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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\u2013CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.<\/jats:p>","DOI":"10.1084\/jem.20211682","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T13:30:00Z","timestamp":1654263000000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Inherited TNFSF9 deficiency causes broad Epstein\u2013Barr virus infection with EBV+ smooth muscle tumors"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4189-996X","authenticated-orcid":true,"given":"Benjamin","family":"Fournier","sequence":"first","affiliation":[{"name":"Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale UMR 1163, Paris, France 1"},{"name":"Paris Cit\u00e9 University, Imagine Institute, Paris, France 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