Loss of BIM in T cells results in BCL-2 family BH3-member compensation but incomplete cell death sensitivity normalization

Abstract

BIM is the master BH3-only BCL-2 family regulator of lymphocyte survival. To understand how long-term loss of BIM affects apoptotic resistance in T cells we studied animals with T cell-specific deletion of Bim. Unlike CD19CREBimfl/fl animals, LCKCREBimfl/fl mice have pronounced early lymphocytosis followed by normalization of lymphocyte counts over time. This normalization occurred in mature T cells, as thymocyte development and apoptotic sensitivity remained abnormal in LCKCREBimfl/fl mice. T cells from aged mice experienced normalization of their absolute cell numbers and responses against various apoptotic stimuli. mRNA expression levels of BCL-2 family proteins in CD4+ and CD8+ T cells from young and old mice revealed upregulation of several BH3-only proteins, including Puma, Noxa, and Bmf. Despite upregulation of various BH3 proteins, there were no differences in anti-apoptotic BCL-2 protein dependency in these cells. However, T cells had continued resistance to direct BIM BH3-induced mitochondrial depolarization. This study further highlights the importance of BIM in cell death maintenance in T cells and provides new insight into the dynamism underlying BH3-only regulation of T cell homeostasis versus induced cell death and suggests that CD4+ and CD8+ T cells compensate differently in response to loss of Bim.

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Acknowledgements

This work was supported by research funds from the National Institutes of Health: NCI K08-CA151450 (to J.L.L.) and the Comer Children’s Hospital Development Board, University of Chicago (to J.L.L). We would like to thank Loren Walensky for initial critical review of our manuscript.

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Correspondence to James L. LaBelle.

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Ludwig, L.M., Roach, L.E., Katz, S.G. et al. Loss of BIM in T cells results in BCL-2 family BH3-member compensation but incomplete cell death sensitivity normalization. Apoptosis 25, 247–260 (2020). https://doi.org/10.1007/s10495-020-01593-6

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Keywords

  • BCL-2
  • T cells
  • BIM
  • Apoptosis