Abstract
Appropriate control of apoptosis during T lymphocyte differentiation is critical for destruction of T cells bearing potentially autoreactive or useless immuno-receptors and for survival of those T cells bearing antigen receptors that may recognize foreign proteins. Despite the well-established importance of thymocyte survival, the exact signals regulating thymocyte apoptosis have not been fully elucidated. Here, we show that thymocytes lacking the endoplasmic reticulum protein calcium-modulating cyclophilin ligand (CAML) failed to undergo normal T-cell development and exhibited dramatically increased rates of apoptosis. In vitro, CAML-deficient thymocytes accumulated high levels of reactive oxygen species (ROS) and underwent abnormally accelerated death in response to several cytotoxic stimuli, including treatment with etoposide, cytokine deprivation, or Fas ligation. Although neither p53 deletion nor loss of Fas rescued the survival and continued development of CAML-deficient thymocytes, removal of the pro-apoptotic BH3-only Bcl-2 family member Bim significantly restored their survival. This work reveals CAML to be a critically important regulator of ROS- and Bim-dependent thymocyte death.
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Abbreviations
- CAML:
-
calcium-modulating cyclophilin ligand
- ROS:
-
reactive oxygen species
- Bim:
-
Bcl-2-interacting mediator of cell death
- MOMP:
-
mitochondrial outer membrane permeabilization
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Acknowledgements
Reagents and mice were kindly provided by Drs Chella David, Virginia Shapiro, and Jan VanDeurson. This work was supported by the National Institute of Heath (grant 2RO1AI074320) (RJB), the Mayo Foundation (RJB), Joseph Bloom Children's Disease Research (RJB), NIH training grant T32 AI07425-14 (CE), and the Australian NHMRC (program 461221, fellowship 461229).
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Edgar, C., Lindquist, L., McKean, D. et al. CAML regulates Bim-dependent thymocyte death. Cell Death Differ 17, 1566–1576 (2010). https://doi.org/10.1038/cdd.2010.30
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DOI: https://doi.org/10.1038/cdd.2010.30
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