Journal Article

TGFβ links EBV to multisystem inflammatory syndrome in children

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

2025

Overview

In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock 1 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 2 and systemic hyperinflammation 3 . 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. Multisystem inflammatory syndrome following SARS-CoV-2 infection results from increased serum levels of TGFβ, which impairs the reactivation of virus-specific T cells.

• Publisher: Nature Publishing Group UK
• Subject: 38/109 / 38/39 / 38/90 / 38/91 / 631/250/2152/1566/1572 / 631/250/2161 / 692/699/255/2514 / 96 / Adolescent / B-Lymphocytes - immunology / B-Lymphocytes - virology / Child / Child, Preschool / COVID-19 - blood / COVID-19 - complications / COVID-19 - immunology / COVID-19 - pathology / COVID-19 - virology / Epstein-Barr Virus Infections - complications / Epstein-Barr Virus Infections - immunology / Epstein-Barr Virus Infections - virology / Female / Herpesvirus 4, Human - immunology / Herpesvirus 4, Human - physiology / Humanities and Social Sciences / Humans / Immunologic Memory / Male / Monocytes - immunology / multidisciplinary / SARS-CoV-2 - immunology / Science / Science (multidisciplinary) / Systemic Inflammatory Response Syndrome - blood / Systemic Inflammatory Response Syndrome - immunology / Systemic Inflammatory Response Syndrome - virology / T-Lymphocytes - immunology / Transforming Growth Factor beta - antagonists & inhibitors / Transforming Growth Factor beta - blood / Transforming Growth Factor beta - immunology / Transforming Growth Factor beta - metabolism / Virus Activation - immunology