Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of E mu LMP2A transgenic mice

Latent membrane protein 2A (LMP2A) is one of only two viral proteins expres sed 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 tryosine kinases. Five genetically un ique LMP2A transgenic mouse lines (E mu LMP2A) with B-cell lineage expressi on of LMP2A were generated in this study to analyze the importance of LMP2A expression in vivo. These animals can be grouped into E mu LMP2A(BCR+) (Tg B, Tg6, and TgC) and E mu LMP2A(BCR-) (Tg7 and TgE) lines based on B-cell p henotype. LMP2A expression in bone marrow cells of E mu LMP2A(BCR-) lines w as associated with a bypass of normal beta-lymphocyte developmental checkpo ints inasmuch as immunoglobulin light-chain gene rearrangement occurred in the absence of complete immuno globulin heavy-chain gene rearrangement. The resulting BCR-negative B cells were able to exit the bone marrow and colon ize peripheral lymphoid organs. LMP2A expression in E mu LMP2A(BCR+) lines was not associated with altered B-cell development in a genetically wild-ty pe background. When crossed into a recombinase activating null (RAG(-/-)) g enetic background, LMP2A expression in either RAG(-/-) E mu LMP2A(BCR+) or RAG-/- E mu LMP2A(BCR-) animals was able to provide a survival signal to BC R negative splenic B cells. Additionally, bone marrow cells from all E mu L MP2A animals were able to proliferate in response to interleukin-7-dependen t developmental signals in vitro. These studies illustrate that LMP2A can p ro,ide a survival signal to BCR negative B cells in two different groups of E mu LMP2A transgenic mice.