Abstract
FOXP3+ regulatory T (Treg) cells are essential for maintaining immunological tolerance. Given their importance in immune-related diseases, cancer and obesity, there is increasing interest in targeting the Treg cell compartment therapeutically. New pharmacological inhibitors that specifically target the prosurvival protein MCL-1 may provide this opportunity, as Treg cells are particularly reliant upon this protein. However, there are two distinct isoforms of MCL-1; one located at the outer mitochondrial membrane (OMM) that is required to antagonize apoptosis, and another at the inner mitochondrial membrane (IMM) that is reported to maintain IMM structure and metabolism via ATP production during oxidative phosphorylation. We set out to elucidate the relative importance of these distinct biological functions of MCL-1 in Treg cells to assess whether MCL-1 inhibition might impact upon the metabolism of cells able to resist apoptosis. Conditional deletion of Mcl1 in FOXP3+ Treg cells resulted in a lethal multiorgan autoimmunity due to the depletion of the Treg cell compartment. This striking phenotype was completely rescued by concomitant deletion of the apoptotic effector proteins BAK and BAX, indicating that apoptosis plays a pivotal role in the homeostasis of Treg cells. Notably, MCL-1-deficient Treg cells rescued from apoptosis displayed normal metabolic capacity. Moreover, pharmacological inhibition of MCL-1 in Treg cells resistant to apoptosis did not perturb their metabolic function. We conclude that Treg cells require MCL-1 only to antagonize apoptosis and not for metabolism. Therefore, MCL-1 inhibition could be used to manipulate Treg cell survival for clinical benefit without affecting the metabolic fitness of cells resisting apoptosis.
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Acknowledgements
We thank A. Rudensky, B. Kile, and P. Bouillet for provision of mice and D. Huang, J. Gong, and A. Kallies for reagents. We are grateful to the WEHI Flow Cytometry Laboratory and Bioservices staff for technical support (particularly H. Marks and G. Siciliano for mouse husbandry) and B. Helbert, C Young, and K. Mackwell for genotyping. This work was supported by National Health and Medical Research Council Australia (Grants or Fellowships 1089072 to CET, 1116936 to MAF, and 1078763, 1090236, 1145888, and 1158024 to DHDG), Fellowships by Swiss National Science Foundation and Novartis Foundation for Medical-Biological Research to SSG and Leukemia and Lymphoma Society (Special Centre of Research Grant 7015-18) to GK. This research was made possible by grants from the Victorian State Government Operational Infrastructure Support and the Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council.
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Researchers at the Walter and Eliza Hall Institute of Medical Research in the Strasser, Kelly, and Gray laboratories collaborate with Servier on the development of MCL-1 inhibitors. All other authors declare no conflict of interest.
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Teh, C.E., Robbins, A.K., Henstridge, D.C. et al. MCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3+ regulatory T cells. Cell Death Differ 27, 3374–3385 (2020). https://doi.org/10.1038/s41418-020-0585-1
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DOI: https://doi.org/10.1038/s41418-020-0585-1
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