These results confirm the observations made by Nemazee and colleagues, who showed that receptor editing in the spleen is marginal and that IgD-positive T2 cells undergo apoptosis upon BCR cross-linking 36. Collectively, our results suggest that BAFF-R expression is regulated by BCR signaling and that the outcome of BCR signaling on BAFF-R expression is B-cell developmental stage dependent, namely a down-modulation on immature B cells

and up-regulation on mature B cells. Recently, Dabrafenib cost we could show that expression of BAFF-R on mature B cells is required for their maintenance and not only for their development beyond transitional type 1 B cells 20. This suggests that for survival, mature B cells do not

rely on surface expression of BCR alone 37. As already mentioned, triggering of both receptors mediates activation of NF-κB, suggesting a potential and elegant mechanism for B cells to determine their lifespan also within the mature compartment. Up-regulation of BAFF-R upon BCR ligation could ensure only on mature B cells an increased survival and allow them to undergo the necessary final differentiation stages within the B-cell follicles. Findings in support of this assumption come from the observations made in mice lacking both Rac-1 and Rac-2. Such mice have defective BCR signaling, resulting in diminished numbers of splenic B cells, but normal numbers of BM B cells. Furthermore, this impaired BCR signaling also leads to reduced levels of BAFF-R, pointing to a direct regulation of BAFF-R expression by BCR signaling via the Rac-1 and Rac-2 pathway 38. Collectively, we suggest a mechanism PI3K Inhibitor Library concentration by which BAFF-BAFF-R signaling determines the survival acetylcholine time window for B cells beyond the immature B-cell stage, and in particular upon rearrangement and expression of their BCR. The tight control of surface BAFF-R expression by BCR ligation according to the developmental stage supports our hypothesis. Thus, B cells can exploit the same signaling mechanisms for two different outcomes according to the biological requirements, namely reduced survival/deletion of auto-reactive B cells

within immature B cells and increased survival within mature B cells. In addition, our data allowed us to link mouse and human B-cell biology in regard to BAFF-R expression. In both species, BAFF-R expression starts at the immature B-cell stage and a correlation exists between BAFF-R and surface IgM expression, suggesting that for human B cells as well, the BCR is controlling BAFF-R up-regulation. Moreover, we show that recombination, by means of RAG2 expression, is almost exclusively confined to the BAFF-R negative fraction. Thus, for immature B cells in the mouse, BAFF-R expression is induced on positively selected cells. Female C57BL/6 mice were purchased from RCC (Füllinsdorf). Mice were used at 6–8 weeks of age.