Complement activation induces excessive T cell cytotoxicity in severe COVID-19
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 Theresa Helbig; Julia Stein; Hannah-Philine Dey; Daniela Paclik; Michael Mülleder; Simran Kaur Aulakh; Henrik E. Mei; Axel R. Schulz; Stefan Hippenstiel; Victor Max Corman; Dieter Beule; Emanuel Wyler; Markus Landthaler; Benedikt Obermayer-Wasserscheid; Peter Boor; Münevve 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-Erik Sander; Nils Blüthgen; Birgit Sawitzki.
Preprint
en Inglés
| PREPRINT-MEDRXIV | ID: ppmedrxiv-21258481
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.
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