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.
- Georg, P.
- Astaburuaga-García, R.
- Bonaguro, L.
- Brumhard, S.
- Michalick, L.
- Lippert, L. J.
- Kostevc, T.
- Gäbel, C.
- Schneider, M.
- Streitz, M.
- Demichev, V.
- Gemünd, I.
- Barone, M.
- Tober-Lau, P.
- Helbig, E. T.
- Hillus, D.
- Petrov, L.
- Stein, J.
- Dey, H. P.
- Paclik, D.
- Iwert, C.
- Mülleder, M.
- Aulakh, S. K.
- Djudjaj, S.
- Bülow, R. D.
- Mei, H. E.
- Schulz, A. R.
- Thiel, A.
- Hippenstiel, S.
- Saliba, A. E.
- Eils, R.
- Lehmann, I.
- Mall, M. A.
- Stricker, S.
- Röhmel, J.
- Corman, V. M.
- Beule, D.
- Wyler, E.
- Landthaler, M.
- Obermayer, B.
- von Stillfried, S.
- Boor, P.
- Demir, M.
- Wesselmann, H.
- Suttorp, N.
- Uhrig, A.
- Müller-Redetzky, H.
- Nattermann, J.
- Kuebler, W. M.
- Meisel, C.
- Ralser, M.
- Schultze, J. L.
- Aschenbrenner, A. C.
- Thibeault, C.
- Kurth, F.
- Sander, L. E.
- Blüthgen, N.
- Sawitzki, B.
Keywords
- Covid-19
- T cells
- complement
- cytotoxicity
- immunopathology
