3型天然淋巴样细胞在不同肠道相关淋巴组织中的区域特性调控研究

The gut mucosal immune system not only protects us from numerous pathogen invasion, but also maintains the homeostasis with commensal bacteria and innocuous food antigens. The failure of gut homeostasis not only increases the risk of gut infection, inflammatory bowel disease (IBD), allergy and cancer, but is also related to autoimmune, metabolic, and neurologic diseases. Recent studies have identified group 3 innate lymphoid cells (ILC3s) relatively enriched in intestinal mucosal area. Despite of tiny population, they unexpectedly play essential roles in the lymphoid tissue development, mucosal homeostasis and host defense. The gut associated lymphoid tissues include both mesenteric lymph nodes and lymphoid tissues in the gut, like Peyer’s patches, isolated lymphoid follicles and scattered lymphoid cells. Our previous study found that the mice with ID2 deletion specifically in the ILC3s developed with normal spleen and lymph nodes including mesenteric lymph nodes, but without Peyer’s patches and isolated lymphoid follicles. Consistently, compared to wild type mice, ID2 specific deficiency mice had very fewer ILC3s in the intestine, but lots more ILC3s in the mesenteric lymph nodes. Thus, we hypothesize that the development, survival or function of ILC3s is differentially regulated by different immune microenvironment, which leads to different development of different gut associated lymphoid tissues. Through combining traditional molecular immunology with systemic biology technologies, we will compare the immune characteristics between gut and mesenteric tissues, to uncover the different regulation of ILC3s by the immune environment and also the specific cellular and molecular network mechanisms, which will further our understanding about the lymphoid tissues development and the roles of ILC3s under different gut homeostatic and pathological conditions for the gut related diseases.

肠道黏膜免疫系统不仅抵御肠道病原体感染，还时刻维持着机体与外环境之间的稳态。3型天然淋巴样细胞（ILC3s）是富集于肠道黏膜的一群天然免疫细胞，数量虽少，但在调控肠道淋巴组织发育、维持肠道稳态方面发挥着重要作用。肠道相关淋巴组织（GALT）包括肠系膜淋巴结（mLN）和肠壁内淋巴组织(PPs等)。前期研究发现ILC3s特异ID2缺陷小鼠mLN发育正常，却缺失PPs；相应地ILC3s在大小肠中显著减少，而在mLN中显著增加。因此我们假设肠系膜和肠道两种不同的区域免疫微环境可以通过不同机制调节ILC3s，继而影响mLN和PPs的发育。本研究将充分利用传统分子免疫学和系统生物学技术，通过比较肠道和mLN微环境与其中ILC3s的免疫特性,揭示不同微环境对ILC3s的差异性影响以及其中的分子和细胞作用网络机制，解释不同GALT发育的差异调控机制，以期更精确阐明ILC3s参与肠道免疫反应的生理病理机制。

3型天然淋巴样细胞（ILC3s）是富集于肠道黏膜的一群天然免疫细胞，数量虽少，但在调控肠道淋巴组织发育、维持肠道稳态方面发挥着重要作用。本研究利用传统免疫学研究以及系统生物学分析方法，比较了肠道固有层和肠系膜淋巴结微环境中ILC3细胞亚群LTi细胞的区域免疫特性并对其发育调控进行了探讨。本项目研究发现不同肠道来源的LTi细胞在ID2调控下表现出的异质性，ID2缺陷导致肠道固有层中LTi细胞减少而肠系膜淋巴结中LTi细胞数目增多，与之相对应，ILC3中ID2特异敲除小鼠中肠道次级淋巴组织包括派氏结、孤立淋巴滤泡等缺失，而其他淋巴结包括肠系膜淋巴结并未有影响。进一步研究发现ID2可以差异调控IL-7与RANK信号通路，肠道中LTi细胞依赖IL-7信号而肠系膜淋巴结中LTi更多依赖于RANK信号。我们进一步发现肠系膜淋巴结中CD4+ T细胞为LTi提供RANKL，通过RANK-RANKL通路调控其发育。本项目揭示了不同微环境对ILC3的差异性影响，同时也为LTi细胞在次级淋巴器官中与T细胞相互作用的网络机制提供了新的依据。