Role of CD4+T cells in maintenance of intestinal homeostasis

CD4 T 细胞在维持肠道稳态中的作用

• 批准号: 8819131
• 负责人: LESZEK IGNATOWICZ
• 金额: $ 33.01万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819131
• 关键词: Affect; Animals; Antigen Receptors; Antigens; Area; Autoimmunity; Bacteria; Bacterial Infections; Benign; Birth; CD4 Positive T Lymphocytes; Cells; Cellularity; Cues; Diet; Effector Cell; Ensure; Environment; Equilibrium; Gastrointestinal tract structure; Genetic; Germ-Free; Gut associated lymphoid tissue; Health; Immune; Immune response; Immune system; Individual; Infection; Inflammatory; Interleukin-10; Intestines; Label; Lamina Propria; Lymphocyte; Lymphoid; Lymphoid Follicle; Maintenance; Mesentery; Microbe; Modeling; Monitor; Mus; Organ; Peripheral; Phenotype; Physiological; Property; Recording of previous events; Regulatory T-Lymphocyte; Reporter; Research; Role; Specificity; Structure of aggregated lymphoid follicle of small intestine; Surface; T cell response; T-Lymphocyte; TNFRSF11B gene; Thymus Gland; Tissues; commensal microbes; complementarity-determining region 3; cytokine; food antigen; gut microbiota; in vivo; intestinal epithelium; intestinal homeostasis; lymph nodes; microbial; microorganism antigen; molecular marker; mouse model; pathogen; pathogenic bacteria; peripheral tolerance; research study; response

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.

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 细胞积聚在肠道相关淋巴组织 (GALT) 中，包括肠系膜淋巴结、派尔氏淋巴结、淋巴滤泡，并分散在固有层和肠上皮中。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内差异显着。粘膜 T 细胞可以识别管腔抗原，但这种识别如何影响 CD4+ T 细胞的克隆分布及其效应器功能目前尚不清楚。在肠道中，除了 作为常驻共生微生物区系，免疫系统不断受到饮食抗原和偶尔致病微生物的挑战。对共生体、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稳态至关重要。负责维持这种平衡的一个重要机制是对效应 T 细胞的抑制性 CD4+Foxp3+ 调节性 T 细胞 (Treg)。在这里，我们建议研究共生细菌的初始细菌定植对肠道 Tregs 上 TCR 多样性的影响（具体目标 1）。在我们的具体目标 2 中，我们将比较具有共生能力和不具备共生能力的小鼠中 Treg 参与感染性细菌的免疫反应。我们还将确定源自幼稚 CD4+ 细胞的不同 Tregs 亚群（适应性 Tregs 和产生 IL-10 的 Tr1）在肠道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，我们将研究促炎症环境中 Tregs 将其表型改变为效应 Th17 和滤泡谱系的频率。