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TGFβ links EBV to multisystem inflammatory syndrome in children

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dc.contributor.authorGoetzke, Carl
dc.contributor.authorMassou, Mona
dc.contributor.authorFrischbutt, Stefan
dc.contributor.authorGuerra, Gabriela
dc.contributor.authorFerreira, Marta
dc.contributor.authorHeinrich, Frederik
dc.contributor.authorVon Stuckra, Anne
dc.contributor.authorWisniewsk, Sebastian
dc.contributor.authorLich, Jan
dc.contributor.authorBondarev, Marina
dc.contributor.authorEhler, Lisa
dc.contributor.authorKhaldi, Samira
dc.contributor.authorJavouhe, Etienne
dc.contributor.authorPons, Sylvie
dc.contributor.authorTrouillet, Sophie
dc.contributor.authorOzsurek, Yasemin
dc.contributor.authorZhang, Yu
dc.contributor.authorPoli Harlowe, María Cecilia
dc.contributor.authorDiscepolo, Valentina
dc.contributor.authorLo Vecchio, Andrea
dc.contributor.authorSahin, Bengü
dc.contributor.authorVerboom, Murielle
dc.contributor.authorHallenslebe, Michael
dc.contributor.authorHeuhse, Anja
dc.contributor.authorAstudillo, Camila
dc.contributor.authorEspinosa, Yazmin
dc.contributor.authorVial, Maria Cecilia
dc.contributor.authorDobbs, Kerry
dc.contributor.authorDelmont, Ottavia
dc.contributor.authorMontealegre, Gina
dc.contributor.authorMagliocco, Mary
dc.contributor.authorBarron, Karyl
dc.contributor.authorDanielson, Jeffrey
dc.contributor.authorPetrov, Lev
dc.contributor.authorUnterwalder, Nadine
dc.contributor.authorSawitzk,i Birgit
dc.contributor.authorMatz, Mareen
dc.contributor.authorLehmann, Katrin
dc.contributor.authorGratop, Alexander
dc.contributor.authorVon Bernuth, Horst
dc.contributor.authorBurkhardt, Lisa
dc.contributor.authorWiese, Niklas
dc.contributor.authorPeter, Lena
dc.contributor.authorSchmueck, Michael
dc.contributor.authorAmini, Leila
dc.contributor.authorMaurer, Marcus
dc.contributor.authorRoehmel, Jobst
dc.contributor.authorGewur, Benjamin
dc.contributor.authorYonker, Lael
dc.contributor.authorWitkowsk, Mario
dc.contributor.authorKruglov, Andrey
dc.contributor.authorMall, Marcus
dc.contributor.authorSu, Helen
dc.contributor.authorOzen, Seza
dc.contributor.authorRadbruch, Andreas
dc.contributor.authorBelot, Alexandre
dc.contributor.authorDurek, Pawel
dc.contributor.authorKallinich, Tilmann
dc.contributor.authorMashregh, Mir-Farzin
dc.date.accessioned2026-08-13T16:08:13Z
dc.date.available2026-08-13T16:08:13Z
dc.date.issued2025
dc.description.abstractIn 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.
dc.description.versionVersión Publicada
dc.identifier.citationGoetzke CC, Massoud M, Frischbutter S, Guerra GM, Ferreira-Gomes M, Heinrich F, von Stuckrad ASL, Wisniewski S, Licha JR, Bondareva M, Ehlers L, Khaldi-Plassart S, Javouhey E, Pons S, Trouillet-Assant S, Ozsurekci Y, Zhang Y, Poli MC, Discepolo V, Lo Vecchio A, Sahin B, Verboom M, Hallensleben M, Heuhsen AI, Astudillo C, Espinosa Y, Vial Cox MC, Dobbs K, Delmonte OM, Montealegre Sanchez GA, Magliocco M, Barron K, Danielson J, Petrov L, Unterwalder N, Sawitzki B, Matz M, Lehmann K, Gratopp A, von Bernuth H, Burkhardt LM, Wiese N, Peter L, Schmueck-Henneresse M, Amini L, Maurer M, Roehmel JF, Gewurz BE, Yonker LM, Witkowski M, Kruglov A, Mall MA, Su HC, Ozen S, Radbruch A, Belot A, Durek P, Kallinich T, Mashreghi MF. TGFβ links EBV to multisystem inflammatory syndrome in children. Nature. 2025 Apr;640(8059):762-771. doi: 10.1038/s41586-025-08697-6.
dc.identifier.doihttps://doi.org/10.1038/s41586-025-08697-6
dc.identifier.urihttps://hdl.handle.net/11447/11008
dc.language.isoen
dc.subjectEpstein-Barr Virus Infections / complications
dc.subjectEpstein-Barr Virus Infections / virology Female Herpesvirus
dc.subjectHuman / immunology Herpesvirus
dc.subjectHuman / physiology
dc.subjectSARS-CoV-2 / immunology
dc.subjectTransforming Growth Factor beta / immunology
dc.titleTGFβ links EBV to multisystem inflammatory syndrome in children
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceNature
dspace.entity.typePublication
relation.isAuthorOfPublicationbf711dbf-cd6f-4a66-97fb-64c15f664de3
relation.isAuthorOfPublication.latestForDiscoverybf711dbf-cd6f-4a66-97fb-64c15f664de3

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