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



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This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv.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:


  1. Department of Infectious Diseases and Respiratory Medicine, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
  2. Institute of Pathology, Charité - Universitätsmedizin, 10117 Berlin, Germany,
  3. IRI Life Sciences, Humboldt-Universität zu Berlin, 10117 Berlin, Germany
  4. Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53115 Bonn, Germany
  5. Systems Medicine, Deutsches Zentrum für Neurodegenerativen Erkrankungen (DZNE), 53127 Bonn, Germany
  6. Institute of Physiology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
  7. Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
  8. Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
  9. Department of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and HumboldtUniversität zu Berlin, 10117 Berlin, Germany
  10. Department of Biochemistry, Cambridge Centre for Proteomics, University of Cambridge, Cambridge, UK
  11. PRECISE Platform for Genomics and Epigenomics, at DZNE, and University of Bonn, 53127 Bonn, Germany
  12. Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Australia
  13. Core Facility - High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
  14. Mass Cytometry Lab, DRFZ Berlin, a Leibniz Institute, 10117 Berlin, Germany
  15. Institute of Virology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
  16. Berlin Institute of Health (BIH), Charitéplatz 1, 10117 Berlin, Germany
  17. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 10115 Berlin, Germany
  18. Institute of Pathology, University Clinic Aachen, RWTH Aachen, Aachen, Germany,
  19. Department of Nephrology, University Clinic Aachen, RWTH Aachen, Aachen, Germany,
  20. Electron Microscopy Facility, University Clinic Aachen, RWTH Aachen, Aachen, Germany
  21. Department of Hepatology and Gastroenterology, Charité - University Medicine, Campus Virchow Clinic and Campus Charité Mitte, 13353 Berlin, Germany
  22. German Center for Lung Research (DZL), 35392 Gießen, Germany
  23. Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany
  24. Department of Immunology, Labor Berlin, Charité Vivantes, 13353 Berlin, Germany
  25. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
  26. 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-García2,3 *, Lorenzo Bonaguro4,5 *, Sophia Brumhard1, Laura Michalick6, Lena J. Lippert1, Tomislav Kostevc7, Christiane Gäbel7, Maria Schneider7, Mathias Streitz7, Vadim Demichev8,9,10, Ioanna Gemünd4,11,12, 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 Landthaler3,17, Benedikt ObermayerWasserscheid16, Peter Boor18,19,20, Münevver Demir21, Hans Wesselmann1, Norbert Suttorp1,22, Alexander Uhrig1, Holger Müller-Redetzky1, Jacob Nattermann23, Wolfgang M. Kuebler6, Christian Meisel7,24, Markus Ralser8,9, Joachim L. Schultze4,5,11, Anna C. Aschenbrenner4,5,11,25, Charlotte Thibeault1, Florian Kurth1,26, Leif-Erik Sander1, Nils Blüthgen2,3 ,#, Birgit Sawitzki7 ,#,$