Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers

Striking cell losses occur during late B lymphocyte maturation [1-3], reflecting BcR-mediated; selection coupled with requisites for viability promoting signals [4-11]. How selection and survival cues are integrated remains unclear, but a key role for B lymphocyte stimulator (BLyS (TM); trademark of Human Genome Sciences, Inc) is suggested by its marked effects on B cell numbers and autoantibody formation [12-18] as well as the B lineage-specific expression of BLyS receptors [19-23]. Our analyses of the B cell-deficient A/WySnJ mouse have established Bcmd as a gene controlling follicular B cell life span [24-27], and recent reports show Bcmd encodes a novel BLyS receptor [23, 28, 29]. Here we show that A/WySnJ B cells are unresponsive to BLyS, affording interrogation of how Bcmd influences B cell homeostasis. Mixed marrow chimeras indicate A/WySnJ peripheral B cells compete poorly for peripheral survival. Moreover, in vivo BrdU labeling shows that (A/WySnJ x BALB/c)F-1 B cells have an intermediate but uniform life span, indicating viability requires continuous signaling via this pathway. Together, these findings establish the BLyS/Bcmd pathway as a dominant mediator of B cell survival, suggesting competition for BLyS/Bcmd signals regulates follicular B cell, numbers.