Abstract
The survival of quiescent T cells in the peripheral immune system is dependent on signals transmitted from the extracellular environment. The requirement for survival factors is also manifested in vitro, providing a robust system to examine molecular mechanisms underlying T-cell death. We show that peripheral T cells cultured in the absence of survival factors accumulate reactive oxygen species (ROS), upregulate BIM (Bcl-2-interacting mediator of death) and inducible nitric oxide synthase (iNOS) expression, culminating in Fas-independent neglect-induced death (NID). We have examined ROS, iNOS and cytokine modulation of T-cell NID. Antioxidants inhibit BIM induction, caspase activation and apoptosis but do not promote cell cycle entry. iNOS-deficient T cells are protected from apoptosis, implicating iNOS in the regulation of NID via suppression of Bcl-xL expression and consequent inhibition of BIM activity. Finally, we show that the prosurvival cytokine IL-7 elevates Bcl-xL expression and transcriptionally regulates iNOS but not BIM expression in T cells.
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Abbreviations
- IL-7:
-
interleukin-7
- NID:
-
neglect-induced death
- NOS:
-
nitric oxide synthase
- ROS:
-
reactive oxygen species
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Acknowledgements
We are very grateful to Satyajit Rath and Vineeta Bal (National Institute of Immunology, New Delhi) for generous access to mutant strains of mice used in this study. We acknowledge Veronica Rodrigues, Gaiti Hasan, MK Mathew and Satyajit Rath for discussion and comments on the manuscript. The work was supported by an International Senior Research Fellowship in Biomedical Science Wellcome Trust, UK and the Department of Science and Technology, India.
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Sade, H., Sarin, A. Reactive oxygen species regulate quiescent T-cell apoptosis via the BH3-only proapoptotic protein BIM. Cell Death Differ 11, 416–423 (2004). https://doi.org/10.1038/sj.cdd.4401347
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DOI: https://doi.org/10.1038/sj.cdd.4401347
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