Keap1-Nrf2 System Plays an Important Role in Invariant Natural Killer T Cell Development and Homeostasis
Keap1-Nrf2 System Plays an Important Role in Invariant Natural Killer T Cell Development and Homeostasis
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DOI：
10.1016/j.celrep.2019.03.052
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发表时间：
2019-04-16
期刊：
影响因子：
8.8
通讯作者：
Chang, Cheong-Hee
中科院分区：
文献类型：
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作者：
Pyaram, Kalyani;Kumar, Ajay;Chang, Cheong-Hee
Kelch样ECH相关蛋白1（Keap 1）和核因子（红细胞衍生2）样2（Nrf 2）蛋白协同作用，调节活性氧（ROS）的水平。Keap 1-Nrf 2抗氧化系统也参与T细胞分化和炎症，但其在先天T细胞发育和功能中的作用仍不清楚。我们报告说，T细胞特异性缺失的Keap 1的结果在有缺陷的发展和不变的自然杀伤T（NKT）细胞在胸腺和外周器官中的细胞内在的方式减少的数量。在这些小鼠中，NKT 2和NKT 17细胞的频率增加，而NKT 1减少。Keap 1缺陷型NKT细胞表现出增殖和凋亡率增加，葡萄糖摄取和线粒体功能增加，但ROS、CD 122和Bcl 2表达减少。在Nrf 2和Keap 1缺陷的NKT细胞中，所有这些表型和代谢缺陷都得到了纠正。因此，Keap 1-Nrf 2系统通过调节细胞代谢而有助于NKT细胞发育和稳态。
Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) proteins work in concert to regulate the levels of reactive oxygen species (ROS). The Keap1-Nrf2 antioxidant system also participates in T cell differentiation and inflammation, but its role in innate T cell development and functions remains unclear. We report that T cell-specific deletion of Keap1 results in defective development and reduced numbers of invariant natural killer T (NKT) cells in the thymus and the peripheral organs in a cell-intrinsic manner. The frequency of NKT2 and NKT17 cells increases while NKT1 decreases in these mice. Keap1-deficient NKT cells show increased rates of proliferation and apoptosis, as well as increased glucose uptake and mitochondrial function, but reduced ROS, CD122, and Bcl2 expression. In NKT cells deficient in Nrf2 and Keap1, all these phenotypic and metabolic defects are corrected. Thus, the Keap1-Nrf2 system contributes to NKT cell development and homeostasis by regulating cell metabolism.