肠道微生物和外周免疫系统发育的关系

Secondary lymphoid organs (SLO) are the primary locations for initiation of immune responses. During embryonic lymphogenesis, lymphoid tissue-inducer cells (LTi) mediate the initial development of these structures upon receiving cues from retinoid acid released from neuronal termini in the vicinity. After birth, LTi gradually disappear；SLO continue to expand in size and cellularity. These structural developments after birth however are arrested in the absence of gut microbiota, suggesting an essential role of gut symbiotic microbes in peripheral lymphoid system development. Our previous work shows that upon colonization a group of CD103+CD11b+RALDH+ DC-like cells from lamina properia travel to peripheral lymph nodes. This migration is driven by gut commensal fungi. These cells imprint lymphocytes in the lymph nodes for homing to the gut, helping establish the earliest gut immune system. At the same time, they gradually inhibit neonatal lymph node addressin MAdCAM-1, yet induce the expression of adult addressin PNAd, thus initiating the mature pattern of lymphocyte homing to peripheral lymph nodes. Upon the establishment of peripheral lymphoid tissues, a small number of these DC-like cells remain there for the structural and cellularity maintenance. This application aims to study three topics: the identity of fungal metabolite that drives the CD103+ DC migration to the periphery; molecular mechanisms of MAdCAM-1 and PNAd regulation; whether these cells initiate the earliest lymphocyte migration to the gut to establish the local immune balance. Answers to these questions have important implications in human gut immunity, regulations of the immune system by commensal microbes, and neonatal immune system development.

二级淋巴器官是免疫应答的主要部位，在胚胎期淋巴结诱导细胞刺激原始的淋巴原基开始生长。出生后淋巴结诱导细胞消失，而二级淋巴器官的体积和细胞数量持续增加。这些结构在无菌鼠中呈现发育缺陷，说明肠道菌群在外周淋巴组织发育过程中起重要作用。我们发现在肠道菌群定植后，新生小鼠外周淋巴结中会出现一群来自肠壁的RALDH+树突状细胞，肠道的真菌诱发了这些细胞的位移。 这些树突状细胞刺激新生鼠外周淋巴结里的淋巴细胞向肠道迁移，同时它们诱导外周淋巴结表达成年期的地址素，从而开始了成年模式淋巴细胞向外周淋巴结的回流。当外周淋巴结成型后，少量这些来自肠道的树突状细胞会在外周淋巴结持续出现，维持这些淋巴结的结构和细胞数量。本申请拟研究这些树突状细胞从肠道外移的驱动因子以及这些细胞如何调节出生后淋巴结发表和肠道免疫平衡。这些问题的答案对人类肠道免疫，共生菌对免疫系统的调节以及出生后免疫系统的发育有重要意义。

二级淋巴器官是免疫应答的主要部位，在胚胎期淋巴结诱导细胞刺激原始的淋巴原基开始生长。出生后淋巴结诱导细胞消失，而二级淋巴器官的体积和细胞数量持续增加。这些结构在无菌鼠中呈现发育缺陷，说明肠道菌群在外周淋巴组织发育过程中起重要作用。我们发现在肠道菌群定植后，新生小鼠外周淋巴结中会出现一群来自肠壁的RALDH+树突状细胞，肠道的真菌诱发了这些细胞的位移。 这些树突状细胞刺激新生鼠外周淋巴结里的淋巴细胞向肠道迁移，同时它们诱导外周淋巴结表达成年期的地址素，从而开始了成年模式淋巴细胞向外周淋巴结的回流。当外周淋巴结成型后，少量这些来自肠道的树突状细胞会在外周淋巴结持续出现，维持这些淋巴结的结构和细胞数量。本申请拟研究这些树突状细胞从肠道外移的驱动因子以及这些细胞如何调节出生后淋巴结发表和肠道免疫平衡。这些问题的答案对人类肠道免疫，共生菌对免疫系统的调节以及出生后免疫系统的发育有重要意义。