B-cell maintenance, response and surveillance (ML11)

B-cell maintenance depends on two key survival signals, one delivered through the BAFF receptor, the other through the B cell antigen receptor (BCR). While it is undisputed that the BAFF receptor signals through the alternative NF-κB signaling pathway, the nature of the BCR-mediated survival signal is controversial. Recent evidence shows, however, that the BCR signals mature B-cell survival through the PI3K pathway (Srinivasan et al., 2009). BCR-dependent PI3K activation is also required for the mitogenic response of B-cells to ligands binding innate receptors like TLRs and CD40. This receptor crosstalk integrates mechanisms of innate and adaptive immunity in the B-cell response. Epstein-Barr-Virus (EBV), a B-cell transforming herpes virus endemic in human populations worldwide, uses the BCR-dependent survival signal and CD40 co-stimulation for its interference with B cell physiology, in that the EBV proteins LMP2A and LMP1 mimic a constitutively active BCR and CD40 co-receptor, respectively. Thus, LMP2A, whose prime activity is PI3K activation, can drive B-cell development and homeostasis in mice as efficiently as the BCR. In the case of LMP1, however, B-cell specific expression induces an immune surveillance mechanism, through which LMP1-expressing B-cells are eliminated by T- and NK-cells, akin to the immune elimination of EBV-infected cells in humans. Evidence will be presented that when this surveillance mechanism is compromised, LMP1-driven B-cell lymphomas rapidly arise in transgenic mice as a fatal disease. Thus, conditional expression of a single EBV protein, LMP1, models the immune surveillance of EBV-infected cells and EBV-driven B-cell lymphomagenesis, establishing a pre-clinical model for therapeutic intervention.