Projects per year
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.
Original language | English |
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Article number | 592 |
Number of pages | 10 |
Journal | Frontiers in Immunology |
Volume | 8 |
Issue number | MAR |
DOIs | |
Publication status | Published - 22 Mar 2018 |
Keywords
- Apoptosis
- B cell lymphoma
- B lymphocytes
- BCL-2 family
- BH3-only protein
- BIM
- Cell death
Projects
- 3 Finished
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NHMRC Principal Research Fellowship
National Health and Medical Research Council (NHMRC) (Australia)
11/01/16 → 31/12/19
Project: Research
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A Systems Approach to the Adaptive Immune Response
Hodgkin, P. D., Corcoran, L. M., Tarlinton, D., Belz, G. T. & Nutt, S. L.
1/01/14 → 31/12/18
Project: Research
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Apoptosis and stem cells in cancer development and therapy
Gerondakis, S., Adams, J. M., Bouillet, P., Colman, P., Cory, S., Huang, D., Kluck, R., Lindeman, G., Strasser, A., Vaux, D. & Visvader, J.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/12 → 31/12/16
Project: Research