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MCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3+ regulatory T cells.
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-07-01 , DOI: 10.1038/s41418-020-0585-1
Charis E Teh 1, 2 , Alissa K Robbins 1, 2 , Darren C Henstridge 3, 4 , Grant Dewson 1, 2 , Sarah T Diepstraten 1, 2 , Gemma Kelly 1, 2 , Mark A Febbraio 3, 5 , Sarah S Gabriel 6, 7 , Lorraine A O'Reilly 1, 2 , Andreas Strasser 1, 2 , Daniel H D Gray 1, 2
Affiliation  

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.



中文翻译:

MCL-1 对生存必不可少,但对 FOXP3+ 调节性 T 细胞的代谢适应性而言则是可有可无的。

FOXP3 +调节性 T (Treg) 细胞对于维持免疫耐受性至关重要。鉴于它们在免疫相关疾病、癌症和肥胖症中的重要性,人们越来越关注在治疗上靶向 Treg 细胞区室。专门针对促存活蛋白 MCL-1 的新药理学抑制剂可能会提供这种机会,因为 Treg 细胞特别依赖这种蛋白。然而,MCL-1 有两种不同的亚型;一个位于线粒体外膜 (OMM) 是拮抗细胞凋亡所需的,另一个位于线粒体内膜 (IMM),据报道在氧化磷酸化过程中通过 ATP 产生维持 IMM 结构和代谢。我们着手阐明 MCL-1 在 Treg 细胞中的这些不同生物学功能的相对重要性,以评估 MCL-1 抑制是否可能影响能够抵抗细胞凋亡的细胞的代谢。有条件删除由于 Treg 细胞室的耗竭,FOXP3 + Treg 细胞中的Mcl1导致致命的多器官自身免疫。这种引人注目的表型通过同时缺失凋亡效应蛋白 BAK 和 BAX 完全恢复,表明凋亡在 Treg 细胞的稳态中起着关键作用。值得注意的是,从细胞凋亡中拯救出来的 MCL-1 缺陷型 Treg 细胞显示出正常的代谢能力。此外,对抗凋亡的 Treg 细胞中 MCL-1 的药理学抑制不会干扰它们的代谢功能。我们得出结论,Treg 细胞只需要 MCL-1 来对抗细胞凋亡,而不是代谢。因此,MCL-1 抑制可用于操纵 Treg 细胞存活以获得临床益处,而不会影响抵抗细胞凋亡的细胞的代谢适应性。

更新日期:2020-07-01
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