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

• Published in: Apoptosis (London) 2020-04, Vol.25 (3-4), p.247-260
• Main Authors: Ludwig, Lindsey M., Roach, Lauren E., Katz, Samuel G., LaBelle, James L.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; B cells; Bcl-2 protein; Bcl-2-Like Protein 11 - deficiency; Bcl-2-Like Protein 11 - genetics; Bcl-2-Like Protein 11 - metabolism; Bcl-2-Like Protein 11 - pharmacology; BIM protein; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD4 antigen; CD8 antigen; Cell Biology; Cell Death; Clonal deletion; Depolarization; Gene expression; Homeostasis; Lymphocyte Count; Lymphocytes; Lymphocytes T; Lymphocytosis; Mice; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mortality; Oncology; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA; Sensitivity; T cells; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Thymocytes - metabolism; Thymocytes - pathology; Up-Regulation; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-020-01593-6

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 CD19 CRE Bim fl/fl animals, LCK CRE Bim fl/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 LCK CRE Bim fl/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 .