TGFβ links EBV to multisystem inflammatory syndrome in children

Journal
Nature
ISSN
0028-0836
Date Issued
2025-03-12
Author(s)
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
Valentina Discepolo
Andrea Lo Vecchio
Bengü Sahin
Murielle Verboom
Michael Hallensleben
Anja Isabelle Heuhsen
Camila Astudillo
Yazmin Espinosa
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
Type
journal-article
DOI
URL
Abstract
<jats:title>Abstract</jats:title>
<jats:p>In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock<jats:sup>1</jats:sup> 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<jats:sup>2</jats:sup> and systemic hyperinflammation<jats:sup>3</jats:sup>. 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. <jats:sup>4,5</jats:sup>). 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.</jats:p>
Project(s)
Dataset(s)
Subjects
adolescent

; 

b-lymphocytes

; 

child

; 

child

; 

preschool

; 

covid-19

; 

epstein-barr virus infections

; 

female

; 

herpesvirus 4

; 

human

; 

humans

; 

immunologic memory

; 

male

; 

monocytes

; 

pediatric multisystem inflammatory disease

; 

covid-19 related

; 

sars-cov-2

; 

systemic inflammatory response syndrome

; 

t-lymphocytes

; 

transforming growth factor beta

; 

virus activation

; 

t lymphocyte receptor

; 

transforming growth factor beta

; 

transforming growth factor beta

; 

cell component

; 

covid-19

; 

infectious disease

; 

protein

; 

serum

; 

severe acute respiratory syndrome

; 

virus

; 

article

; 

b lymphocyte

; 

blood sampling

; 

cell isolation

; 

child

; 

controlled study

; 

coronavirus disease 2019

; 

cytotoxicity

; 

disease severity

; 

dna extraction

; 

epstein barr virus

; 

flow cytometry

; 

follow up

; 

gene expression

; 

gene set enrichment analysis

; 

genotyping

; 

haplotype

; 

hek293t cell line

; 

high throughput sequencing

; 

human

; 

human cell

; 

hyperinflammation

; 

memory t lymphocyte

; 

monocyte

; 

pediatric multisystem inflammatory syndrome

; 

peripheral blood mononuclear cell

; 

polymerase chain reaction

; 

protein expression

; 

public health service

; 

real time polymerase chain reaction

; 

seroprevalence

; 

single cell rna seq

; 

t lymphocyte

; 

transcriptome sequencing

; 

virus reactivation

; 

virus reactive memory t cell

; 

western blotting

; 

adolescent

; 

blood

; 

complication

; 

coronavirus disease 2019

; 

epstein barr virus infection

; 

female

; 

immunological memory

; 

immunology

; 

male

; 

metabolism

; 

pathology

; 

physiology

; 

preschool child

; 

severe acute respiratory syndrome coronavirus 2

; 

systemic inflammatory response syndrome

; 

virology

; 

virus activation