Role of CD4+T cells in maintenance of intestinal homeostasis

描述（由申请方提供）：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细胞积聚在肠相关淋巴组织（GALT）中，包括肠系膜淋巴结、派尔集合淋巴结、淋巴滤泡，并且散布在整个固有层和肠上皮中。在无菌小鼠中，GALT细胞结构减少，表明肠道共生体对粘膜淋巴器官中T细胞积累的重要影响。肠道细菌产生影响淋巴细胞营养和效应功能的免疫调节代谢物。肠道微生物群也是抗原的主要贡献者，并且这些抗原的多样性在整个肠道中显著变化。粘液T细胞可以识别管腔抗原，但这种识别如何影响CD 4 + T细胞的克隆分布及其效应功能目前尚不清楚。在肠道中，除了 由于肠道微生物群落的存在，免疫系统受到饮食抗原的持续挑战，偶尔也会受到致病微生物的挑战。肠道对抗生素、食物抗原的耐受性和对病原体的免疫反应性之间的平衡对于维持肠道内稳态至关重要。负责维持这种平衡的一个重要机制是抑制性CD 4 + Foxp 3+调节性T细胞（TcR）对效应T细胞的作用。在这里，我们建议研究共生细菌的初始细菌定殖对肠道TCRs多样性的影响（具体目标1）。在我们的具体目标2中，我们将比较Tceptide参与有免疫能力和无免疫能力小鼠对感染性细菌的免疫应答。我们还将确定来自幼稚CD 4+细胞的不同Tcl 3亚群（适应性Tcl 3和Tr 1产生IL-10）在肠道内稳态中是否具有互补或冗余的作用。最后，在我们的最后一个目标中，我们将研究在促炎环境中TCLs如何频繁地将其表型改变为效应子Th 17和滤泡谱系。

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.