Inherited TNFSF9 deficiency causes broad Epstein-Barr virus infection with EBV+ smooth muscle tumors.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
04 07 2022
04 07 2022
Historique:
received:
06
08
2021
revised:
16
03
2022
accepted:
25
04
2022
entrez:
3
6
2022
pubmed:
4
6
2022
medline:
9
6
2022
Statut:
ppublish
Résumé
Epstein-Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137-CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.
Identifiants
pubmed: 35657354
pii: 213262
doi: 10.1084/jem.20211682
pmc: PMC9170382
pii:
doi:
Substances chimiques
4-1BB Ligand
0
TNFSF9 protein, human
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Centre National de la Recherche Scientifique
Organisme : Fondation pour la Recherche Médicale
ID : FDM20170638301
Organisme : Ligue Contre le Cancer
Organisme : Institut National de la Santé et de la Recherche Médicale
Organisme : Agence Nationale de Recherche
ID : ANR-18-CE15-0025-01
Organisme : Institut National du Cancer
ID : PLBIO-2020
Organisme : Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent
Organisme : Fédération Enfants et Santé
Organisme : Rare Diseases Foundation
Informations de copyright
© 2022 Fournier et al.
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