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<p>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, <i>TNFRSF9</i> (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 <i>TNFRSF9</i> 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 <i>TNFRSF9</i> deficiency, correlating with clinical improvement and paving the way for future gene therapy strategies for this IEI.</p>

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Somatic reversion in CD137 deficiency correlating with Epstein-Barr virus control and clinical improvement

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Laura Batlle-Masó,
  • Joan Padrosa Pulido,
  • Anna Esteve-Codina,
  • Janire Perurena-Prieto,
  • Clara Franco-Jarava,
  • Aina Aguiló-Cucurull,
  • Mónica Martínez-Gallo,
  • Cristina Cea,
  • Marta Rodriguez-Aliberas,
  • Pere Soler-Palacín,
  • Ferran Casals,
  • Sara Redondo Velao,
  • Montserrat Torrent,
  • Laia Alsina,
  • Roger Colobran

摘要

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.