o:25455 Reduced expression of autophagy markers and expansion of myeloid- derived suppressor cells correlate with poor T cell response in severe COVID-19 patients Umanjena ekspresija markera autofagije i ekspanzija mijeloidnih supresorskih ćelija koreliraju sa lošim odgovorom T ćelija kod teških pacijenata sa COVID-19 en ABSTRACT Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease. COVID-19, autophagy, cytokines, myeloid-derived suppressor cells, regulatory lymphocytes 1552099 10.3389/fimmu.2021.614599 2022-05-18T07:22:10.341Z 44 yes 46 Sergej Tomić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka 0000-0003-2570-1295 Nebojša Mitrović University of Belgrade, Faculty of Medicine, Clinical Hospital Center Zemun, Serbia person Marina Bekić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia person 0000-0002-6945-4241 Ratko Tomašević University of Belgrade, Faculty of Medicine, Clinical Hospital Center Zemun, Serbia person Dragan Mikić Military Medical Academy, Clinics for Infectious and Tropical Diseases, Belgrade, Serbia person Dragoš Stojanović University of Belgrade, Faculty of Medicine, Clinical Hospital Center Zemun, Serbia person Miodrag Čolić Serbian Academy of Sciences and Arts, Department for Medical Sciences, Belgrade, Serbia akademik person Dušan Radojević University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Microbiology, Serbia person Miroslav Dinić University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Microbiology, Serbia person Alisa Gruden-Movsesijan University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka person 0000-0002-3061-5474 Jelena Đokić University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Microbiology, Serbia person Nataša Ilić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka person 0000-0001-6738-7033 Dejan Stevanović University of Belgrade, Faculty of Medicine, Clinical Hospital Center Zemun, Serbia person application/pdf 4777272 https://phaidrabg.bg.ac.rs/o:25455 no yes 16 70 92000001 11A29 11A2904 11A26 11A2602 11A32 11A3283 Frontiers in immunology Viral Immunology 12 2021