Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Journal of Experimental Medicine Année : 2022

Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors

Julie Bruneau
Roman Klifa
Romain Lévy

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.
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Dates et versions

hal-03864154 , version 1 (21-11-2022)

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Benjamin Fournier, Akihiro Hoshino, Julie Bruneau, Camille Bachelet, Mathieu Fusaro, et al.. Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors. Journal of Experimental Medicine, 2022, 219 (7), ⟨10.1084/jem.20211682⟩. ⟨hal-03864154⟩
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