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

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journal contribution
posted on 08.02.2022, 14:08 authored by 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 Kaur 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
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.

Funding

Crick (Grant ID: 10134, Grant title: Ralser FC001134)

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