NOX/ROS信号调节炎性肠病异常CD8+ T 细胞免疫反应的机制研究

Recently, we and other investigators have indicated the pivotal roles of CD8+ T cells in the pathogenesis of inflammatory bowel disease (IBD). Our preliminary studies have further noted that NADPH oxidase (NOX)/reactive oxygen species (ROS) pathway in CD8+ T cells mediates activation of CD3/CD28 signal components including PI3K-Akt-mTOR and NFkB, and subsequently regulates cytokine expression and functions of CD8+ T cells. So far, the expression and function of NOX/ROS pathway in CD8+ T cells of IBD remains unclear, and the molecular mechanisms how NOX/ROS pathway controls aberrant CD8+ T cell responses in IBD are still to be elucidated. We hypothesize that NOX/ROS pathway regualtes aberrant CD8+ T cell responses as seen in IBD through mediating cell signals, regulating functional gene expression, and controlling cytotoxic CD8+ T cell (Tc) differentiation, activity, and functions. We propose to address the functions of NOX/ROS pathway in three specific aims. First, to explore the pivotal roles of NOX/ROS pathway in regulation of CD8+ T cell functions including cytokine production, Tc differentiation (including Tc1, Tc2, Tc17 and regulatory Tc cells) and activities. Second, to investigate the downstream key signals of NOX/ROS pathway which regulate functional gene expression and cell function. Last, to study the impacts of NOX/ROS pathway on the development of aberrant CD8+ T cell responses of animal colitis models and human IBD. The project will be performed with CD8+ T cells in vitro, experimental models of colitis and human IBD, to discuss the mechanisms of NOX/ROS pathway in regulation of CD8+ T cell function, and aberrant CD8+ T cell responses of IBD and murine colitis. In summary, the proposed project will explore the roles of CD8+ T cells in the pathogenesis of IBD, provide novel information about the mechanisms and molecular signals of NOX/ROS pathway, and may offer a promising alternative to our current approaches of managing immune diseases including IBD.

新近他人及我们研究提示CD8+T细胞在IBD发病中发挥重要作用。前期进一步发现，NOX/ROS信号介导CD8+T细胞激活、信号通路、分化和功能。而NOX/ROS信号在IBD肠粘膜CD8+T细胞及不同分化的Tc细胞表达、NOX/ROS信号是否参与调节IBD异常CD8+T细胞反应等直接关系其病理机制的问题尚亟待研究。本研究以NOX/ROS信号调节CD8+T细胞激活信号为切入点，进一步研究NOX/ROS信号调节IBD、结肠炎小鼠肠粘膜CD8+T细胞信号通路及功能的分子机制；利用结肠炎模型，探讨体内NOX/ROS信号对肠道异常CD8+T细胞反应的调节和机制。本项目从细胞、动物、人体多方面探讨NOX/ROS信号对IBD炎症肠粘膜CD8+T细胞功能的调节，以阐明NOX/ROS信号调节肠道异常CD8+T细胞反应的机制，为将来利用NOX/ROS信号治疗IBD、深入NOX/ROS信号的药理研发打下理论基础。

课题探讨了NOX2信号对免疫细胞功能的调节及参与IBD肠道炎症反应的机制，发现：NOX2信号介导了LPS所诱导的巨噬细胞激活，抑制NOX2活性能抑制巨噬细胞的激活及功能；NOX2介导了CD8+ T细胞CD3/CD28的信号传导，调节细胞的活化及增殖功能；NOX2介导了实验性结肠炎肠粘膜免疫细胞功能，包括CD4+及CD8+ T细胞等；抑制NOX2能明显抑制实验性结肠炎肠粘膜免疫细胞功能；NOX2也可能介导了IBD患者LPMC中免疫细胞的功能，抑制NOX2信号能抑制 IBD患者肠组织免疫细胞的激活及炎症细胞因子的释放。上述研究较深入地探讨了NOX2信号体外调节人及小鼠CD4+、CD8+ T细胞免疫反应、巨噬细胞功能的机制，及利用该信号可调节实验性结肠炎模型的病情。上述研究提示NOX2信号作为免疫调节信号，为人类免疫性疾病的治疗提供了思路。