Peripheral B cell selection and homeostasis.

The size and makeup of mature B cell compartments are controlled by the proportion of immature B cells that complete differentiation, coupled with the average lifespan of mature B cells. Thus, determining the selective and homeostatic factors controlling these parameters is key to understanding how the B cell repertoire is established and maintained. Our previous work defined the developmental stages spanning immature B cell formation in the marrow and final maturation in the periphery. More recently, we have focused on the molecular basis for survival and differentiation within these developmental subsets, with emphasis on the role of BLyS and BLyS receptors. Through developmental and kinetic studies in normal and mutant mice, we have found that BLyS controls peripheral 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 follicular B cell lifespan. Ongoing studies are aimed at determining the mechanism of BLyS activity in these subsets, as well as how BLyS responsiveness is integrated with BcR signaling. Additionally, we have begun studies on how these selective and homeostatic processes change with age. Our results indicate that the size and dynamics of most B cell subsets shift with age, suggesting age-associated alterations in both intrinsic and microenvironmental factors that govern these processes.