TGFβ links EBV to multisystem inflammatory syndrome in children

• 成果类型: Article
• 署名作者: Goetzke, Carl Christoph; Massoud, Mona; Frischbutter, Stefan; Guerra, Gabriela Maria; Ferreira-Gomes, Marta; Heinrich, Frederik; von Stuckrad, Anne Sae Lim; Wisniewski, Sebastian; Licha, Jan Robin; Bondareva, Marina; Ehlers, Lisa; Khaldi-Plassart, Samira; Javouhey, Etienne; Pons, Sylvie; Trouillet-Assant, Sophie; Ozsurekci, Yasemin; Zhang, Yu; Poli, Maria Cecilia; Discepolo, Valentina; Lo Vecchio, Andrea; Sahin, Bengue; Verboom, Murielle; Hallensleben, Michael; Heuhsen, Anja Isabelle; Astudillo, Camila; Espinosa, Yazmin; Vial Cox, Maria Cecilia; Dobbs, Kerry; Delmonte, Ottavia M.; Montealegre Sanchez, Gina A.; Magliocco, Mary; Barron, Karyl; Danielson, Jeffrey; Petrov, Lev; Unterwalder, Nadine; Sawitzki, Birgit; Matz, Mareen; Lehmann, Katrin; Gratopp, Alexander; von Bernuth, Horst; Burkhardt, Lisa-Marie; Wiese, Niklas; Peter, Lena; Schmueck-Henneresse, Michael; Amini, Leila; Maurer, Marcus; Roehmel, Jobst Fridolin; Gewurz, Benjamin E.; Yonker, Lael M.; Witkowski, Mario; Kruglov, Andrey; Mall, Marcus Alexander; Su, Helen C.; Ozen, Seza; Radbruch, Andreas; Belot, Alexandre; Durek, Pawel; Kallinich, Tilmann; Mashreghi, Mir-Farzin
• 署名单位: Leibniz Association; Deutsches Rheuma-Forschungszentrum (DRFZ); Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; CHU Lyon; CHU Lyon; Institut National de la Sante et de la Recherche Medicale (Inserm); CHU Lyon; CHU Lyon; Institut National de la Sante et de la Recherche Medicale (Inserm); Ecole Normale Superieure de Lyon (ENS de LYON); Centre National de la Recherche Scientifique (CNRS); Universite Claude Bernard Lyon 1; Hacettepe University; National Institutes of Health (NIH) - USA; Division of Intramural Research (DIR); Universidad del Desarrollo; University of Naples Federico II; University of Naples Federico II; Hannover Medical School; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Massachusetts Institute of Technology (MIT); Lomonosov Moscow State University; Hacettepe University; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Universite Claude Bernard Lyon 1; Ecole Normale Superieure de Lyon (ENS de LYON)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1356
• DOI: 10.1038/s41586-025-08697-6
• 发表日期: 2025-04-17
• 关键词: epstein-barr-virus; t-cell responses; identification; expression; genes

摘要

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 TGF beta resembling those that occur during severe COVID-19 (refs. 4,5). This functional impairment in T cell reactivity is accompanied by the presence of TGF beta-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGF beta. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRV beta 21.3, resembling Epstein-Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGF beta in patients with MIS-C can trigger EBV reactivation, which is reversible with TGF beta blockade. Clinically, the TGF beta-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 TGF beta overproduction leads to EBV reactivation and subsequent hyperinflammation.