Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner
AuthorLiu, R; King, A; Bouillet, P; Tarlinton, DM; Strasser, A; Heierhorst, J
Source TitleFrontiers in Immunology
PublisherFRONTIERS MEDIA SA
University of Melbourne Author/sBouillet, Philippe; Strasser, Andreas; Heierhorst, Jorg; King, Ashleigh
AffiliationMedical Biology (W.E.H.I.)
Medicine (St Vincent's)
Document TypeJournal Article
CitationsLiu, R., King, A., Bouillet, P., Tarlinton, D. M., Strasser, A. & Heierhorst, J. (2018). Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner. FRONTIERS IN IMMUNOLOGY, 9 (MAR), https://doi.org/10.3389/fimmu.2018.00592.
Access StatusOpen Access
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 of Bim results 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 of Bim during early development (i.e., in pro-B cells using Mb1-Cre) or during the final differentiation steps (i.e., in transitional B cells using Cd23-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 germline Bim-deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro, conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc-driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. 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.
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