Cited by 222COVID-19 Clinical Research StudiesSARS-CoV-2 and COVID-19 ResearchComplement system in diseases

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

Open access
Georg, Philipp, Astaburuaga-García, Rosario, Bonaguro, Lorenzo, Brumhard, Sophia, Michalick, Laura, Lippert, Lena J., Kostevc, Tomislav, Gäbel, Christiane +50 more·2022·Cell

Published version of a preprint

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.

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Crossref · 10.1016/j.cell.2021.12.040

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  • Complement activation aggravates tissue injury in COVID-19 by inducing excessive T cell cytotoxicity through immune complex-induced and T cell receptor-independent degranulation, potentially linking VIS and the SASP to uncontrolled T cell-mediated tissue damage.

    “Of note, complement activation has recently been shown to aggravate tissue injury in patients with COVID-19 by inducing excessive T cell cytotoxicity via immune complex-induced and T cell receptor-independent degranulation, thereby potentially linking VIS and the SASP to uncontrolled T cell-mediated tissue damage92.”

    From COVID-19 and cellular senescence (2023) · cites this paper as [92]

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Authors
Georg, P., Astaburuaga-García, R., Bonaguro, L., Brumhard, S., Michalick, L., Lippert, L. J., Kostevc, T., Gäbel, C., Schneider, M., Streitz, M., Demichev, V., Gemünd, I., Barone, M., Tober-Lau, P., Helbig, E. T., Hillus, D., Petrov, L., Stein, J., Dey, H.-P., Paclik, D., Iwert, C., Mülleder, M., Aulakh, S. K., Djudjaj, S., Bülow, R. D., Mei, H. E., Schulz, A. R., Thiel, A., Hippenstiel, S., Saliba, A.-E., Eils, R., Lehmann, I., Mall, M. A., Stricker, S., Röhmel, J., Corman, V. M., Beule, D., Wyler, E., Landthaler, M., Obermayer, B., von Stillfried, S., Boor, P., Demir, M., Wesselmann, H., Suttorp, N., Uhrig, A., Müller-Redetzky, H., Nattermann, J., Kuebler, W. M., Meisel, C., Ralser, M., Schultze, J. L., Aschenbrenner, A. C., Thibeault, C., Kurth, F., Sander, L. E., Blüthgen, N., & Sawitzki, B.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • University of Bonn (DE)
  • Charité – Universitätsmedizin Berlin (DE)
  • University of Cambridge (GB)
  • The Francis Crick Institute (GB)
  • Universitätsklinikum Aachen (DE)
  • German Rheumatism Research Centre (DE)
  • Helmholtz Institute for RNA-based Infection Research (DE)
  • German Center for Lung Research (DE)
  • Stiftung Charité (DE)
  • Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
  • Max Delbrück Center (DE)
  • University Hospital Bonn (DE)
Corresponding author
Sawitzki, Birgit
Venue
Cell
Publisher
Elsevier BV
Published
2022-02
Volume
185
Issue
3
Pages
493-512.e25
ISSN
0092-8674 (ISSN-L)
OpenAlex
W4226055319
Cited by
218
References
110
Citations by year
2026: 10 · 2025: 32 · 2024: 48 · 2023: 65 · 2022: 61 · 2021: 2
FWCI
14.25
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by)
  • OpenAgrar (submittedVersion, cc-by)
  • RWTH Publications (RWTH Aachen)
Funders
  • Bundesministerium für Gesundheit (ZMVI1-2520COR201)
  • Medical Research Council
  • Hector Stiftung
  • Francis Crick Institute
  • Berlin University Alliance
  • European Research Council
  • Berlin Institute of Health
  • Wellcome Trust (IA 200829/Z/16/Z)
  • UK Research and Innovation
  • RWTH Aachen University (125/17, 148/21)
  • European Commission (733100, 860003, 260687, 305147)
  • MDC
  • Deutsches Zentrum für Infektionsforschung (TTU 04.816, 04.817)
  • Deutsche Forschungsgemeinschaft (SPP1937, INST 217/577-1, GRK 2168 \u2013 272482170, EXC2151-390873048, INST 269/768-1, INST 37/1049-1, SA1383/3-1, SFB TR57, INST 217/988-1, INST 216/981-1, ERA CVD 00160389, GRK2157, ME 3644/5-1, INST 257/605-1, SFB 1454 \u2013 432325352, BO3755/13-1 Project-ID 454024652, SFB-TRR219 322900939, RTG2424, SFB-TR84 114933180)
  • Cancer Research UK (FC001134)
  • National Institute for Health and Care Research
  • Helmholtz-Gemeinschaft
  • Bundesministerium für Bildung und Forschung (STOP-FSGS-01GM1901A, FKZ 01KX2021, 02NUK047E, 031L0220A, 01KI20337, 01KI2021, 01KX2021)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Keywords
severe COVID-19, complement activation, T cell cytotoxicity, C3a, T cell clones, fatal outcome, immunopathology
MeSH terms
COVID-19, SARS-CoV-2, Adult, Aged, Aged, 80 and over, Chemotactic Factors, Complement Activation, Cytotoxicity, Immunologic, Female, Humans, Lymphocyte Activation, Male, Middle Aged, Monocytes, Neutrophils, T-Lymphocytes, Cytotoxic, Receptors, IgG, Proteome, Endothelial Cells, Microvessels, Young Adult, Single-Cell Analysis, Transcriptome

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