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

Cell. 2022 Feb 3;185(3):493-512.e25. doi: 10.1016/j.cell.2021.12.040. Epub 2021 Dec 28.


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.

Keywords: COVID-19; T cells; complement; cytotoxicity; immunopathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • COVID-19 / immunology*
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Chemotactic Factors / metabolism
  • Complement Activation*
  • Cytotoxicity, Immunologic
  • Endothelial Cells / virology
  • Female
  • Humans
  • Lymphocyte Activation
  • Male
  • Microvessels / virology
  • Middle Aged
  • Monocytes / metabolism
  • Neutrophils / metabolism
  • Proteome*
  • Receptors, IgG / metabolism
  • SARS-CoV-2 / immunology*
  • Single-Cell Analysis
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transcriptome*
  • Young Adult


  • Chemotactic Factors
  • Proteome
  • Receptors, IgG