B lymphocyte stimulator promotes survival in peripheral B cells and their progenitors

B Lymphocyte Stimulator (BLyS) profoundly influences peripheral B cell homeostasis and selection. Of the three known BLyS receptors, Bcmd/BR3 plays a dominant role in maintaining peripheral B cell numbers. I have demonstrated that BLyS signaling through Bcmd/BR3 regulates peripheral B cell numbers by enhancing the success of transit across developmental subsets and by improving survival within the mature peripheral B cell pool. I have also shown that treatment with BLyS affects late transitional and mature peripheral B cell populations only, and is dependent on normal Bcmd/BR3 function. Together, these data provide a mechanism whereby BLyS mediates increased B cell numbers in vivo and establishes Bcmd/BR3 as the primary receptor for BLyS-mediated survival.; The BCR also plays a crucial role in B cell differentiation and survival. Immature B cells are targets of BCR mediated selection, and continued BCR expression is requisite for mature B cell survival. Importantly, both BCR specificity per se as well as altered BCR signaling can dictate relative advantage for peripheral survival. Given these striking parallels, I explored potential relationships between BCR signaling and BLyS responsiveness. These data show that BCR-stimulated B cells remain responsive to BLyS and exhibit increased BLyS binding capacity. This increase was shown to correlate with increased Bcmd/BR3 message expression in mature peripheral B cells and their immediate progenitors. These data, taken together with demonstrations of BLyS-based mature B cell competition in vivo, support a model whereby positive selection and mature B cell homeostasis are mediated through a common mechanism.