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

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    Author
    Liu, R; King, A; Bouillet, P; Tarlinton, DM; Strasser, A; Heierhorst, J
    Date
    2018-03-22
    Source Title
    Frontiers in Immunology
    Publisher
    FRONTIERS MEDIA SA
    University of Melbourne Author/s
    Bouillet, Philippe; Strasser, Andreas; Heierhorst, Jorg; King, Ashleigh
    Affiliation
    Medicine and Radiology
    Medical Biology (W.E.H.I.)
    Metadata
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    Document Type
    Journal Article
    Citations
    Liu, 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 Status
    Open Access
    URI
    http://hdl.handle.net/11343/254639
    DOI
    10.3389/fimmu.2018.00592
    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.

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