STING贩运激活了MAPK-CREB信号,从而触发了调控性T细胞分化的过程
Wei Lin1, Claudia Szabo1, Tao Liu1
1Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
概括
在T细胞中干扰素基因 (STING) 激活的刺激剂通过IFN独立的途径促进调节性T细胞 (Treg) 差异化. 这种STING-MAPK-CREB信号轴影响了适应性免疫和自身免疫性疾病.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 干扰素基因刺激器 (STING) 对天生的免疫非常重要,主要介导I型干扰素 (IFN-I) 反应.
- STING在T细胞中高度表达,但其在这些适应性免疫细胞中的功能在很大程度上是未知的.
- 之前的研究表明,T细胞中的STING激活可以触发IFN独立的活动.
研究的目的:
- 阐明T细胞中STING的内在功能,重点关注IFN独立通路.
- 确定STING激活影响T细胞分化的分子机制.
- 研究STING在Treg分化中的作用及其对自身免疫性疾病的潜在影响.
主要方法:
- 研究了从内质网膜到戈尔吉器官的STING转位.
- 分析了基因激活蛋白激酶 (MAPK) 和cAMP反应元素结合蛋白 (CREB) 信号通路的激活.
- 利用了MAPK p38的基因淘汰和MAPK p38和CREB的药理抑制.
- 在小鼠中注射了STING激动剂,并分析了Trex1自身免疫疾病模型.
主要成果:
- 激活STING诱导调控性T细胞 (Treg) 的分化,独立于IRF3和IFN.
- 将STING转移到Golgi激活了MAPK通路,从而导致CREB激活.
- -MAPK-CREB通路对IL-2和TGF-β2的表达进行上调,促进Treg的分化.
- 抑制MAPK p38或CREB显著损害了STING介导的Treg分化.
- 刺激激活促进Treg分化在体内和自免疫性疾病的小鼠模型.
结论:
- 在T细胞中的STING激活通过IFN独立的STING-MAPK-CREB信号轴驱动Treg分化.
- 这一途径在调节T细胞效应因子功能和适应性免疫力方面发挥着重要作用.
- 通过STING介导的Treg诱导可能会为自身免疫病理提供平衡.
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