EBV immortalization alters B cell repertoire dynamics

Epstein-Barr Virus (EBV), a double-stranded linear DNA gamma herpesvirus that primarily infects human B cells, causes infectious mononucleosis, lymphoma, and other cancers in humans. Immunogenetic changes in B cell populations may contribute to disease outcomes. However, despite the fact that more than 90% of the global population has been exposed to the virus, few studies have examined these changes in response to EBV infection. Here, we tested the hypothesis that EBV alters primary B cell population dynamics during immortalization. To test this hypothesis, we compared populations of primary B cells freshly isolated from three human donors (EBV-CpG-) to populations of EBV-immortalized lymphoblastoid cell lines (LCL) from the same three donors. We found that all sequenced populations shared similar general features. However, immortalized B cell populations displayed reduced IGHV gene segment and CDR H3 diversity compared to their non-immortalized B cells. Additionally, none of the clonotype repertoires in these patient populations shared features observed in EBV patients or EBV-immortalized LCL, suggesting that cell lines may represent geographical repertoires, with B cells trained on common antigens from localized regions. These results suggest that EBV-immortalization may selectively amplify geographical repertoires in patient populations in which B cell transformation has occurred, a feature that may promote patient-specific disease features and outcomes. These findings may contribute to explaining why highly general strategies for defeating EBV-induced diseases may be challenging to achieve.