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MCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3+ regulatory T cells
journal contribution
posted on 2023-05-20, 15:40 authored by Teh, CE, Robbins, AK, Darren HenstridgeDarren Henstridge, Dewson, G, Diepstraten, S, Kelly, G, Febbraio, MA, Gabriel, SS, O'Reilly, LA, Strasser, A, Gray, DHDFOXP3+ 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.
History
Publication title
Cell Death and DifferentiationVolume
27Issue
12Pagination
3374-3385ISSN
1350-9047Department/School
School of Health SciencesPublisher
Nature Publishing GroupPlace of publication
Macmillan Building, 4 Crinan St, London, England, N1 9XwRights statement
Copyright 2020 The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020Repository Status
- Restricted