Complement activation induces excessive T cell cytotoxicity in severe COVID-19

10.1101/2021.06.08.21258481

medRxiv

11th June 2021

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This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv. This is a preliminary report that should not be regarded as conclusive, guide clinical practice/health-related behaviour, or be reported in news media as established information.

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells also contribute to disease pathology. Here, we combined single-cell transcriptomics and 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. Age-dependent generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

Author list:

Affiliations

Department of Infectious Diseases and Respiratory Medicine, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
Institute of Pathology, Charité - Universitätsmedizin, 10117 Berlin, Germany,
IRI Life Sciences, Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
Systems Medicine, Deutsches Zentrum für Neurodegenerativen Erkrankungen (DZNE), 53127 Bonn, Germany
Institute of Physiology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
Department of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and HumboldtUniversität zu Berlin, 10117 Berlin, Germany
Department of Biochemistry, Cambridge Centre for Proteomics, University of Cambridge, Cambridge, UK
PRECISE Platform for Genomics and Epigenomics, at DZNE, and University of Bonn, 53127 Bonn, Germany
Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Australia
Core Facility - High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Mass Cytometry Lab, DRFZ Berlin, a Leibniz Institute, 10117 Berlin, Germany
Institute of Virology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
Berlin Institute of Health (BIH), Charitéplatz 1, 10117 Berlin, Germany
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 10115 Berlin, Germany
Institute of Pathology, University Clinic Aachen, RWTH Aachen, Aachen, Germany,
Department of Nephrology, University Clinic Aachen, RWTH Aachen, Aachen, Germany,
Electron Microscopy Facility, University Clinic Aachen, RWTH Aachen, Aachen, Germany
Department of Hepatology and Gastroenterology, Charité - University Medicine, Campus Virchow Clinic and Campus Charité Mitte, 13353 Berlin, Germany
German Center for Lung Research (DZL), 35392 Gießen, Germany
Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany
Department of Immunology, Labor Berlin, Charité Vivantes, 13353 Berlin, Germany
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine, and Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20359 Hamburg, Germany

Philipp Georg¹*, Rosario Astaburuaga-García^2,3 *, Lorenzo Bonaguro^4,5*, Sophia Brumhard¹, Laura Michalick⁶, Lena J. Lippert¹, Tomislav Kostevc⁷, Christiane Gäbel⁷, Maria Schneider⁷, Mathias Streitz⁷, Vadim Demichev^8,9,10, Ioanna Gemünd^4,11,12, Matthias Barone⁷, Pinkus ToberLau¹, Elisa Theresa Helbig1, Julia Stein7, Hannah-Philine Dey⁷, Daniela Paclik⁷, Michael Mülleder¹³, Simran Kaur Aulakh⁸, Henrik E. Mei¹⁴, Axel R. Schulz¹⁴, Stefan Hippenstiel¹, Victor Max Corman¹⁵, Dieter Beule¹⁶, Emanuel Wyler¹⁷, Markus Landthaler^3,17, Benedikt ObermayerWasserscheid¹⁶, Peter Boor^18,19,20, Münevver Demir²¹, Hans Wesselmann¹, Norbert Suttorp^1,22, Alexander Uhrig1, Holger Müller-Redetzky¹, Jacob Nattermann²³, Wolfgang M. Kuebler⁶, Christian Meisel^7,24, Markus Ralser^8,9, Joachim L. Schultze^4,5,11, Anna C. Aschenbrenner4,5,11,25, Charlotte Thibeault¹, Florian Kurth^1,26, Leif-Erik Sander¹, Nils Blüthgen^{2,3 ,#}, Birgit Sawitzki^{7 ,#,$}