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

Abstract

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.

• Authors: Benjamin Fournier, Akihiro Hoshino, Julie Bruneau, Camille Bachelet, Mathieu Fusaro, Roman Klifa, Romain Lévy, Christelle Lenoir, Claire Soudais, Capucine Picard, Stéphane Blanche, Martin Castelle, Despina Moshous, Thierry Molina, Anne-Sophie Defachelles, Bénédicte Neven, Sylvain Latour
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 219 Issue 7 (07 04 2022) ISSN: 1540-9538 [Electronic] United States
• PMID: 35657354 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Fournier et al.

Chemical References

• 4-1BB Ligand
• TNFSF9 protein, human

Topics

• 4-1BB Ligand
• B-Lymphocytes
• Epstein-Barr Virus Infections
• Herpesvirus 4, Human
• Humans
• Smooth Muscle Tumor (genetics, metabolism, pathology)
• T-Lymphocytes