I型干扰素通过STAT1-IRF1通路调控慢性烟草烟雾暴露下树突状细胞促进T淋巴细胞免疫的作用与机制研究

慢阻肺是全球主要死亡原因之一。树突状细胞启动的T淋巴细胞免疫反应是肺部慢性炎症放大并持续进展的重要机制，但其调控机制尚不清楚。最新研究发现，I型干扰素在适应性免疫及慢性炎症中具有重要的调控作用。我们前期工作显示，慢性烟草烟雾暴露小鼠肺部I型干扰素表达上调及树突状细胞过度活化，提示其可能正向调控树突状细胞活化。据此，本项目在以往系列研究的基础上，通过构建IFNAR1及IRF1在树突状细胞上条件性敲除的小鼠模型与体外细胞实验，深入探讨慢性烟草烟雾暴露下I型干扰素在树突状细胞活化中的作用；探讨STAT1-IRF1通路在树突状细胞过度活化和“促炎”表型转化中的调控作用及相关机制；通过特异性阻断I型干扰素-IFNAR与STAT1-IRF1通路探讨能否减轻慢性树突状细胞的过度活化及T淋巴细胞介导的免疫反应，以阐明慢性烟草烟雾暴露肺部炎症的免疫发病机制，为与吸烟相关慢阻肺的抗炎策略提供精准的干预靶点。

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death in the world. T lymphocytes immunity initiated by dendritic cells contributes to the amplified and progressive chronic inflammation of lungs, but its regulatory mechanism is still unclear. Recent studies have found that type I interferons play an important regulatory role in adaptive immunity and chronic inflammation. Our previous work showed that the expression of type I interferons was up-regulated in lungs of mice chronic exposed cigarette smoke, which was associated with over-activated of dendritic cells, suggesting that they may promote the activation of dendritic cells. Based on this observation, by employing a mouse model of conditional knockout of IFNAR1 and IRF1 on dendritic cells and in vitro experiments, we try to explore the role of type I interferons in the activation of dendritic cells in the context of chronic cigarette smoke exposure; and to evaluate the regulatory effects of STAT1-IRF1 pathway on the excessive activation of dendritic cells and the "pro-inflammatory" phenotypic transformation. Furthermore, by specifically blocking the type I interferons-IFNAR and STAT1-IRF1 pathways, we try to explore whether it can down-regulate the excessive activation of dendritic cells and T lymphocyte-mediated immune response. This study will provide precise target for anti-inflammatory strategies of smoking-related COPD.