B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor

One remarkable feature of the immune system is its capacity to maintain constant numbers of resting immune cells despite the complex nature of signals needed throughout development and maturation. For many years, B-cell survival was thought to rely solely on B-cell receptor (BCR) tonic signals that would trigger necessary basal survival pathways. The discovery of the tumor necrosis factor (TNF)-like ligand BAFF(B-cell activating factor belonging to the TNF family)/BLyS (B-lymphocyte stimulator) changed these views entirely, as BAFF-deficient mice lack most mature B cells, and treatment with BAFF inhibitors leads to their loss, establishing BAFF as an unappreciated key B-cell survival factor. BAFF-mediated survival signals have been mapped and signaling crosstalk with the BCR has been identified, explaining the need for both BCR- and BAFF-mediated signals for B-cell survival. However, this crosstalk only explains how BCR and BAFF signals cooperate to produce survival proteins and yet, inactivating pro-apoptotic factors such as FOXO proteins, which may be managed separately by BAFF and the BCR, has emerged as an equally important step for survival. In this review, we present new views on B-cell survival, at all stages of B-cell life, and suggest that, in most cases, survival results from the production of appropriate survival factors balanced with the adequate and timely degradation of pro-apoptotic proteins.