TGFβ links EBV to multisystem inflammatory syndrome in children

Carl Christoph Goetzke (), Mona Massoud, Stefan Frischbutter, Gabriela Maria Guerra, Marta Ferreira-Gomes, Frederik Heinrich, Anne Sae Lim Stuckrad, Sebastian Wisniewski, Jan Robin Licha, Marina Bondareva, Lisa Ehlers, Samira Khaldi-Plassart, Etienne Javouhey, Sylvie Pons, Sophie Trouillet-Assant, Yasemin Ozsurekci, Yu Zhang, Maria Cecilia Poli, Valentina Discepolo, Andrea Lo Vecchio, Bengü Sahin, Murielle Verboom, Michael Hallensleben, Anja Isabelle Heuhsen, Camila Astudillo, Yazmin Espinosa, Maria Cecilia Vial Cox, Kerry Dobbs, Ottavia M. Delmonte, Gina A. Montealegre Sanchez, Mary Magliocco, Karyl Barron, Jeffrey Danielson, Lev Petrov, Nadine Unterwalder, Birgit Sawitzki, Mareen Matz, Katrin Lehmann, Alexander Gratopp, Horst Bernuth, Lisa-Marie Burkhardt, Niklas Wiese, Lena Peter, Michael Schmueck-Henneresse, Leila Amini, Marcus Maurer, Jobst Fridolin Roehmel, Benjamin E. Gewurz, Lael M. Yonker, Mario Witkowski, Andrey Kruglov, Marcus Alexander Mall, Helen C. Su, Seza Ozen, Andreas Radbruch, Alexandre Belot, Pawel Durek, Tilmann Kallinich () and Mir-Farzin Mashreghi ()
Additional contact information
Carl Christoph Goetzke: a Leibniz-Institute (DRFZ)
Mona Massoud: a Leibniz-Institute (DRFZ)
Stefan Frischbutter: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Gabriela Maria Guerra: a Leibniz-Institute (DRFZ)
Marta Ferreira-Gomes: a Leibniz-Institute (DRFZ)
Frederik Heinrich: a Leibniz-Institute (DRFZ)
Anne Sae Lim Stuckrad: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Sebastian Wisniewski: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Jan Robin Licha: a Leibniz-Institute (DRFZ)
Marina Bondareva: a Leibniz-Institute (DRFZ)
Lisa Ehlers: a Leibniz-Institute (DRFZ)
Samira Khaldi-Plassart: Hospices Civils de Lyon
Etienne Javouhey: Hospices Civils de Lyon
Sylvie Pons: Lyon Sud Hospital
Sophie Trouillet-Assant: Lyon Sud Hospital
Yasemin Ozsurekci: Hacettepe University
Yu Zhang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Maria Cecilia Poli: Clínica Alemana-Universidad del Desarrollo
Valentina Discepolo: University of Naples Federico II
Andrea Lo Vecchio: University of Naples Federico II
Bengü Sahin: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Murielle Verboom: Institute of Transfusion Medicine and Transplant Engineering
Michael Hallensleben: Institute of Transfusion Medicine and Transplant Engineering
Anja Isabelle Heuhsen: a Leibniz-Institute (DRFZ)
Camila Astudillo: Hospital de Niños Dr. Roberto del Río
Yazmin Espinosa: Hospital de Niños Dr. Roberto del Río
Maria Cecilia Vial Cox: Clínica Alemana-Universidad del Desarrollo
Kerry Dobbs: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Ottavia M. Delmonte: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gina A. Montealegre Sanchez: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Mary Magliocco: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Karyl Barron: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jeffrey Danielson: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Lev Petrov: Berlin Institute of Health (BIH) and Charité University Medicine
Nadine Unterwalder: Charité-Vivantes
Birgit Sawitzki: Berlin Institute of Health (BIH) and Charité University Medicine
Mareen Matz: Berlin Institute of Health at Charité-Universitätsmedizin Berlin
Katrin Lehmann: a Leibniz-Institute (DRFZ)
Alexander Gratopp: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Horst Bernuth: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Lisa-Marie Burkhardt: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Niklas Wiese: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Lena Peter: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Michael Schmueck-Henneresse: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Leila Amini: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Marcus Maurer: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Jobst Fridolin Roehmel: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Benjamin E. Gewurz: Harvard Medical School
Lael M. Yonker: Massachusetts General Hospital
Mario Witkowski: a Leibniz-Institute (DRFZ)
Andrey Kruglov: a Leibniz-Institute (DRFZ)
Marcus Alexander Mall: Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Helen C. Su: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Seza Ozen: Hacettepe University
Andreas Radbruch: a Leibniz-Institute (DRFZ)
Alexandre Belot: Hospices Civils de Lyon
Pawel Durek: a Leibniz-Institute (DRFZ)
Tilmann Kallinich: a Leibniz-Institute (DRFZ)
Mir-Farzin Mashreghi: a Leibniz-Institute (DRFZ)

Nature, 2025, vol. 640, issue 8059, 762-771

Abstract: Abstract In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock1 termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion2 and systemic hyperinflammation3. 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. 4,5). 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.

Date: 2025
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DOI: 10.1038/s41586-025-08697-6

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