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

Authors

  • P. Georg
  • R. Astaburuaga-García
  • L. Bonaguro
  • S. Brumhard
  • L. Michalick
  • L.J. Lippert
  • T. Kostevc
  • C. Gäbel
  • M. Schneider
  • M. Streitz
  • V. Demichev
  • I. Gemünd
  • M. Barone
  • P. Tober-Lau
  • E.T. Helbig
  • D. Hillus
  • L. Petrov
  • J. Stein
  • H.P. Dey
  • D. Paclik
  • C. Iwert
  • M. Mülleder
  • S.K. Aulakh
  • S. Djudjaj
  • R.D. Bülow
  • H.E. Mei
  • A.R. Schulz
  • A. Thiel
  • S. Hippenstiel
  • A.E. Saliba
  • R. Eils
  • I. Lehmann
  • M.A. Mall
  • S. Stricker
  • J. Röhmel
  • V.M. Corman
  • D. Beule
  • E. Wyler
  • M. Landthaler
  • B. Obermayer
  • S. von Stillfried
  • P. Boor
  • M. Demir
  • H. Wesselmann
  • N. Suttorp
  • A. Uhrig
  • H. Müller-Redetzky
  • J. Nattermann
  • W.M. Kuebler
  • C. Meisel
  • M. Ralser
  • J.L. Schultze
  • A.C. Aschenbrenner
  • C. Thibeault
  • F. Kurth
  • L.E. Sander
  • N. Blüthgen
  • B. Sawitzki

Journal

  • Cell

Citation

  • Cell

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.


DOI

doi:10.1016/j.cell.2021.12.040