Generation of Cytotoxic T Cells and Dysfunctional CD8 T Cells in Severe COVID-19 Patients
Sarah Cristina Gozzi-Silva,
Luana de Mendonça Oliveira,
Ricardo Wesley Alberca,
Natalli Zanete Pereira,
Fábio Seiti Yoshikawa,
Anna Julia Pietrobon,
Tatiana Mina Yendo,
Milena Mary de Souza Andrade,
Yasmim Alefe Leuzzi Ramos,
Cyro Alves Brito,
Emily Araujo Oliveira,
Danielle Rosa Beserra,
Raquel Leão Orfali,
Valéria Aoki,
Alberto Jose da Silva Duarte,
Maria Notomi Sato
Affiliations
Sarah Cristina Gozzi-Silva
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Luana de Mendonça Oliveira
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Ricardo Wesley Alberca
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Natalli Zanete Pereira
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Fábio Seiti Yoshikawa
Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 263-8522, Japan
Anna Julia Pietrobon
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Tatiana Mina Yendo
Hospital das Clínicas of the University of São Paulo (HCFMUSP), University of São Paulo, São Paulo 05403-000, Brazil
Milena Mary de Souza Andrade
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Yasmim Alefe Leuzzi Ramos
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Cyro Alves Brito
Center of Immunology, Adolfo Lutz Institute, São Paulo 05403-000, Brazil
Emily Araujo Oliveira
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Danielle Rosa Beserra
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Raquel Leão Orfali
Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar 470, São Paulo 05403-000, Brazil
Valéria Aoki
Laboratory of Dermatology and Immunodeficiencies 56 (LIM-56), Division of Dermatology, Medical School, University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar 470, São Paulo 05403-000, Brazil
Alberto Jose da Silva Duarte
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
Maria Notomi Sato
Institute of Tropical Medicine, University of São Paulo, São Paulo 05403-000, Brazil
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-α. 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.
