An investigation of the contribution of LMP1 to the differentiation of germinal centre B cells

The latent membrane protein 1 (LMP1) of the Epstein Barr virus (EBV) is believed to be important for the transformation of germinal centre (GC) B cells which may contribute to the development of EBV associated lymphomas, such as Hodgkin´s lymphoma. When expressed in GC B cells, LMP1 induces transcriptional changes that show a striking overlap with those induced in the same cells by the B lymphocyte-induced maturation protein-1 (BLIMP1), a key transcription factor that
is essential for plasma cell differentiation. For example, LMP1 and BLIMP1 coordinately regulate 230 genes, including the B cell differentiation-associated transcription factors, BCL6, PAX5 and IRF4. However, this mimicry is only partial, as unlike LMP1, BLIMP1 does not up-regulate the anti-apoptotic gene BCL2A1 or the chemokine CCL22. In addition, a proposed function of LMP1 is the up-regulation of the inhibitor of DNA binding 2 (ID2), which can inhibit PAX5 mediated maintenance of B cell identity. However, ID2 is not regulated by BLIMP1. Furthermore, the similarity between LMP1 and BLIMP1 targets is not a simple consequence of BLIMP1 up-regulation by LMP1. Additionally, LMP1 down-regulates BLIMP1 in GC B cells. Our data suggest that while LMP1-expressing cells are driven into the post-GC stages of B cell differentiation, they fail to induce BLIMP1 and so are prevented from completing plasma cell differentiation.
Given that plasma cell differentiation is associated with induction of the virus replicative cycle, then the LMP1-mediated disruption of this process could facilitate viral persistence.