Local immune tolerance in the large intestine mediated by GPR15

GPR15 介导的大肠局部免疫耐受

• 批准号: 10553237
• 负责人: Sangwon Vincent Kim
• 金额: $ 54.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553237
• 关键词: Antigens; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Binding Sites; CCR9 gene; Celiac Disease; Cell Separation; Cells; ChIP-seq; Chemicals; Chromosome 10; Circulation; Colitis; Cues; Data; Diet; Ensure; Event; Exposure to; Extravasation; FOXP3 gene; Failure; Food Hypersensitivity; Frequencies; GPR15 gene; Generations; Germ Cells; Goals; Health; Health Care Costs; Homing; Human; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunosuppression; Immunotherapy; In Vitro; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Invaded; Knowledge; Lamina Propria; Large Intestine; Ligands; Location; Mediating; Microbe; Molecular; Molecular Genetics; Mucous Membrane; Open Reading Frames; Patients; Physiological; Play; Predisposition; Prevalence; Process; Proliferating; Public Health; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Small Intestines; Small intestine mucous membrane; Source; Surface; T cell differentiation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Tissues; Transgenic Organisms; Tretinoin; Tryptophan; Work; absorption; aryl hydrocarbon receptor ligand; dietary; genetic approach; gut microbes; in vivo; microorganism antigen; migration; mouse model; novel; novel therapeutic intervention; oral tolerance; prevent; receptor; therapeutic evaluation; trafficking

PROJECT SUMMARY/ABSTRACT It is critical that the host immune system does not mount outright inflammatory responses against foreign antigens abundant in the lumen of the intestine (such as dietary antigens exposed through the small intestine mucosa and microbial antigens coming predominantly from the lumen of the large intestine). Failure in this process leads to a significant health threat to the host as evidenced by prevalence of celiac disease and inflammatory bowel diseases. Regulatory T cells (Tregs) have evolved to play a critical role to ensure this tolerance. Dietary antigens are known to generate inducible Tregs (iTregs) and systemic tolerance against those antigens is achieved by circulation of these iTregs throughout the body (oral tolerance). In contrast, it may not be beneficial for the host to establish systemic, Treg-mediated tolerance against antigens from the large intestine since self-replicating microbes, the primary source of antigens in the large intestine, can easily escape and invade tissues outside of the intestine. Our long-term goal is to characterize how Treg-mediated tolerance against antigens from the large intestine is accomplished. Our central hypotheses are that activation of the aryl hydrocarbon receptor (AHR) in T cells induces GPR15 expression and promotes iTreg differentiation simultaneously to produce GPR15+ iTregs and that the GPR15-C10orf99 receptor-ligand pair mediates the retention of Tregs in the large intestine and prevents systemic dissemination of iTregs, accomplishing local tolerance by GPR15+ iTregs. Guided by strong preliminary data, we have generated novel mouse models that will enable us to test these hypotheses. We propose to pursue the following two aims: (1) To characterize Treg-mediated immune tolerance against microbial antigens in the large intestine compared to systemic oral tolerance against dietary antigens from the small intestine, we will check whether GPR15-C10orf99 mediate trafficking of Tregs inside the large intestine lamina propria and Treg retention, in addition to their known function during extravasation. We will also determine the fate of GPR15+ iTregs and the consequences in Treg-mediated tolerance against gut microbial antigens after inducible deletion of GPR15. (2) To characterize the effect of AHR signaling on iTreg differentiation and GPR15 induction, we will test chemicals with reported AHR ligand activity for their ability to induce FOXP3 and GPR15 expression. We will also examine mechanisms underlying AHR-induced increase of GPR15+ Tregs in vivo at the cellular level. To understand the molecular mechanisms for AHR-mediated expression of FOXP3 and GPR15, we will perform CHIPseq analysis in T cells after AHR activation by specific ligands that we will identify. Our findings will significantly advance understanding of Treg-mediated tolerance and will help to develop novel therapeutic strategies to treat various immunological disorders.

项目总结/摘要 至关重要的是，宿主免疫系统不会对外来免疫细胞产生直接的炎症反应。 肠腔中丰富的抗原（例如通过小肠暴露的饮食抗原 粘膜和主要来自大肠内腔的微生物抗原）。失败在此 这一过程导致对宿主的显著健康威胁，如乳糜泻的流行所证明， 炎症性肠病。调节性T细胞（TCFs）已经进化到发挥关键作用，以确保这一点 宽容已知膳食抗原产生诱导型THBE（iTHBE）和针对THBE的系统耐受性。 这些抗原是通过这些iTreg在全身循环（口服耐受性）来实现的。而在非功能性 可能不利于宿主建立系统性Treg介导的针对来自 由于自我复制的微生物是大肠中抗原的主要来源， 逃逸并侵入肠外组织。我们的长期目标是描述Treg介导的 实现了对来自大肠的抗原的耐受性。我们的核心假设是， T细胞中芳香烃受体（AHR）的表达诱导GPR 15表达并促进iTreg分化 并且GPR 15-C10 orf 99受体-配体对介导了细胞内的免疫应答。 保留在大肠中的TdR，并防止iTdR的全身性传播，实现局部 通过GPR 15 + iTglutamine的耐受性。在强有力的初步数据的指导下，我们已经产生了新的小鼠模型， 能让我们检验这些假设我们建议追求以下两个目标：（1）描述 与全身口服相比，大肠中Treg介导的针对微生物抗原的免疫耐受 为了检测对小肠饮食抗原的耐受性，我们将检查GPR 15-C10 orf 99是否介导 大肠固有层内的T细胞运输和Treg保留，除了它们已知的 在外渗过程中发挥作用。我们还将确定GPR 15 + iTdR的命运及其后果， 诱导缺失GPR 15后Treg介导的对肠道微生物抗原的耐受性。(2)表征 AHR信号传导对iTreg分化和GPR 15诱导的影响，我们将用报道的方法测试化学品。 AHR配体活性用于其诱导FOXP 3和GPR 15表达的能力。我们亦会研究 AHR诱导的GPR 15 + T细胞在体内细胞水平增加的潜在机制。了解 AHR介导的FOXP 3和GPR 15表达的分子机制，我们将进行CHIPseq 我们将鉴定的特异性配体激活AHR后的T细胞分析。我们的发现将大大 促进对Treg介导的耐受性的理解，并将有助于开发新的治疗策略， 治疗各种免疫系统疾病。