BLyS: The Pivotal Determinant of Peripheral B Cell Selection and Lifespan

The mechanisms that maintain a steady state pool of B cells that is adequately diverse yet devoid of autoreactivity remain poorly understood. B cells are generated throughout life from pluripotent stem cells and transit a series of phenotypically and functionally defined subsets prior to final maturation in the periphery. Kinetic analyses of these subsets have revealed that considerable cell losses occur during late stages of B cell differentiation, such that only a fraction of newly formed B cells survive to join the mature peripheral pool. These losses reflect the aggregate of negative selection against autoreactive clonotypes and the positive selection of specificities. Because B cell genesis in the marrow is not coupled to peripheral numbers and most mature B ells are quiescent, homeostatic control of the peripheral pool relies largely upon the proportion of B cells that complete maturation and the lifespan of mature B cells. The newly discovered TNF family member, BLySä2, plays a critical role in the maturation, selection and survival of B cells. In these capacities, BLyS acts primarily through the Bcmd / BR3 receptor, affording B cell survival at least in part through the regulation of Bcl-2 family members via NFk-B mediated mechanisms. Recent evidence suggests that Bcmd / BR3 receptor expression is controlled by B cell antigen receptor signaling, forging a mechanistic link between specificity based selection and BLyS mediated survival. Our rapidly expanding understanding of BLyS and its receptors may eventually afford novel pharmacologic strategies aimed at the direct manipulation of peripheral B cell selection and homeostasis.