全基因组分析确定NR4A1是T细胞功能障碍的关键媒介
Xindong Liu1, Yun Wang2, Huiping Lu3
1Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. xindongliu@hotmail.com.
Nature
|March 1, 2019
概括
转录因子NR4A1驱动T细胞功能障碍和耐受性. 它的删除增强了抗瘤免疫力,这表明NR4A1是癌症免疫治疗的目标.
科学领域:
- 免疫学
- 分子生物学
- 表观遗传学
背景情况:
- 由自我抗原,慢性感染或瘤微环境引起的.
- 虽然共刺激信号调节T细胞功能,但功能障碍的分子机制尚不清楚.
研究的目的:
- 在耐受性T细胞中描述全基因组表观和基因表达特征.
- 确定T细胞功能障碍和耐受性的关键调节者.
主要方法:
- 在小鼠体外T细胞耐受感应系统.
- 基因组范围内的表观遗传和基因表达特征.
- NR4A1过度表达和删除研究.
主要成果:
- 与效应细胞和调节性T细胞相比,耐受性T细胞表现出不同的表观遗传和基因表达特征.
- 在耐受性T细胞中稳定地表达NR4A1并抑制效应性T细胞的分化.
- 删除NR4A1可以逆转T细胞耐受性,增强效应器功能,改善抗瘤和抗病毒免疫力.
- NR4A1通过抑制AP-1功能来抑制效应基因表达,并通过H3K27ac促进与耐受性相关的基因激活.
结论:
- NR4A1是诱导T细胞功能障碍和耐受性的关键调节剂.
- NR4A1是增强抗瘤免疫力的潜在治疗点.
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