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

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 func...

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Autores principales: Georg, Philipp, Astaburuaga-García, Rosario, Bonaguro, Lorenzo, Brumhard, Sophia, Michalick, Laura, Lippert, Lena J., Kostevc, Tomislav, Gäbel, Christiane, Schneider, Maria, Streitz, Mathias, Demichev, Vadim, Gemünd, Ioanna, Barone, Matthias, Tober-Lau, Pinkus, Helbig, Elisa T., Hillus, David, Petrov, Lev, Stein, Julia, Dey, Hannah-Philine, Paclik, Daniela, Iwert, Christina, Mülleder, Michael, Aulakh, Simran Kaur, Djudjaj, Sonja, Bülow, Roman D., Mei, Henrik E., Schulz, Axel R., Thiel, Andreas, Hippenstiel, Stefan, Saliba, Antoine-Emmanuel, Eils, Roland, Lehmann, Irina, Mall, Marcus A., Stricker, Sebastian, Röhmel, Jobst, Corman, Victor M., Beule, Dieter, Wyler, Emanuel, Landthaler, Markus, Obermayer, Benedikt, von Stillfried, Saskia, Boor, Peter, Demir, Münevver, Wesselmann, Hans, Suttorp, Norbert, Uhrig, Alexander, Müller-Redetzky, Holger, Nattermann, Jacob, Kuebler, Wolfgang M., Meisel, Christian, Ralser, Markus, Schultze, Joachim L., Aschenbrenner, Anna C., Thibeault, Charlotte, Kurth, Florian, Sander, Leif E., Blüthgen, Nils, Sawitzki, Birgit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Authors. Published by Elsevier Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712270/
https://www.ncbi.nlm.nih.gov/pubmed/35032429
http://dx.doi.org/10.1016/j.cell.2021.12.040
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author Georg, Philipp
Astaburuaga-García, Rosario
Bonaguro, Lorenzo
Brumhard, Sophia
Michalick, Laura
Lippert, Lena J.
Kostevc, Tomislav
Gäbel, Christiane
Schneider, Maria
Streitz, Mathias
Demichev, Vadim
Gemünd, Ioanna
Barone, Matthias
Tober-Lau, Pinkus
Helbig, Elisa T.
Hillus, David
Petrov, Lev
Stein, Julia
Dey, Hannah-Philine
Paclik, Daniela
Iwert, Christina
Mülleder, Michael
Aulakh, Simran Kaur
Djudjaj, Sonja
Bülow, Roman D.
Mei, Henrik E.
Schulz, Axel R.
Thiel, Andreas
Hippenstiel, Stefan
Saliba, Antoine-Emmanuel
Eils, Roland
Lehmann, Irina
Mall, Marcus A.
Stricker, Sebastian
Röhmel, Jobst
Corman, Victor M.
Beule, Dieter
Wyler, Emanuel
Landthaler, Markus
Obermayer, Benedikt
von Stillfried, Saskia
Boor, Peter
Demir, Münevver
Wesselmann, Hans
Suttorp, Norbert
Uhrig, Alexander
Müller-Redetzky, Holger
Nattermann, Jacob
Kuebler, Wolfgang M.
Meisel, Christian
Ralser, Markus
Schultze, Joachim L.
Aschenbrenner, Anna C.
Thibeault, Charlotte
Kurth, Florian
Sander, Leif E.
Blüthgen, Nils
Sawitzki, Birgit
author_facet Georg, Philipp
Astaburuaga-García, Rosario
Bonaguro, Lorenzo
Brumhard, Sophia
Michalick, Laura
Lippert, Lena J.
Kostevc, Tomislav
Gäbel, Christiane
Schneider, Maria
Streitz, Mathias
Demichev, Vadim
Gemünd, Ioanna
Barone, Matthias
Tober-Lau, Pinkus
Helbig, Elisa T.
Hillus, David
Petrov, Lev
Stein, Julia
Dey, Hannah-Philine
Paclik, Daniela
Iwert, Christina
Mülleder, Michael
Aulakh, Simran Kaur
Djudjaj, Sonja
Bülow, Roman D.
Mei, Henrik E.
Schulz, Axel R.
Thiel, Andreas
Hippenstiel, Stefan
Saliba, Antoine-Emmanuel
Eils, Roland
Lehmann, Irina
Mall, Marcus A.
Stricker, Sebastian
Röhmel, Jobst
Corman, Victor M.
Beule, Dieter
Wyler, Emanuel
Landthaler, Markus
Obermayer, Benedikt
von Stillfried, Saskia
Boor, Peter
Demir, Münevver
Wesselmann, Hans
Suttorp, Norbert
Uhrig, Alexander
Müller-Redetzky, Holger
Nattermann, Jacob
Kuebler, Wolfgang M.
Meisel, Christian
Ralser, Markus
Schultze, Joachim L.
Aschenbrenner, Anna C.
Thibeault, Charlotte
Kurth, Florian
Sander, Leif E.
Blüthgen, Nils
Sawitzki, Birgit
author_sort Georg, Philipp
collection PubMed
description 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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spelling pubmed-87122702021-12-28 Complement activation induces excessive T cell cytotoxicity in severe COVID-19 Georg, Philipp Astaburuaga-García, Rosario Bonaguro, Lorenzo Brumhard, Sophia Michalick, Laura Lippert, Lena J. Kostevc, Tomislav Gäbel, Christiane Schneider, Maria Streitz, Mathias Demichev, Vadim Gemünd, Ioanna Barone, Matthias Tober-Lau, Pinkus Helbig, Elisa T. Hillus, David Petrov, Lev Stein, Julia Dey, Hannah-Philine Paclik, Daniela Iwert, Christina Mülleder, Michael Aulakh, Simran Kaur Djudjaj, Sonja Bülow, Roman D. Mei, Henrik E. Schulz, Axel R. Thiel, Andreas Hippenstiel, Stefan Saliba, Antoine-Emmanuel Eils, Roland Lehmann, Irina Mall, Marcus A. Stricker, Sebastian Röhmel, Jobst Corman, Victor M. Beule, Dieter Wyler, Emanuel Landthaler, Markus Obermayer, Benedikt von Stillfried, Saskia Boor, Peter Demir, Münevver Wesselmann, Hans Suttorp, Norbert Uhrig, Alexander Müller-Redetzky, Holger Nattermann, Jacob Kuebler, Wolfgang M. Meisel, Christian Ralser, Markus Schultze, Joachim L. Aschenbrenner, Anna C. Thibeault, Charlotte Kurth, Florian Sander, Leif E. Blüthgen, Nils Sawitzki, Birgit Cell Article 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. The Authors. Published by Elsevier Inc. 2022-02-03 2021-12-28 /pmc/articles/PMC8712270/ /pubmed/35032429 http://dx.doi.org/10.1016/j.cell.2021.12.040 Text en © 2022 The Authors Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Georg, Philipp
Astaburuaga-García, Rosario
Bonaguro, Lorenzo
Brumhard, Sophia
Michalick, Laura
Lippert, Lena J.
Kostevc, Tomislav
Gäbel, Christiane
Schneider, Maria
Streitz, Mathias
Demichev, Vadim
Gemünd, Ioanna
Barone, Matthias
Tober-Lau, Pinkus
Helbig, Elisa T.
Hillus, David
Petrov, Lev
Stein, Julia
Dey, Hannah-Philine
Paclik, Daniela
Iwert, Christina
Mülleder, Michael
Aulakh, Simran Kaur
Djudjaj, Sonja
Bülow, Roman D.
Mei, Henrik E.
Schulz, Axel R.
Thiel, Andreas
Hippenstiel, Stefan
Saliba, Antoine-Emmanuel
Eils, Roland
Lehmann, Irina
Mall, Marcus A.
Stricker, Sebastian
Röhmel, Jobst
Corman, Victor M.
Beule, Dieter
Wyler, Emanuel
Landthaler, Markus
Obermayer, Benedikt
von Stillfried, Saskia
Boor, Peter
Demir, Münevver
Wesselmann, Hans
Suttorp, Norbert
Uhrig, Alexander
Müller-Redetzky, Holger
Nattermann, Jacob
Kuebler, Wolfgang M.
Meisel, Christian
Ralser, Markus
Schultze, Joachim L.
Aschenbrenner, Anna C.
Thibeault, Charlotte
Kurth, Florian
Sander, Leif E.
Blüthgen, Nils
Sawitzki, Birgit
Complement activation induces excessive T cell cytotoxicity in severe COVID-19
title Complement activation induces excessive T cell cytotoxicity in severe COVID-19
title_full Complement activation induces excessive T cell cytotoxicity in severe COVID-19
title_fullStr Complement activation induces excessive T cell cytotoxicity in severe COVID-19
title_full_unstemmed Complement activation induces excessive T cell cytotoxicity in severe COVID-19
title_short Complement activation induces excessive T cell cytotoxicity in severe COVID-19
title_sort complement activation induces excessive t cell cytotoxicity in severe covid-19
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712270/
https://www.ncbi.nlm.nih.gov/pubmed/35032429
http://dx.doi.org/10.1016/j.cell.2021.12.040
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