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 |
---|---|
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
-
NHMRC Principal Research Fellowship
Tarlinton, D. (Primary Chief Investigator (PCI))
National Health and Medical Research Council (NHMRC) (Australia)
11/01/16 → 31/12/19
Project: Research
-
A Systems Approach to the Adaptive Immune Response
Hodgkin, P. D. (Primary Chief Investigator (PCI)), Corcoran, L. M. (Chief Investigator (CI)), Tarlinton, D. (Chief Investigator (CI)), Belz, G. (Chief Investigator (CI)) & Nutt, S. L. (Chief Investigator (CI))
1/01/14 → 31/12/18
Project: Research
-
Apoptosis and stem cells in cancer development and therapy
Gerondakis, S. (Primary Chief Investigator (PCI)), Adams, J. M. (Chief Investigator (CI)), Bouillet, P. (Chief Investigator (CI)), Colman, P. G. (Chief Investigator (CI)), Cory, S. (Chief Investigator (CI)), Huang, D. (Chief Investigator (CI)), Kluck, R. (Chief Investigator (CI)), Lindeman, G. (Chief Investigator (CI)), Strasser, A. (Chief Investigator (CI)), Vaux, D. (Chief Investigator (CI)) & Visvader, J. E. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/12 → 31/12/16
Project: Research