Epstein-Barr virus-infected tonsillar marginal zone B cells in vivo as a precursor for immunosuppression-related...

The germinal center model (GCM) of Epstein-Barr virus (EBV) persistence in humans proposes that EBV infects and drives naïve B cells through the GC to establish a quiescent lifelong persistent infection in memory B cells. EBV causes several cancers, and the normal in vivo counterparts of major EBV-associated cancers have been identified in the GCM. Yet, the normal in vivo counterparts of immunosuppression-related/immunoblastic B-cell lymphoma (IL), which occurs in immunosuppressed transplant and HIV patients and resembles lymphoblastoid cell lines (LCLs), remain elusive. We performed a comparative analysis of human tonsillar B cells to identify the closest normal in vivo counterparts of ILs/LCLs. Here we show that EBV-infected tonsillar marginal zone (MZ) B cells, which are GC-independent, are the closest in vivo correlates of ILs/LCLs. Like LCLs, EBV-infected MZ B cells express the EBV growth program, which includes high expression of the oncogenic LMP1 and the DNA-mutating enzyme activation-induced cytidine deaminase (AID), in the absence of the transcription factor BCL6. Furthermore, these EBV-infected MZ B cells are proliferating extensively and are Ki67⁺. AID expression, rapid proliferation, and LMP1 expression put these cells at high risk for tumor development. Of therapeutic importance, the high expression of LMP1 could prove to be the Achilles' heel of IL/LCL-like EBV-infected MZ B cells to be targeted. Consequently, we now propose that there are two pathways of EBV persistence in vivo: (i) the established GC model and (ii) the GC-independent MZ model, and EBV-infected MZ B cells are plausibly the in vivo precursors of IL.IMPORTANCEEpstein-Barr virus (EBV) causes several cancers, and the normal counterparts of major EBV-associated cancers have been identified in the germinal center model (GCM) of EBV persistence in humans. We searched for the normal in vivo counterparts of immunoblastic B-cell lymphoma (IL) that occurs in immunosuppressed individuals. IL resembles in vitro EBV-infected B cells driven by EBV to become indefinitely proliferating lymphoblastoid cell lines (LCLs). Here, we demonstrate that EBV-infected tonsillar marginal zone (MZ) B cells, which are GC-independent, are the in vivo correlates of LCLs/ILs and the plausible precursors of IL in humans. EBV-infected MZ B cells express the EBV growth program with high expression of the oncogenic LMP1 and the DNA-mutating enzyme AID and are proliferating extensively. AID expression, rapid proliferation, and LMP1 expression put these cells at high risk for cancer development. Clinical interventions that target LMP1-expressing MZ B cells should dramatically decrease the incidence of IL.