共生菌调控肺脏γδT细胞抗肿瘤免疫应答的细胞与分子机制

项目名称： 共生菌调控肺脏γδT细胞抗肿瘤免疫应答的细胞与分子机制

项目编号： No.81471552

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 程民

作者单位： 安徽医科大学

项目金额： 70万元

中文摘要： 共生菌信号维持机体粘膜免疫稳态，与感染性、代谢性及慢性炎性疾病密切相关，但其对肿瘤免疫应答的影响尚不明确。我们已有的研究发现抗生素水饲喂(ABX)小鼠更易发生肺脏黑色素瘤及Lewis肺癌，并伴随γδT数量与比例显著降低。鉴于肺脏γδT细胞重要的免疫学效应，且其与共生菌的关系尚未有报道。本课题拟深入分析ABX小鼠及其肺脏肿瘤形成过程中各淋巴细胞亚群比例、数量、表型及功能（细胞因子谱、转录因子谱）等特性，明确共生菌对肺脏γδT1/17亚群分布、抗肿瘤应答的影响及其与肿瘤发生发展的关系；利用细胞转输/清除、抗体阻断/中和、基因缺陷小鼠等手段验证γδT亚群的关键作用与机制，及其对Th1、CTL等免疫应答的调控；确定发挥关键作用的共生菌种类及其天然免疫信号(TLR、NOD等)及细胞因子信号，揭示共生菌促进肺脏γδT应答的细胞与分子机制。本研究将为深入理解共生菌与机体免疫系统之间的关系提供有力的证据。

中文关键词： γδT细胞；共生菌；肺脏；粘膜免疫；肿瘤免疫

英文摘要： Commensal microbiota signals play important role in maintaining mucosal immune homeostasis, which is closely related to infectious, metabolic and chronic inflammatory diseases. However, its effect on anti-tumor immune responses is unclear. Our previous study has found that antibiotics-treated (ABX) mice were more susceptible to lung melanoma and Lewis lung cancer, with significant decrease in the number and percentage of γδT cells in the lungs. Given the importance of lung γδT cells for their immune effects, and its unknown relation with commensal microbiota, we proposed the project on the basis of the previous study. In this study, the percentage, number, phenotypes and function (cytokines, transcription factors) of each lymphocyte subset will be analyzed and compared between the ABX mice and the control mice to determine the regulation effects of commensal microbiota on lung γδT cell subsets (γδT1 and γδT17), and their anti-tumor immune responses and relations with tumor progression. By using cell transfer/depletion, antibody blockade/neutralization and gene-deficient mice, the roles and molecular mechanisms of γδT cell subsets will be explored, and further their immune regulation on adaptive immune responses of Th1 and CTL. Further, the critical commensal microbiota and their innate immune signals such as TLR/NOD and cytokine signals will be determined to reveal the cellular and molecular mechanisms in regulating lung γδT cells. This study will provide strong evidence for deeply understanding the relationship between the commensal microbiota and the immune system.

英文关键词： γδT cell;commensal microbiota;lung;mucosal immunity;tumor immunity