Complement activation induces excessive T cell cytotoxicity in severe COVID-19
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Philipp Georg Rosario Astaburuaga-García Lorenzo Bonaguro Sophia Brumhard Laura Michalick Lena J Lippert Tomislav Kostevc Christiane Gäbel Maria Schneider Mathias Streitz Vadim Demichev Ioanna Gemünd Matthias Barone Pinkus Tober-Lau Elisa T Helbig David Hillus Lev Petrov Julia Stein Hannah-Philine Dey Daniela Paclik Christina Iwert Michael Mülleder Simran Aulakh Sonja Djudjaj Roman D Bülow Henrik E Mei Axel R Schulz Andreas Thiel Stefan Hippenstiel Antoine-Emmanuel Saliba Roland Eils Irina Lehmann Marcus A Mall Sebastian Stricker Jobst Röhmel Victor M Corman Dieter Beule Emanuel Wyler Markus Landthaler Benedikt Obermayer Saskia von Stillfried Peter Boor Münevver Demir Hans Wesselmann Norbert Suttorp Alexander Uhrig Holger Müller-Redetzky Jacob Nattermann Wolfgang M Kuebler Christian Meisel Markus Ralser Joachim L Schultze Anna C Aschenbrenner Charlotte Thibeault Florian Kurth Leif E Sander Nils Blüthgen Birgit Sawitzki PA-COVID-19 Study Group Toggle all authors (59)
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.
Journal details
Journal Cell
Volume 185
Issue number 3
Pages 493-512.e25
Available online
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Publisher website (DOI) 10.1016/j.cell.2021.12.040
Europe PubMed Central 35032429
Pubmed 35032429
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