TGFβ links EBV to multisystem inflammatory syndrome in children

In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock<sup>1</sup> termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion<sup>2</sup> and systemic hyperinflammation<sup>3</sup>. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. <sup>4,5</sup>). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein-Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.

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Journal
Nature
Published
2025-03-12
DOI
https://doi.org/10.1038/s41586-025-08697-6
Citations
24
Primary Topic
Kawasaki Disease and Coronary Complications
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article
Field-Weighted Citation Impact
48.15
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article

TGFβ links EBV to multisystem inflammatory syndrome in children

Étienne Javouhey, Katrin Lehmann, Andreas Radbruch, Helen C. Su et al.
24 citations
Nature
Kawasaki Disease and Coronary Complications
48.15
article

TGFβ links EBV to multisystem inflammatory syndrome in children

Étienne Javouhey, Katrin Lehmann, Andreas Radbruch, Helen C. Su, Murielle Verboom, Anne Sae Lim von Stuckrad, Horst von Bernuth, Jeffrey J. Danielson, Camila Astudillo, Lael M. Yonker, Birgit Sawitzki, Sophie Trouillet‐Assant, Nadine Unterwalder, Samira Khaldi-Plassart, Valentina Discepolo, M. Cecilia Poli, Ottavia M. Delmonte, Michael Hallensleben, Karyl S. Barron, Kerry Dobbs, Jobst Roehmel, Pawel Durek, Alexandre Bélot, Marcus Alexander Mall, Mir‐Farzin Mashreghi, Stefan Frischbutter, Mario Witkowski, Mona Massoud, Tilmann Kallinich, Yazmín Espinosa, Betül Şahin, Yasemin Özsürekçi, Sylvie Pons, Andrey Kruglov, Lisa-Marie Burkhardt, Marina Bondareva, Alexander Gratopp, Frederik Heinrich, Leila Amini, Lisa Ehlers, Carl Christoph Goetzke, Michael Schmueck‐Henneresse, Mary Magliocco, Benjamin E. Gewurz, Gina A. Montealegre Sanchez, Gabriela Maria Guerra, Seza Özen, L. A. Petrov, Andrea Lo Vecchio, Marta Ferreira‐Gomes, Mareen Matz, Marcus Maurer, Lena Peter, Niklas Wiese, Yu Zhang, Sebastian Wisniewski, Mary Jude Cox, Anja Isabelle Heuhsen, Jan Robin Licha
article en
24 citations

Abstract

In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock<sup>1</sup> termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion<sup>2</sup> and systemic hyperinflammation<sup>3</sup>. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. <sup>4,5</sup>). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein-Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.

NatureVol. 640(8059)
Université Claude Bernard Lyon 1 (FR), Broad Institute (US), Brigham and Women's Hospital (US), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Universidad del Desarrollo (CL), Harvard University (US), Inserm (FR), Lomonosov Moscow State University (RU), Clínica Alemana (CL), Leibniz Association (DE), Medizinische Hochschule Hannover (DE), Humboldt-Universität zu Berlin (DE), German Center for Pediatric and Adolescent Rheumatology (DE), Hôpital Femme Mère Enfant (FR), Massachusetts General Hospital (US), German Rheumatism Research Centre (DE), Hospital Roberto del Rio (CL), Hospices Civils de Lyon (FR), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), Vivantes Klinikum (DE), Christophorus Kliniken (DE), German Center for Lung Research (DE), National Institute of Allergy and Infectious Diseases (US), bioMérieux (France) (FR), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), German Central Institute for Social Issues (DE), German Center for Diabetes Research (DE), Centre International de Recherche en Infectiologie (FR), Massachusetts Institute of Technology (US), Hacettepe University (TR), University of Naples Federico II (IT), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), Université Jean Monnet (FR)
Good health and well-being
Openalex Percentile: Top 0%
Kawasaki Disease and Coronary Complications
48.15
DOIOpen Access PDFOpenAlex
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