ARID5B regulates metabolic programming in human adaptive NK cells.
ARID5B regulates metabolic programming in human adaptive NK cells.
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DOI：
10.1084/jem.20172168
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发表时间：
2018-09-03
期刊：
影响因子：
--
通讯作者：
Miller JS
中科院分区：
文献类型：
--
作者：
Cichocki F;Wu CY;Zhang B;Felices M;Tesi B;Tuininga K;Dougherty P;Taras E;Hinderlie P;Blazar BR;Bryceson YT;Miller JS
表达活化受体NKG 2C的“适应性”NK细胞在HCMV血清阳性个体中扩增并持续存在。Ciclidki等人证明了适应性NK细胞的氧化和糖酵解代谢增强，并暗示ARID 5 B是线粒体代谢、IFN-γ产生和存活的重要调节剂。具有适应性免疫特性的自然杀伤（NK）细胞对人巨细胞病毒的反应是扩增和持续的。在这里，我们探索了这些细胞特有的代谢过程。适应性CD 3-CD 56 dimCD 57 + NKG 2C + NK细胞表现出淋巴细胞记忆的代谢特征，包括氧化线粒体呼吸、线粒体膜电位和备用呼吸能力增加。从机制上讲，我们发现，染色质修饰转录调节因子，AT丰富的相互作用结构域5 B（ARID 5 B）的短亚型，选择性诱导通过DNA低甲基化在适应性NK细胞。敲除和过表达研究表明，ARID 5 B在促进线粒体膜电位、编码电子传递链组分的基因表达、氧化代谢、存活和IFN-γ产生中发挥直接作用。总的来说，我们的数据表明，ARID 5 B是人类适应性NK细胞代谢的关键调节因子，如果靶向，可能具有治疗价值。
“Adaptive” NK cells expressing the activating receptor NKG2C expand and persist in HCMV-seropositive individuals. Cichocki et al. demonstrate enhanced oxidative and glycolytic metabolism for adaptive NK cells and implicate ARID5B as an important regulator of mitochondrial metabolism, IFN-γ production, and survival. Natural killer (NK) cells with adaptive immunological properties expand and persist in response to human cytomegalovirus. Here, we explored the metabolic processes unique to these cells. Adaptive CD3−CD56dimCD57+NKG2C+ NK cells exhibited metabolic hallmarks of lymphocyte memory, including increased oxidative mitochondrial respiration, mitochondrial membrane potential, and spare respiratory capacity. Mechanistically, we found that a short isoform of the chromatin-modifying transcriptional regulator, AT-rich interaction domain 5B (ARID5B), was selectively induced through DNA hypomethylation in adaptive NK cells. Knockdown and overexpression studies demonstrated that ARID5B played a direct role in promoting mitochondrial membrane potential, expression of genes encoding electron transport chain components, oxidative metabolism, survival, and IFN-γ production. Collectively, our data demonstrate that ARID5B is a key regulator of metabolism in human adaptive NK cells, which, if targeted, may be of therapeutic value.
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