LTbetaR信号介导小肠杯状细胞分化与免疫应答的作用机制

小肠杯状细胞通过分泌粘蛋白等物质在肠道粘膜免疫中发挥重要作用，研究其分化与功能的调控机制具有重要意义。以往研究多限于细胞内源性转录因子或外源性细胞因子、肠道菌等对杯状细胞分化和功能的调控，而作为肠道微环境重要组成部分的各种各样的免疫细胞，它们对杯状细胞分化和功能的作用和机制尚不清楚。我们的前期工作提示小肠上皮细胞表达的LTbetaR信号通路可能参与调节李斯特菌感染状态下小肠杯状细胞的分化与功能，小肠内3型固有淋巴样细胞或gamma-delta T细胞可能通过LT-LTbetaR信号与杯状细胞（或其前体细胞——肠上皮干细胞）交互作用，影响杯状细胞的分化或功能，调节小肠固有免疫功能，控制感染。本课题将利用多种条件基因敲除小鼠模型，围绕LT-LTbR信号通路介导的细胞对话，深入探讨感染状态下小肠杯状细胞与免疫细胞动态变化和相互作用的规律及分子机制，揭示免疫细胞调控小肠杯状细胞分化功能新机制。

Intestinal mucosal immune system is the frontline protecting body against infection and disease. Goblet cells (GCs) in the small intestine play vital roles in intestinal homeostasis and mucosal immune response, however, the mechanisms of the regulation of goblet cell differentiation and function are not completely understood. Previous studies mainly emphasize the role of intrinsic transcriptional factors, extrinsic cytokines, and microbiota. However, whether immunes cells, as the major players in the intestinal immune microenvironment, having roles in the regulation of goblet cell differentiation and function remains unknown. Our previous data indicate that small intestinal epithelial cell-expressed LTbetaR signaling might play roles in regulating GC differentiation and function under Listeria infection, to control the early stage of Listeria infection. Moreover, gamma-delta T cell/ innate lymphoid cell type 3 may interact and cross-talk with GCs through LT-LTbetaR signaling for small intestinal innate immunity regulation. Therefore, we hypothesize that the cross-talk between GC or its precursor intestinal epithelial stem cell with immune cells is required for GC differentiation and function for infectious control. In this project, we will use specific transgenic mouse models combined with different analysis techniques to dissect the role of LT-LTbetaR signaling in goblet cell differentiation and function during anti-bacterial immune responses. We will explore the detailed cellular and molecular mechanisms of the cross-talks of epithelial cell-immune cell. And we will also explore SIEC single cell identification controlled by LTbetaR signaling under infectious state via single cell sequencing. This study will provide clues to better understand uncovered principles of intestinal homeostasis and immune responses to pathogens, as well as shed a light on unidentified markers and programs in small intestinal epithelial cells for potential therapeutic targets.