Somatic reversion in CD137 deficiency correlating with Epstein-Barr virus control and clinical improvement
Batlle-Masó, Laura (Hospital Universitari Vall d'Hebron)
Padrosa Pulido, Joan (Hospital Clínic i Provincial de Barcelona)
Esteve-Codina, Anna (Universitat de Barcelona)
Perurena-Prieto, Janire (Hospital Universitari Vall d'Hebron)
Franco-Jarava, Clara (Laboratori Clínic ICS Camp de Tarragona)
Aguiló-Cucurull, Aina (Hospital Universitari Vall d'Hebron)
Martínez Gallo, Mónica (Hospital Universitari Vall d'Hebron)
Cea López, Cristina (Hospital Universitari Vall d'Hebron)
Rodriguez-Aliberas, Marta (Universitat Autònoma de Barcelona. Banc de Sang i Teixits)
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron)
Casals, Ferran (Institut de Recerca Sant Joan de Déu)
Redondo, Sara (Institut de Recerca Sant Pau)
Torrent, Montserrat (Institut de Recerca Sant Pau)
Alsina Manrique, Laia (Universitat de Barcelona)
Colobrán Oriol, Roger (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona. Departament de Medicina

Date:	2025
Abstract:	Epstein-Barr virus (EBV) is an oncogenic virus ubiquitous in human populations. CD8 T cells play a crucial role in establishing a strong anti-EBV immune response. Among the various inborn errors of immunity (IEI) showing a restricted vulnerability to EBV, TNFRSF9 (CD137, 4-1BB) deficiency was described in 2019 in patients with chronic EBV viremia and EBV-associated lymphoproliferative diseases. We here investigated a patient with a history of chronic EBV infection and CD137 deficiency who had previously undergone transplantation from her HLA-identical brother. We found that the brother was also a homozygous carrier of the same TNFRSF9 variant, explaining the patient's inability to control EBV after transplantation. Remarkably, during a period of spontaneous clinical improvement and EBV control, we detected two somatic variants in the patient, which resulted in the emergence of two independent revertant CD8 T cell clones that accounted for up to 20% of CD8 T cells in peripheral blood. Using single cell RNA sequencing we demonstrated that both revertant clones originated post-transplant from donor-derived cells. We report here the first described case of a somatic reversion phenomenon in TNFRSF9 deficiency, correlating with clinical improvement and paving the way for future gene therapy strategies for this IEI.
Grants:	Instituto de Salud Carlos III PI20/00761 Instituto de Salud Carlos III PI23/00161 Agencia Estatal de Investigación PID2021-125106OB-C32
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Primary immunodeficiency disorders ; Viral infection ; Immunogenetics ; Molecular medicine
Published in:	npj genomic medicine, Vol. 10 (November 2025) , art. 78, ISSN 2056-7944

DOI: 10.1038/s41525-025-00535-y
PMID: 41315311

8 p, 1.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles