Kim Yeung-Hyen, Kumar Ajay, Chang Cheong-Hee, Pyaram Kalyani
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
J Immunol. 2017 Nov 15;199(10):3478-3487. doi: 10.4049/jimmunol.1700567. Epub 2017 Oct 11.
Reactive oxygen species (ROS) are byproducts of aerobic metabolism and contribute to both physiological and pathological conditions as second messengers. ROS are essential for activation of T cells, but how ROS influence NKT cells is unknown. In the present study, we investigated the role of ROS in NKT cell function. We found that NKT cells, but not CD4 or CD8 T cells, have dramatically high ROS in the spleen and liver of mice but not in the thymus or adipose tissues. Accordingly, ROS-high NKT cells exhibited increased susceptibility and apoptotic cell death with oxidative stress. High ROS in the peripheral NKT cells were primarily produced by NADPH oxidases and not mitochondria. We observed that sorted ROS-high NKT cells were enriched in NKT1 and NKT17 cells, whereas NKT2 cells were dominant in ROS-low cells. Furthermore, treatment of NKT cells with antioxidants led to reduced frequencies of IFN-γ- and IL-17-expressing cells, indicating that ROS play a role in regulating the inflammatory function of NKT cells. The transcription factor promyelocytic leukemia zinc finger (PLZF) seemed to control the ROS levels. NKT cells from adipose tissues that do not express PLZF and those from PLZF haplodeficient mice have low ROS. Conversely, ROS were highly elevated in CD4 T cells from mice ectopically expressing PLZF. Thus, our findings demonstrate that PLZF controls ROS levels, which in turn governs the inflammatory function of NKT cells.
活性氧（ROS）是有氧代谢的副产物，作为第二信使参与生理和病理过程。ROS对T细胞的激活至关重要，但ROS如何影响自然杀伤T细胞（NKT细胞）尚不清楚。在本研究中，我们调查了ROS在NKT细胞功能中的作用。我们发现，NKT细胞而非CD4或CD8 T细胞，在小鼠脾脏和肝脏中具有显著高水平的ROS，但在胸腺或脂肪组织中则不然。相应地，ROS水平高的NKT细胞在氧化应激下表现出更高的易感性和凋亡性细胞死亡。外周NKT细胞中的高ROS主要由烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生，而非线粒体。我们观察到，分选出来的ROS水平高的NKT细胞富含NKT1和NKT17细胞，而NKT2细胞在ROS水平低的细胞中占主导地位。此外，用抗氧化剂处理NKT细胞导致表达干扰素-γ（IFN-γ）和白细胞介素-17（IL-17）的细胞频率降低，表明ROS在调节NKT细胞的炎症功能中发挥作用。转录因子早幼粒细胞白血病锌指蛋白（PLZF）似乎控制着ROS水平。来自不表达PLZF的脂肪组织的NKT细胞以及来自PLZF单倍体缺陷小鼠的NKT细胞具有低水平的ROS。相反，在异位表达PLZF的小鼠的CD4 T细胞中，ROS水平显著升高。因此，我们的研究结果表明，PLZF控制ROS水平，进而调控NKT细胞的炎症功能。
