CFTR调控γδ T细胞的机制及其在肠道黏膜防御中的功能研究

肠道黏膜是机体阻止微生物入侵的第一道屏障。肠黏膜防御功能减弱，将导致细菌移位以及机体感染，直至多器官衰竭而危及生命。在肠道黏膜防御中，肠道上皮细胞与其紧密接触的γδ肠上皮内淋巴细胞（γδ IEL）扮演十分重要的角色，但具体分子机制尚未明确。我们近期的研究发现囊性纤维化跨膜转导调节因子（CFTR）的功能缺失引起γδ T细胞IFN-γ的分泌降低，而且CFTR-/-小鼠肠道γδ IEL细胞的数量大大降低。本项目拟应用CFTR-/-小鼠、肠道上皮细胞与γδ T细胞共培养、γδ IEL过继转输以及沙门氏杆菌感染等模型深入探讨CFTR调控γδ IEL的分子机理，提出的关键科学问题是CFTR如何调控γδ IEL的功能？CFTR是否通过调控γδ IEL的功能从而对肠道黏膜进行保护？我们将有望发现调控γδ IEL功能的新机制，拓展我们对肠道黏膜防御的认知，并为肠道疾病的治疗提供新的靶点。

The intestinal mucosal layer acts as the first barrier to the entry of the foreign antigen and pathogens. The dysfunction of mucosal defense leads to the bacterial translocation and host infection, in turn causes mortality. Intestinal epithelial cells and adjacent γδ intraepithelial lymphocytes (γδ IEL) are key players of the intestinal defense, yet little is known about the mechanism of their functions. Our current work suggested that the deficiency of cystic fibrosis transmembrane conductance regulator (CFTR) altered the production of IFN-γ in γδ T cells, and interestingly, the population of γδ IEL decreased a lot in CFTR-/- mice. This proposal seeks to deeply investigate the regulatory role of CFTR on γδ IEL using CFTR-/- mice, intestinal epithelium and γδ T co-culture, γδ IEL adoptive transfer and Salmonella Typhimurium infection. In this proposal, we will address the following scientific questions: ⑴ how CFTR regulates the function of γδ IEL? ⑵ whether the regulatory role of CFTR on γδ IEL protects the intestine from the pathogens invasion? We expect to reveal the new regulatory mechanism of γδ IEL function and provide a new sight on the intestinal mucosal defense, therefore identify a new target for the therapy of intestinal damage.