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