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 von Stuckrad, Sebastian Wisniewski, Jan Robin Licha, Marina Bondareva, Lisa Ehlers, Samira Khaldi-Plassart, Étienne Javouhey, Sylvie Pons, Sophie Trouillet‐Assant, Yasemin Özsürekçi, Yu Zhang, M. Cecilia Poli, Valentina Discepolo, Andrea Lo Vecchio, Bengü Sahin, Murielle Verboom, Michael Hallensleben, Anja Isabelle Heuhsen, Camila Astudillo, Yazmín Espinosa, Maria Cecilia Vial Cox, Kerry Dobbs, Ottavia M. Delmonte, Gina A. Montealegre Sanchez, Mary Magliocco, Karyl S. Barron, Jeffrey J. Danielson, L. A. Petrov, Nadine Unterwalder, Birgit Sawitzki, Mareen Matz, Katrin Lehmann, Alexander Gratopp, Horst von Bernuth, Lisa-Marie Burkhardt, Niklas Wiese, Lena Peter, Michael Schmueck‐Henneresse, Leila Amini, Marcus Maurer, Jobst Roehmel, Benjamin E. Gewurz, Lael M. Yonker, Mario Witkowski, Andrey Kruglov, Marcus Mall, Helen C. Su, Seza Özen, Andreas Radbruch, Alexandre Bélot, Pawel Durek, Tilmann Kallinich, Mir‐Farzin Mashreghi
Abstract
Abstract 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.