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 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 Study Group

doi:10.1016/j.cell.2021.12.040

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

Standard

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; Pa-COVID Study Group.

in: CELL, Jahrgang 185, Nr. 3, 03.02.2022, S. 493-512.e25.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Georg, P, Astaburuaga-García, R, Bonaguro, L, Brumhard, S, Michalick, L, Lippert, LJ, Kostevc, T, Gäbel, C, Schneider, M, Streitz, M, Demichev, V, Gemünd, I, Barone, M, Tober-Lau, P, Helbig, ET, Hillus, D, Petrov, L, Stein, J, Dey, H-P, Paclik, D, Iwert, C, Mülleder, M, Aulakh, SK, Djudjaj, S, Bülow, RD, Mei, HE, Schulz, AR, Thiel, A, Hippenstiel, S, Saliba, A-E, Eils, R, Lehmann, I, Mall, MA, Stricker, S, Röhmel, J, Corman, VM, 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, WM, Meisel, C, Ralser, M, Schultze, JL, Aschenbrenner, AC, Thibeault, C, Kurth, F, Sander, LE, Blüthgen, N, Sawitzki, B & Pa-COVID Study Group 2022, 'Complement activation induces excessive T cell cytotoxicity in severe COVID-19', CELL, Jg. 185, Nr. 3, S. 493-512.e25. https://doi.org/10.1016/j.cell.2021.12.040

APA

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., ... Pa-COVID Study Group (2022). Complement activation induces excessive T cell cytotoxicity in severe COVID-19. CELL, 185(3), 493-512.e25. https://doi.org/10.1016/j.cell.2021.12.040

Vancouver

Georg P, Astaburuaga-García R, Bonaguro L, Brumhard S, Michalick L, Lippert LJ et al. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. CELL. 2022 Feb 3;185(3):493-512.e25. https://doi.org/10.1016/j.cell.2021.12.040

Bibtex

@article{05ed743b2f794da9b843aaf984dc8264,

title = "Complement activation induces excessive T cell cytotoxicity in severe COVID-19",

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.",

keywords = "Adult, Aged, Aged, 80 and over, COVID-19/immunology, Chemotactic Factors/metabolism, Complement Activation, Cytotoxicity, Immunologic, Endothelial Cells/virology, Female, Humans, Lymphocyte Activation, Male, Microvessels/virology, Middle Aged, Monocytes/metabolism, Neutrophils/metabolism, Proteome, Receptors, IgG/metabolism, SARS-CoV-2/immunology, Single-Cell Analysis, T-Lymphocytes, Cytotoxic/immunology, Transcriptome, Young Adult",

author = "Philipp Georg and Rosario Astaburuaga-Garc{\'i}a and Lorenzo Bonaguro and Sophia Brumhard and Laura Michalick and Lippert, {Lena J} and Tomislav Kostevc and Christiane G{\"a}bel and Maria Schneider and Mathias Streitz and Vadim Demichev and Ioanna Gem{\"u}nd and Matthias Barone and Pinkus Tober-Lau and Helbig, {Elisa T} and David Hillus and Lev Petrov and Julia Stein and Hannah-Philine Dey and Daniela Paclik and Christina Iwert and Michael M{\"u}lleder and Aulakh, {Simran Kaur} and Sonja Djudjaj and B{\"u}low, {Roman D} and Mei, {Henrik E} and Schulz, {Axel R} and Andreas Thiel and Stefan Hippenstiel and Antoine-Emmanuel Saliba and Roland Eils and Irina Lehmann and Mall, {Marcus A} and Sebastian Stricker and Jobst R{\"o}hmel and Corman, {Victor M} and Dieter Beule and Emanuel Wyler and Markus Landthaler and Benedikt Obermayer and {von Stillfried}, Saskia and Peter Boor and M{\"u}nevver Demir and Hans Wesselmann and Norbert Suttorp and Alexander Uhrig and Holger M{\"u}ller-Redetzky and Jacob Nattermann and Kuebler, {Wolfgang M} and Christian Meisel and Markus Ralser and Schultze, {Joachim L} and Aschenbrenner, {Anna C} and Charlotte Thibeault and Florian Kurth and Sander, {Leif E} and Nils Bl{\"u}thgen and Birgit Sawitzki and {Pa-COVID Study Group}",

year = "2022",

month = feb,

day = "3",

doi = "10.1016/j.cell.2021.12.040",

language = "English",

volume = "185",

pages = "493--512.e25",

journal = "CELL",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

RIS

TY - JOUR

T1 - Complement activation induces excessive T cell cytotoxicity in severe COVID-19

AU - Georg, Philipp

AU - Astaburuaga-García, Rosario

AU - Bonaguro, Lorenzo

AU - Brumhard, Sophia

AU - Michalick, Laura

AU - Lippert, Lena J

AU - Kostevc, Tomislav

AU - Gäbel, Christiane

AU - Schneider, Maria

AU - Streitz, Mathias

AU - Demichev, Vadim

AU - Gemünd, Ioanna

AU - Barone, Matthias

AU - Tober-Lau, Pinkus

AU - Helbig, Elisa T

AU - Hillus, David

AU - Petrov, Lev

AU - Stein, Julia

AU - Dey, Hannah-Philine

AU - Paclik, Daniela

AU - Iwert, Christina

AU - Mülleder, Michael

AU - Aulakh, Simran Kaur

AU - Djudjaj, Sonja

AU - Bülow, Roman D

AU - Mei, Henrik E

AU - Schulz, Axel R

AU - Thiel, Andreas

AU - Hippenstiel, Stefan

AU - Saliba, Antoine-Emmanuel

AU - Eils, Roland

AU - Lehmann, Irina

AU - Mall, Marcus A

AU - Stricker, Sebastian

AU - Röhmel, Jobst

AU - Corman, Victor M

AU - Beule, Dieter

AU - Wyler, Emanuel

AU - Landthaler, Markus

AU - Obermayer, Benedikt

AU - von Stillfried, Saskia

AU - Boor, Peter

AU - Demir, Münevver

AU - Wesselmann, Hans

AU - Suttorp, Norbert

AU - Uhrig, Alexander

AU - Müller-Redetzky, Holger

AU - Nattermann, Jacob

AU - Kuebler, Wolfgang M

AU - Meisel, Christian

AU - Ralser, Markus

AU - Schultze, Joachim L

AU - Aschenbrenner, Anna C

AU - Thibeault, Charlotte

AU - Kurth, Florian

AU - Sander, Leif E

AU - Blüthgen, Nils

AU - Sawitzki, Birgit

AU - Pa-COVID Study Group

PY - 2022/2/3

Y1 - 2022/2/3

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - COVID-19/immunology

KW - Chemotactic Factors/metabolism

KW - Complement Activation

KW - Cytotoxicity, Immunologic

KW - Endothelial Cells/virology

KW - Female

KW - Humans

KW - Lymphocyte Activation

KW - Male

KW - Microvessels/virology

KW - Middle Aged

KW - Monocytes/metabolism

KW - Neutrophils/metabolism

KW - Proteome

KW - Receptors, IgG/metabolism

KW - SARS-CoV-2/immunology

KW - Single-Cell Analysis

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Transcriptome

KW - Young Adult

U2 - 10.1016/j.cell.2021.12.040

DO - 10.1016/j.cell.2021.12.040

M3 - SCORING: Journal article

C2 - 35032429

VL - 185

SP - 493-512.e25

JO - CELL

JF - CELL

SN - 0092-8674

IS - 3

ER -