Peripheral B-cell maturation: the intersection of selection and homeostasis.

B cells complete maturation after migrating to the periphery, where they transit several intermediate developmental stages prior to recruitment into the long-lived primary pool. Because B-lineage commitment is not regulated by peripheral pool size and most peripheral B cells are quiescent, the primary factors governing steady-state numbers are the proportion of immature B cells surviving transit through later developmental stages and the longevity of mature B cells themselves. Substantial evidence indicates that the B-cell receptor (BCR) plays an essential role in all these processes, but recent findings suggest a central role for the recently described tumor necrosis factor (TNF) family member, B-lymphocyte stimulator (BLyS). Signaling through one of the BLyS receptors, BLyS receptor 3 (BR3), controls B-cell numbers in two ways: by varying the proportion of cells that complete transitional B-cell development and by serving as the primary determinant of mature B-cell longevity. The recent discovery that BCR signaling is selectively coupled to BR3 expression in a developmentally regulated fashion links BCR- and BLyS-mediated events, suggesting that specificity-based selection and survival may be mechanistically similar processes.