TGFβ links EBV to multisystem inflammatory syndrome in children
Abstract
Abstract In 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.
Article Details
Authors (59)
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
Etienne Javouhey
Sylvie Pons
Sophie Trouillet-Assant
Yasemin Ozsurekci
Yu Zhang
Xiangya Hospital, Central South University Changsha China
Maria Cecilia Poli
Valentina Discepolo
Andrea Lo Vecchio
Bengü Sahin
Murielle Verboom
Michael Hallensleben
Anja Isabelle Heuhsen
Camila Astudillo
Yazmin Espinosa
Maria Cecilia Vial Cox
Kerry Dobbs
Ottavia M. Delmonte
Gina A. Montealegre Sanchez
Mary Magliocco
Karyl Barron
Jeffrey Danielson
Lev 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 Fridolin Roehmel
Benjamin E. Gewurz
Lael M. Yonker
Mario Witkowski
Andrey Kruglov
Marcus Alexander Mall
Helen C. Su
Seza Ozen
Andreas Radbruch
Alexandre Belot
Pawel Durek
Tilmann Kallinich
Mir-Farzin Mashreghi