Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T-cell development and function.
Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T-cell development and function.
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DOI：
10.1002/eji.201343571
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发表时间：
2013-12
影响因子：
5.4
通讯作者：
Marti F
中科院分区：
文献类型：
--
作者：
Ellis GI;Zhi L;Akundi R;Büeler H;Marti F
PINK 1是一种与家族性早发性帕金森症相关的丝氨酸/苏氨酸激酶，其突变会损害线粒体完整性和代谢，并损害AKT信号传导。由于幼稚T细胞的活化需要细胞代谢机制的AKT依赖性重组，因此我们试图确定PINK 1缺陷型T细胞是否缺乏进行活化和分化的能力。我们发现，来自PINK 1敲除小鼠的CD 4 + T细胞在活化后不能正确磷酸化AKT，导致IL-2受体亚基CD 25的表达减少。随后，IL-2信号传导缺陷使呼吸能力和线粒体膜电位的激活诱导的增加沉默。在有利于诱导调节性T细胞发育的极化条件下，尽管FoxP 3表达动力学正常，但PINK 1 −/− T细胞抑制旁观者T细胞增殖的能力降低。我们的研究结果描述了PINK 1在T细胞命运决定过程中整合细胞外信号与代谢状态的关键作用，并可能对理解活动性帕金森病或其他免疫病理学进展过程中改变的T细胞群和免疫力产生影响。
Mutations in PINK1, a serine/threonine kinase linked to familial early onset Parkinsonism, compromise mitochondrial integrity and metabolism and impair AKT signaling. As the activation of a naïve T cell requires an AKT-dependent reorganization of a cell’s metabolic machinery, we sought to determine if PINK1 deficient T cells lack the ability to undergo activation and differentiation. We show that CD4+ T cells from PINK1 knockout mice fail to properly phosphorylate AKT upon activation, resulting in reduced expression of the IL-2 receptor subunit CD25. Following, deficient IL-2 signaling mutes the activation-induced increase in respiratory capacity and mitochondrial membrane potential. Under polarization conditions favoring the development of induced regulatory T cells, PINK1−/− T cells exhibit a reduced ability to suppress bystander T cell proliferation despite normal FoxP3 expression kinetics. Our results describe a critical role for PINK1 in integrating extra-cellular signals with metabolic state during T cell fate determination, and may have implications for the understanding of altered T cell populations and immunity during the progression of active Parkinson’s disease or other immunopathologies.