Role of CD4+T cells in maintenance of intestinal homeostasis

描述（由申请人提供）：胃肠道是外部环境与粘膜免疫系统直接接触的最大表面积。T细胞聚集在肠相关淋巴组织（GALT），包括肠系膜淋巴结、Peyer’s斑块、淋巴滤泡，并分散在固有层和肠上皮。无菌小鼠GALT细胞数量减少，表明肠道共生体对粘膜淋巴器官T细胞积累的重要影响。肠道细菌产生免疫调节代谢物，影响淋巴细胞营养和效应功能。肠道微生物群也是抗原的主要贡献者，这些抗原的多样性在肠道中差异很大。粘膜T细胞可以识别腔内抗原，但这种识别如何影响CD4+ T细胞的克隆分布及其效应功能目前尚不清楚。在肠内，除了

DESCRIPTION (provided by applicant): The gastrointestinal tract represents the largest surface area of direct contact between the external environment and the mucosal immune system. T cells accumulate in the gut-associated lymphoid tissue (GALT), including the mesenteric lymph nodes, Peyer's patches, lymphoid follicles, and are scattered throughout the lamina propria and intestinal epithelium. In germ-free mice GALT cellularity is reduced, indicative of the important influence of intestinal symbionts on T cell accumulation in mucosal lymphoid organs. Intestinal bacteria generate immunomodulatory metabolites that influence lymphocyte trophism and effector functions. The intestinal microbiota is also a major contributor of antigens and the diversity of these antigens varies significantly across the intestine. Mucosal T cells can recognize luminal antigens, but how this recognition affects clonal distribution of CD4+ T cells and their effector function is currently unknown. In the intestine, in addition to the resident commensal microflora, the immune system is exposed to continual challenge by dietary antigens, and occasionally pathogenic microbes. A balance between tolerance towards commensals, food antigens and immune reactivity towards pathogens is critical to the maintenance of intestinal homeostasis. One important mechanism responsible for the maintenance of this balance is the suppressive CD4+Foxp3+ regulatory T cells (Tregs) towards effector T cells. Here, we propose to study an impact of initial bacterial colonization with symbiotic bacteria on the diversity of TCRs on intestinal Tregs (Specific Aim 1). In our Specific Aim 2, we will compare Tregs participation in immunoresponse to infectious bacteria in commensal-competent and incompetent mice. We will also determine if different subsets of Tregs derived from na¿ve CD4+ cells (adaptive Tregs and Tr1 producing IL-10) have complementary or redundant roles in intestinal homeostasis. Finally in our last aim we will study how frequently Tregs change their phenotype to effector Th17 and follicular lineages in pro- inflammatory milieu.