Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice.
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 (EmuLMP2A) 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 EmuLMP2A(BCR+) (TgB, Tg6, and TgC) and EmuLMP2A(BCR-) (Tg7 and TgE) lines based on B-cell phenotype. LMP2A expression in bone marrow cells of EmuLMP2A(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 EmuLMP2A(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(-/-) EmuLMP2A(BCR+) or RAG(-/-) EmuLMP2A(BCR-) animals was able to provide a survival signal to BCR-negative splenic B cells. Additionally, bone marrow cells from all EmuLMP2A 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 EmuLMP2A transgenic mice.
Caldwell
R G
RG
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Brown
R C
RC
Longnecker
R
R
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism / Q000494:pharmacology; D019891:Leukopoiesis; D008221:Lymphoid Tissue / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology; D014158:Transcription, Genetic; D019076:Transgenes; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007075:Immunoglobulin M; D015851:Interleukin-7; D011947:Receptors, Antigen, B-Cell; D014763:Viral Matrix Proteins