cells in Severe COVID-19 Patients"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5937-2402","authenticated-orcid":false,"given":"Sarah Cristina","family":"Gozzi-Silva","sequence":"first","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana de Mendon\u00e7a","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3602-3306","authenticated-orcid":false,"given":"Ricardo Wesley","family":"Alberca","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalli Zanete","family":"Pereira","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of S\u00e3o Paulo, Av. Dr. En\u00e9as Carvalho de Aguiar 470, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6112-7107","authenticated-orcid":false,"given":"F\u00e1bio Seiti","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 263-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Julia","family":"Pietrobon","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana Mina","family":"Yendo","sequence":"additional","affiliation":[{"name":"Hospital das Cl\u00ednicas of the University of S\u00e3o Paulo (HCFMUSP), University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-3413","authenticated-orcid":false,"given":"Milena Mary","family":"de Souza Andrade","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of S\u00e3o Paulo, Av. Dr. En\u00e9as Carvalho de Aguiar 470, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmim Alefe Leuzzi","family":"Ramos","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of S\u00e3o Paulo, Av. Dr. En\u00e9as Carvalho de Aguiar 470, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9934-6102","authenticated-orcid":false,"given":"Cyro Alves","family":"Brito","sequence":"additional","affiliation":[{"name":"Center of Immunology, Adolfo Lutz Institute, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Araujo","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle Rosa","family":"Beserra","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of S\u00e3o Paulo, Av. Dr. En\u00e9as Carvalho de Aguiar 470, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2807-1404","authenticated-orcid":false,"given":"Raquel Le\u00e3o","family":"Orfali","sequence":"additional","affiliation":[{"name":"Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of S\u00e3o Paulo, Av. Dr. En\u00e9as Carvalho de Aguiar 470, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9ria","family":"Aoki","sequence":"additional","affiliation":[{"name":"Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of S\u00e3o Paulo, Av. 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