Epstein-Barr Virus LMP2A-Induced B-Cell Survival in Two Unique Classes of EμLMP2A Transgenic Mice

Abstract

ABSTRACT Latent membrane protein 2A (LMP2A) is one of only two viral proteins expressed during latent Epstein-Barr virus (EBV) infections in human peripheral B cells. LMP2A blocks B-cell receptor (BCR) signal transduction in vitro by modulation of the Syk and Lyn protein tyrosine kinases. Five genetically unique LMP2A transgenic mouse lines (EμLMP2A) with B-cell lineage expression of LMP2A were generated in this study to analyze the importance of LMP2A expression in vivo. These animals can be grouped into EμLMP2A BCR+ (TgB, Tg6, and TgC) and EμLMP2A BCR− (Tg7 and TgE) lines based on B-cell phenotype. LMP2A expression in bone marrow cells of EμLMP2A BCR− lines was associated with a bypass of normal B-lymphocyte developmental checkpoints inasmuch as immunoglobulin light-chain gene rearrangement occurred in the absence of complete immunoglobulin heavy-chain gene rearrangement. The resulting BCR-negative B cells were able to exit the bone marrow and colonize peripheral lymphoid organs. LMP2A expression in EμLMP2A BCR+ lines was not associated with altered B-cell development in a genetically wild-type background. When crossed into a recombinase activating null (RAG −/− ) genetic background, LMP2A expression in either RAG −/− EμLMP2A BCR+ or RAG −/− EμLMP2A BCR− animals was able to provide a survival signal to BCR-negative splenic B cells. Additionally, bone marrow cells from all EμLMP2A animals were able to proliferate in response to interleukin-7-dependent developmental signals in vitro. These studies illustrate that LMP2A can provide a survival signal to BCR-negative B cells in two different groups of EμLMP2A transgenic mice.