Somatic reversion in CD137 deficiency correlating with Epstein-Barr virus control and clinical improvement
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.
Authors
- Pere Soler‐Palacín (ORCID: https://orcid.org/0000-0002-0346-5570)
- Aina Aguiló‐Cucurull (ORCID: https://orcid.org/0000-0001-5622-778X)
- Anna Esteve‐Codina (ORCID: https://orcid.org/0000-0003-0361-2873)
- Laia Alsina (ORCID: https://orcid.org/0000-0002-3559-0018)
- Joan Padrosa (ORCID: https://orcid.org/0000-0002-3354-5811)
- Marta Rosa Ferriol Rodríguez (ORCID: https://orcid.org/0000-0003-4426-3649)
- Laura Batlle-Masó (ORCID: https://orcid.org/0000-0002-4209-176X)
- Ferrán Casals (ORCID: https://orcid.org/0000-0002-8941-0369)
- Clara Franco‐Jarava (ORCID: https://orcid.org/0000-0002-9788-189X)
- Sara Redondo (ORCID: https://orcid.org/0000-0001-8967-7410)
- Roger Colobrán
- Mónica Martínez‐Gallo
- Janire Perurena-Prieto (ORCID: https://orcid.org/0000-0002-3048-1058)
- Cristina Cea
- Montserrat Torrent
Institutions
- Universitat Autònoma de Barcelona (ES)
- Hospital Sant Joan de Déu Barcelona (ES)
- Institut Barcelona d'Estudis Internacionals (ES)
- Hospital de Sant Pau (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Institut Botànic de Barcelona (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Hospital Clínic de Barcelona (ES)
- Institute for Research in Biomedicine (ES)
- Sant Joan de Déu Research Foundation (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Centro Nacional de Análisis Genómico (ES)
- Hospital Universitari Joan XXIII de Tarragona (ES)
- Banc de Sang i Teixits (ES)
- Jeffrey Modell Foundation (AU)
- Instituto de Investigación de Enfermedades Raras (ES)
- Institut de Recerca Sant Joan de Déu
- Universitat de Barcelona (ES)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41525-025-00535-y
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación