Memory B cell reconstitution following allogeneic haematopoietic stem cell transplantation is an EBV-associated transformation event

Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B cell system. While many allo-HSCT recipients maintain low or undetectable levels of EBV DNA post-transplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated post-transplant lymphoproliferative disease. Intriguingly this high level EBV reactivation typically arises in the first three months post-transplant, at a time when the peripheral blood contains low numbers of CD27(+) memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B cell reconstitution in a cohort of allo-HSCT patients for up to 12 months post-transplant. In patients with low or undetectable levels of EBV, the circulating B cell pool consisted predominantly of transitional and naïve cells, with a marked deficiency of CD27(+) memory cells which lasted more than twelve months. However, amongst patients with high EBV loads, there was a significant increase in both the proportion and number of CD27(+) memory B cells. Analysis of sorted CD27(+) memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B cell growth transformation, had a plasmablastic phenotype and frequently expressed the proliferation marker Ki-67. These findings suggest that high level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27(+) B lymphoblasts in the peripheral blood.