NPJ Genom Med

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.