GOBLET CELLS IN INTESTINAL IMMUNE HOMEOSTASIS

肠道免疫稳态中的杯状细胞

• 批准号: 9751270
• 负责人: Rodney D Newberry
• 金额: $ 41.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751270
• 关键词: Acetylcholine; Affect; Antigen-Presenting Cells; Antigens; Award; Cell model; Cell physiology; Cells; Cellular biology; Collection; Data; Diet; Electron Microscopy; Endocytosis; Environment; Environmental Exposure; Epidermal Growth Factor Receptor; Epithelium; Exocytosis; Exposure to; Gastrointestinal tract structure; Genetic; Goblet Cells; Health Promotion; Homeostasis; Immune; Immune response; Immune system; Immunity; Infection; Inflammatory Response; Intestines; Lamina Propria; Ligands; Link; Maintenance; Mediating; Mesentery; Monitor; Mononuclear; Mus; Nature; Neurons; Outcome; Pathway interactions; Pattern; Phagocytes; Pharmacology; Phenotype; Process; Property; Regulation; Regulatory T-Lymphocyte; Role; Salmonella typhimurium; Stimulus; Surface; Techniques; Variant; Work; adaptive immune response; cytokine; enteric infection; genetic manipulation; gut microbiota; imaging approach; lymph nodes; microbiota; novel; pathogen; prevent; response; three-dimensional modeling; uptake

Project Summary/Abstract The body’s largest collection of immune cells underlies the single layer epithelium lining the GI tract and monitors the luminal contents to maintain tolerance to dietary antigens in the steady-state and to induce immunity to pathogens during infection. How the immune system’s exposure to luminal antigens is controlled in the steady-state to promote tolerance and during infection to avoid inappropriate responses and promote immunity remains a significant gap in our understanding. We propose that luminal antigen delivery to the immune system is tightly controlled, has regional variation through the GI tract, and serves to supply antigens to the immune system and guide the phenotype of immune responses. Goblet cells (GCs) can take up luminal substances deliver them to antigen presenting cells in the underlying lamina propria (LP) in a manner capable of inducing adaptive immune responses, in a process termed Goblet cell-associated Antigen Passages (GAPs). GAP formation is induced by acetylcholine acting on GCs, is linked with secretion, and is inhibited by GC intrinsic sensing of the gut microbiota. We propose that the pathways controlling GAP formation and the properties of GAPs in various regions of the GI tract allow for a regional antigen delivery supporting tolerance to dietary antigens in the steady-state and limiting immune responses to innocuous luminal antigens and shifting the phenotype of the immune response during enteric infection. These observations give rise to the overarching hypothesis that GC-mediated antigen delivery occurs via bulk endocytosis (BE) in GCs, is a major and closely regulated mechanism promoting tolerance in the steady-state, and inhibition of this pathway shifts immune responses to promote pathogen clearance and immunity during infection. To explore this hypothesis we propose the following specific aims: Aim 1 will define the ultrastructural basis and cellular biology of GAP formation using state-of-the-art imaging approaches, and genetic and pharmacologic manipulation of endocytosis and GAPs. Aim 2 will define the role of GC/GAPs in the induction and maintenance of tolerance to luminal antigens in the steady-state using genetic manipulation of GAP formation. Aim 3 will define if altering GCs/GAPs results in inappropriate inflammatory responses to dietary antigens and/or worsened outcomes during infection using genetic manipulation of GAPs in Salmonella typhimurium infection.

项目摘要/摘要 人体最大的免疫收集是胃肠道的单层上皮的基础 监视腔内含量，以保持稳态中对饮食抗原的耐受性，并诱导 感染期间病原体的免疫力。如何控制免疫系统暴露于腔抗原 在稳态以促进耐受性和感染期间，以避免不适当的反应并促进 免疫力仍然是我们理解的重大差距。我们提出向腔抗原递送到 免疫系统受到严格控制，通过胃肠道具有区域变化，并提供抗原 到免疫系统并指导免疫反应的表型。杯状细胞（GC）可以占用腔 物质以能够的方式将它们传递到基础固有层（LP）中的抗原呈现细胞 在称为杯状细胞相关的抗原通道的过程中诱导适应性免疫调查 （差距）。间隙形成是由作用于GCS的乙酰胆碱诱导的，与分泌有关，并被抑制 肠道菌群的GC内在灵敏度。我们建议控制间隙形成的途径和 胃肠道各个区域中间隙的特性允许宽区域抗原递送支持公差 在稳态中的饮食抗原，并限制对无害腔抗原的免疫反应 转移肠道感染期间免疫反应的表型。这些观察结果引起了 GC介导的抗原递送的总体假设是通过GCS中的大量内吞作用（BE）发生的，这是一个主要的 并密切调节的机制，促进稳态中的耐受性，并抑制该途径移动 免疫反应以促进感染过程中的病原体清除和免疫力。探索这一假设 我们提出以下特定目的：AIM 1将定义GAP的超微结构基础和细胞生物学 使用最先进的成像方法以及遗传和药物操纵的形成 内吞作用和间隙。 AIM 2将定义GC/差距在诱导和维持耐受性中的作用 使用间隙形成的基因操纵稳态中的腔抗原。 AIM 3将定义是否更改 GC/GAPS导致对饮食抗原和/或预后恶化的不当炎症反应 在感染过程中，使用遗传操纵伤寒沙门氏菌感染中的间隙。