Abstract
Survival of various immune cell populations has been proposed to preferentially rely on a particular anti-apoptotic BCL-2 family member, for example, naive T cells require BCL-2, while regulatory T cells require MCL-1. Here we examined the survival requirements of multiple immune cell subsets in vitro and in vivo, using both genetic and pharmacological approaches. Our findings support a model in which survival is determined by quantitative participation of multiple anti-apoptotic proteins rather than by a single anti-apoptotic protein. This model provides both an insight into how the sum of relative levels of anti-apoptotic proteins BCL-2, MCL-1 and A1 influence survival of T cells, B cells and dendritic cells, and a framework for ascertaining how these different immune cells can be optimally targeted in treatment of immunopathology, transplantation rejection or hematological cancers.
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Acknowledgements
We thank M Dayton, M Iliopoulos, T Mason, H Johnson and M Hancock for technical assistance. This work was supported by Rebecca L. Cooper Foundation, National Health and Medical Research Council of Australia (NHMRC) grants and fellowships #1037321, #1043414, #1080321 and #1105209 to AML, #461221 and #1042629 to PB, #1020363 and #1016701 to AS, #1054925 and #1060675 to DT, #1016647 to JGZ, #1049720 to MH, the Leukemia and Lymphoma Society (LLS) Specialized Center of Research grant (#7001-13 to AS), Cancer Council Victoria (CCV) Grant-in-aid (#1102104 to AS), Austrian Academy of Science (ÖAW) Doc-fellowship (to MH), Leukemia Foundation National Research Program PhD Scholarship (to RS), NHMRC Independent Research Institutes Infrastructure Support Scheme grant (361646) and Victorian State Government Operational Infrastructure Support grant. We acknowledge the Wurundjeri people of the Kulin nation as the traditional owners and custodians of the land on which most of the work was performed.
Author contributions
Designed research: EMC, AML, IBV, DMT, JGZ and YZ. Performed research: EMC, JLB, JGZ and RMS. Contributed vital new reagents or analytical tools: NSA, RLS, MJH, RBD, NDH, DS, DCSH, SC, PB and AS. Collected, analyzed and interpreted data: EMC, JLB, JGZ, RMS and AML. Wrote the manuscript: EMC, AML, AS, DMT, SC and YZ.
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All relevant authors are employees of The Walter and Eliza Hall Institute. This institute receives milestone payments for the development of BH3 mimetic drugs for therapy from Genentech and AbbVie.
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Carrington, E., Zhan, Y., Brady, J. et al. Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo. Cell Death Differ 24, 878–888 (2017). https://doi.org/10.1038/cdd.2017.30
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DOI: https://doi.org/10.1038/cdd.2017.30
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