Proapoptotic BIM impacts B lymphoid homeostasis by limiting the survival of mature B cells in a cell-autonomous manner
Journal Title
Frontiers in Immunology
Publication Type
Journal Article
Abstract
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.
Publisher
Frontiers Media
WEHI Research Division(s)
Molecular Genetics Of Cancer
PubMed ID
29623080
Open Access at Publisher's Site
https://doi.org/10.3389/fimmu.2018.00592
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-04-11 08:53:37
Last Modified: 2018-04-11 09:36:58
An error has occurred. This application may no longer respond until reloaded. Reload 🗙