1. Complement activation induces excessive T cell cytotoxicity in severe COVID-19
- Author
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Georg, Philipp, Astaburuaga-García, Rosario, Demichev, Vadim, Gemünd, Ioanna Dafni, Barone, Matthias, Tober-Lau, Pinkus, Helbig, Elisa T, Hillus, David, Petrov, Lev, Stein, Julia, Dey, Hannah-Philine, Paclik, Daniela, Bonaguro, Lorenzo, Iwert, Christina, Mülleder, Michael, Aulakh, Simran Kaur, Djudjaj, Sonja, Bülow, Roman D, Mei, Henrik E, Schulz, Axel R, Thiel, Andreas, Hippenstiel, Stefan, Saliba, Antoine-Emmanuel, Brumhard, Sophia, Eils, Roland, Lehmann, Irina, Mall, Marcus A, Stricker, Sebastian, Röhmel, Jobst, Corman, Victor, Beule, Dieter, Wyler, Emanuel, Landthaler, Markus, Obermayer, Benedikt, Michalick, Laura, von Stillfried, Saskia, Boor, Peter, Demir, Münevver, Wesselmann, Hans, Suttorp, Norbert, Uhrig, Alexander, Müller-Redetzky, Holger, Nattermann, Jacob, Kuebler, Wolfgang M, Meisel, Christian, Lippert, Lena J, Ralser, Markus, Schultze, Joachim L, Aschenbrenner, Anna C, Thibeault, Charlotte, Kurth, Florian, Sander, Leif E, Blüthgen, Nils, Sawitzki, Birgit, Group, PA-COVID-19 Study, Kostevc, Tomislav, Gäbel, Christiane, Schneider, Maria, Streitz, Mathias, and HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.
- Subjects
Adult ,Cytotoxicity, Immunologic ,Male ,Cancer Research ,metabolism [Receptors, IgG] ,immunology [T-Lymphocytes, Cytotoxic] ,virology [Endothelial Cells] ,Proteome ,Neutrophils ,virology [COVID-19] ,T cells ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,Monocytes ,Article ,General Biochemistry, Genetics and Molecular Biology ,pathology [COVID-19] ,Young Adult ,Ecology,Evolution & Ethology ,virology [Microvessels] ,immunology [SARS-CoV-2] ,Humans ,immunopathology ,immunology [COVID-19] ,complement ,ddc:610 ,Complement Activation ,Computational & Systems Biology ,Aged ,Chemical Biology & High Throughput ,Aged, 80 and over ,Chemotactic Factors ,SARS-CoV-2 ,Receptors, IgG ,Endothelial Cells ,COVID-19 ,Middle Aged ,metabolism [Neutrophils] ,metabolism [Chemotactic Factors] ,Metabolism ,Microvessels ,cytotoxicity ,Synthetic Biology ,Female ,Technology Platforms ,Single-Cell Analysis ,Transcriptome ,T-Lymphocytes, Cytotoxic ,metabolism [Monocytes] - Abstract
Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19., Generation of the C3a complement protein fragment by SARS-CoV-2 infection drives differentiation of a CD16-expressing T cell population that associates with severe COVID-19 disease outcomes.
- Published
- 2022