Goetzke, CarlMassou, MonaFrischbutt, StefanGuerra, GabrielaFerreira, MartaHeinrich, FrederikVon Stuckra, AnneWisniewsk, SebastianLich, JanBondarev, MarinaEhler, LisaKhaldi, SamiraJavouhe, EtiennePons, SylvieTrouillet, SophieOzsurek, YaseminZhang, YuPoli Harlowe, María CeciliaDiscepolo, ValentinaLo Vecchio, AndreaSahin, BengüVerboom, MurielleHallenslebe, MichaelHeuhse, AnjaAstudillo, CamilaEspinosa, YazminVial, Maria CeciliaDobbs, KerryDelmont, OttaviaMontealegre, GinaMagliocco, MaryBarron, KarylDanielson, JeffreyPetrov, LevUnterwalder, NadineSawitzk,i BirgitMatz, MareenLehmann, KatrinGratop, AlexanderVon Bernuth, HorstBurkhardt, LisaWiese, NiklasPeter, LenaSchmueck, MichaelAmini, LeilaMaurer, MarcusRoehmel, JobstGewur, BenjaminYonker, LaelWitkowsk, MarioKruglov, AndreyMall, MarcusSu, HelenOzen, SezaRadbruch, AndreasBelot, AlexandreDurek, PawelKallinich, TilmannMashregh, Mir-Farzin2026-08-132026-08-132025Goetzke 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.https://hdl.handle.net/11447/11008In 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.enEpstein-Barr Virus Infections / complicationsEpstein-Barr Virus Infections / virology Female HerpesvirusHuman / immunology HerpesvirusHuman / physiologySARS-CoV-2 / immunologyTransforming Growth Factor beta / immunologyArticlehttps://doi.org/10.1038/s41586-025-08697-6