GOBLET CELLS IN INTESTINAL IMMUNE HOMEOSTATSIS

肠道免疫稳态中的杯状细胞

• 批准号: 8690054
• 负责人: MARK James MILLER
• 金额: $ 33.06万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690054
• 关键词: Acetylcholine; Antigens; Cell physiology; Cell secretion; Cholinergic Agonists; Chronic; Colon; Data; Defect; Dendritic Cells; Enzymes; Epithelium; Exocytosis; Germ-Free; Gnotobiotic; Goblet Cells; Homeostasis; Homing; House mice; Immune; Immune response; Immune system; Immunity; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Lamina Propria; Life; Ligands; Lymphocyte; Maintenance; Mediating; Mesentery; Microscopy; Mucous body substance; Mus; Muscarinic Acetylcholine Receptor; Mutant Strains Mice; Nature; Pathway interactions; Phenotype; Play; Population; Process; Production; Property; Proteins; Receptor Signaling; Recruitment Activity; Regimen; Regulation; Resistance; Role; Shapes; Signal Pathway; Signal Transduction; Small Intestines; Source; Specific Pathogen Frees; Stimulus; Tretinoin; base; cell type; cholinergic; conditioning; germ free condition; imprint; improved; in vivo imaging; lymph nodes; microbial; migration; novel therapeutic intervention; oral tolerance; oral vaccine; receptor; response; two-photon

DESCRIPTION (provided by applicant): The small intestine lamina propria (LP) DC population is largely comprised of two divergent subtypes; CD103+ DCs with homeostatic/tolerogenic properties and CD103- DCs with inflammatory properties. These observations imply a critical role for delivering antigens to the appropriate LP-DC subtype to guide immune responses toward homeostasis or immunity. Recently it was discovered that goblet cells (GCs) act as a passages to deliver soluble luminal antigens to CD103+ LP-DCs. This discovery suggests that GCs play an important and previously unappreciated role in the induction and maintenance of intestinal immune homeostasis. However, mechanistic details are lacking for how this GC function is regulated and how GC mediated antigen delivery contributes to mucosal immune homeostasis. We observed that cholingeric stimuli induce the goblet cell associated antigen passages (GAPs), and that GCs sensitivity to cholinergic stimuli is regulated by sensing the luminal flora. Moreover in the absence of GCs, the cellular intestinal immune compartment is altered, suggesting that GCs play additional roles in shaping the intestinal immune system. Therefore we hypothesize that GCs play a crucial role shaping intestinal immunity through the recruitment and conditioning of LP-DCs, and by regulating antigen delivery in response to intestinal microbiota to promote homeostasis. In aim 1 we will evaluate how sensing the luminal microbiota alters GC sensitivity to cholinergic stimuli using in vivo imaging and ex vivo studies on gnotobiotic mice, specific pathogen free mice, and induced mutant mice strains. In aim 2 we will evaluate the cellular source of acetylycholine inducing GAPs and how it is regulated, using ex vivo approaches and induced mutant mice with cell type specific defects in acetylcholine production. In aim 3 we will evaluate the role of GCs and GAPs in homeostatic immune responses to luminal protein antigens using regimens to induce and challenge oral tolerance. These studies will also evaluate the role of GCs in recruiting and imprinting LP-DCs. Understandning GAP regulation and the role of GAPs in intestinal immune homeostasis may offer new therapeutic interventions for intestinal inflammatory diseases and avenues to optimize oral vaccines.

描述（由申请人提供）：小肠固有层（LP）DC种群在很大程度上由两个不同的亚型组成； CD103+ DC具有稳态/耐受性特性和具有炎症特性的CD103-DC。这些观察结果意味着将抗原传递到适当的LP-DC亚型以指导对稳态或免疫力的免疫反应的关键作用。最近，发现杯状细胞（GCS）充当将可溶性腔抗原传递给CD103+ LP-DCS的通道。这一发现表明，GCS在肠道免疫稳态的归纳和维持中起着重要且以前没有批准的作用。但是，缺乏该GC功能如何调节该GC功能以及GC介导的抗原递送如何有助于粘膜免疫稳态的机械细节。我们观察到凝胶刺激会诱导杯状细胞相关的抗原通道（GAP），并且通过感测腔植物群来调节GCS对胆碱能刺激的敏感性。此外，在没有GC的情况下，细胞肠道免疫区室发生了改变，这表明GCS在塑造肠道免疫系统中起了额外的作用。因此，我们假设GC通过LP-DCS的募集和调节，并通过调节抗原递送以响应肠道菌群来促进稳态，从而扮演肠道免疫的关键作用。在AIM 1中，我们将使用体内成像和对gnotobiotic小鼠，特定病原体的特定病原体小鼠和诱导的突变小鼠菌株的体内成像和离体研究来评估如何使用体内成像和离体研究来改变GC对胆碱能刺激的敏感性。在AIM 2中，我们将使用离体方法和诱导的突变小鼠评估乙酰胆碱诱导间隙的细胞来源，并在乙酰胆碱产生中具有细胞类型特异性缺陷。在AIM 3中，我们将使用方案来评估GC和GAP在对腔蛋白抗原的稳态免疫反应中的作用，以诱导和挑战口服耐受性。这些研究还将评估GC在招募和印迹LP-DC中的作用。了解间隙调节以及差距在肠道免疫稳态中的作用可能会为肠道炎症性疾病和优化口服疫苗的途径提供新的治疗干预措施。