Hp感染诱导CD4+组织原位记忆T细胞活化导致胃黏膜免疫病理损害作用及机制研究

Tissue resident memory T cell (TRM) is a novel subset involved in infection and inflammatory. TRM located in gastric mucosa of healthy donor, but the regulation of TRM differentiation and function under Hp accosiated gastritis disease remains unclear. Our previous data indicated that increased frequency of CD69+CD103+CD4+TRM in gastric mucosa of patients with Hp infection, accompany with TGF-β and IL-15. In vitro peripheral blood CD4+T cells could differentiate into CD4+TRM and upregulate Blimp1 expression induced by TGF-β combined with IL-15. After co-culture with CD4+TRM, cell death of gastric epithelial cells increased. Based on the literature and our preliminary data, we hypothesize that TGF-β and IL-15 induce the differentiation of CD4+TRM via STAT5/Blimp1 signal pathway, and then CD4+TRM promote inflammatory response to lead to damage of gastric mucosa. To investigate the hypothesis, we use gastric biopsy tissue, in vitro differentiation and animal model to study the role and mechanism of CD4+TRM in Hp accosiated gastritis. This project will provide substantive information for prevention and clinical treatment of HP associated gastritis.

组织原位记忆T细胞（TRM）是新发现与感染炎症密切相关的细胞亚群。文献报导TRM存在于胃黏膜组织中，然而TRM是否参与幽门螺杆菌（Hp）感染所致胃黏膜损伤？预实验显示：Hp感染的胃黏膜组织中CD4+TRM（CD69+CD103+）比例升高，且TGF-β和IL-15表达上调，后者致转录因子Blimp1表达上调和CD4+TRM活化，CD4+TRM与胃上皮细胞共培养，胃上皮细胞死亡增加。本项目假说是：Hp感染致TGF-β/IL-15增加，TGF-β/IL-15通过STAT5/Blimp1通路诱导CD4+TRM活化，诱发胃黏膜免疫病理反应，从而导致感染性胃黏膜损伤。本项目拟通过临床样本、体外分化和动物模型等试验方法研究Hp感染诱导CD4+TRM活化机制及CD4+TRM在胃黏膜中的免疫病理作用，阐明Hp感染胃黏膜炎症损伤机制，为Hp致胃黏膜损伤性疾病治疗提供新思路和分子靶点。

在本项目支持下，申请人完成以下内容：1）确定Hp感染诱导胃黏膜CD4+TRM活化，收集临床胃黏膜组织样本，检测并比较感染前后不同时期胃黏膜中CD4+TRM的比例及组织分布情况，确定CD4+ TRM与胃黏膜损伤的严重程度呈正相关；2）阐明Hp感染诱导CD4+TRM活化的信号转导机制，检测胃黏膜CD4+TRM比例和STAT5/Blimp1通路活化情况，证实STAT5/Blimp1信号通路参与调控CD4+TRM活化；3）探讨CD4+TRM活化和放大炎症反应的作用机制，检测胃黏膜CD4+TRM细胞亚群比例、炎性细胞因子（TNF、IFN-、IL-17A）表达情况，明确CD4+TRM细胞亚群主要分泌的炎性因子和介质；4）明确CD4+TRM活化介导的免疫病理反应在胃黏膜损伤性疾病的作用。在完成以上所有研究内容基础上，进一步拓展分析胃黏膜定植的T细胞的调控机制，具体如下：1）阐明OX40调控MAIT细胞分泌IL-9调控胃黏膜炎症的作用机制；2）揭示GITR调控TFH样细胞极化和分泌IL-21诱导胃黏膜炎症的作用机制。以上成果以论文形式发表在Cell, Cell death disease, Frontier in Immunology等期刊，共计13篇，申请专利4项。