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.
%0 Journal Article
%1 noauthororeditor2021complement
%A Georg, Philipp
%A Astaburuaga-García, Rosario
%A Bonaguro, Lorenzo
%A Brumhard, Sophia
%A Michalick, Laura
%A Lippert, Lena J
%A Kostevc, Tomislav
%A Gäbel, Christiane
%A Schneider, Maria
%A Streitz, Mathias
%A Demichev, Vadim
%A Gemünd, Ivana
%A Barone, Matthias
%A Tober-Lau, Pinkus
%A Helbig, Elisa Theresa
%A Stein, Julia
%A Dey, Hannah-Philine
%A Paclik, Daniela
%A Mülleder, Michael
%A Aulakh, Simran Kaur
%A Mei, Henrik E
%A Schulz, Alex R
%A Hippenstiel, Stefan
%A Max Corman, Victor
%A Beule, Dieter
%A Wyler, Emanuel
%A Landthaler, Markus
%A Obermayer-Wasserscheid, Benedikt
%A Boor, Peter
%A Demir, Münevver
%A Wesselmann, Hans
%A Suttorp, Norbert
%A Uhrig, Alexander
%A Müller-Redetzky, Holger
%A Nattermann, Jacob
%A M. Kuebler, Wolfgang M
%A Meisel, Christian
%A Ralser, Markus
%A Schultze, Joachim L
%A Aschenbrenner, Anna C
%A Thibeault, Charlotte
%A Kurth, Florian
%A Sander, Leif-Erik
%A Blüthgen, Nils
%A Sawitzki, Birgit
%D 2021
%J Med Rx IV
%K COVID-19 T-cell complement severity
%R 10.1101/2021.06.08.2125848
%T Complement activation induces excessive T cell cytotoxity in severe COVID-19
%U https://www.medrxiv.org/content/10.1101/2021.06.08.21258481v1
%X 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.
@article{noauthororeditor2021complement,
abstract = {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.},
added-at = {2021-08-20T15:11:39.000+0200},
author = {Georg, Philipp and Astaburuaga-García, Rosario and Bonaguro, Lorenzo and Brumhard, Sophia and Michalick, Laura and Lippert, Lena J and Kostevc, Tomislav and Gäbel, Christiane and Schneider, Maria and Streitz, Mathias and Demichev, Vadim and Gemünd, Ivana and Barone, Matthias and Tober-Lau, Pinkus and Helbig, Elisa Theresa and Stein, Julia and Dey, Hannah-Philine and Paclik, Daniela and Mülleder, Michael and Aulakh, Simran Kaur and Mei, Henrik E and Schulz, Alex R and Hippenstiel, Stefan and Max Corman, Victor and Beule, Dieter and Wyler, Emanuel and Landthaler, Markus and Obermayer-Wasserscheid, Benedikt and Boor, Peter and Demir, Münevver and Wesselmann, Hans and Suttorp, Norbert and Uhrig, Alexander and Müller-Redetzky, Holger and Nattermann, Jacob and M. Kuebler, Wolfgang M and Meisel, Christian and Ralser, Markus and Schultze, Joachim L and Aschenbrenner, Anna C and Thibeault, Charlotte and Kurth, Florian and Sander, Leif-Erik and Blüthgen, Nils and Sawitzki, Birgit},
biburl = {https://www.bibsonomy.org/bibtex/20a39923c2a12a72b3fce44cb6ef11856/bellao},
doi = {10.1101/2021.06.08.2125848},
interhash = {0945e15bea9ddbe4b26caf5c2aeee946},
intrahash = {0a39923c2a12a72b3fce44cb6ef11856},
journal = {Med Rx IV},
keywords = {COVID-19 T-cell complement severity},
language = {English},
month = {June },
timestamp = {2022-04-24T11:08:01.000+0200},
title = {Complement activation induces excessive T cell cytotoxity in severe COVID-19},
url = {https://www.medrxiv.org/content/10.1101/2021.06.08.21258481v1},
year = 2021
}