Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner

Rui Liu, Ashleigh King, Philippe Bouillet, David M. Tarlinton, Andreas Strasser, Jörg Heierhorst

The proapoptotic BH3-only protein BIM (Bcl2l11) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion ofBimresults in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion ofBimduring early development (i.e., in pro-B cells usingMb1-Cre) or during the final differentiation steps (i.e., in transitional B cells usingCd23-Cre) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germlineBim-deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to globalBimdeletion.In vitro, conditional loss ofBimsubstantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just oneBimallele byMb1-Credramatically accelerated the development ofMyc-driven B cell lymphoma, in a manner that was comparable to the effect of germlineBimheterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions.