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

• Published in: The Journal of experimental medicine Vol. 219; no. 7
• Main Authors: Fournier, Benjamin, Hoshino, Akihiro, Bruneau, Julie, Bachelet, Camille, Fusaro, Mathieu, Klifa, Roman, Lévy, Romain, Lenoir, Christelle, Soudais, Claire, Picard, Capucine, Blanche, Stéphane, Castelle, Martin, Moshous, Despina, Molina, Thierry, Defachelles, Anne-Sophie, Neven, Bénédicte, Latour, Sylvain
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.07.2022
• Subjects: 4-1BB Ligand; B-Lymphocytes; Brief Definitive Report; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Human Disease Genetics; Humans; Immunodeficiency; Life Sciences; Smooth Muscle Tumor - genetics; Smooth Muscle Tumor - metabolism; Smooth Muscle Tumor - pathology; T-Lymphocytes; Tumor Immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20211682

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.