Migration and function of Th17 cells in the gut

Th17 细胞在肠道中的迁移和功能

• 批准号: 7882855
• 负责人: CHANG H KIM
• 金额: $ 33.55万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882855
• 关键词: Affect; Anatomic Sites; Anatomy; Area; Attention; Autoimmune Diseases; Binding; Biological; Biology; CCL20 gene; CCR6 gene; CCR9 gene; Cell Lineage; Cells; Data; Disease; Generations; Goals; Gut associated lymphoid tissue; Heterogeneity; Human; Immigration; Immune; Immune Tolerance; Immune response; Immunity; Immunotherapy; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Intestines; Investigation; Knowledge; Maintenance; Mus; Organ; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Play; Public Health; Publications; Regulation; Reporting; Research; Role; Site; T-Lymphocyte; Testing; Tissues; Tretinoin; antimicrobial; cancer cell; cell motility; chemokine; cytokine; experience; flexibility; in vivo; innovation; insight; migration; novel; novel strategies; pathogen; prevent; public health relevance; receptor; tissue tropism; trafficking

DESCRIPTION (provided by applicant): Th17 cells play important roles in immunity, tissue inflammation and autoimmune diseases. The intestine is the most Th17 cell-enriched organ in the body. Therefore, investigation into the migration and function of Th17 cells in the gut would yield important information on the functions of Th17 cells in regulation of immune responses and immune tolerance in the intestine. It is unknown how Th17 cells are induced, maintained and localized in the gut. This is a significant problem in our understanding and control of this important T cell lineage. The central hypothesis of this application is that trafficking receptors play important roles in regulation of migration, induction, and/or maintenance of Th17 cells in the intestine. Our rationale is that it will become possible to more effectively control inflammatory diseases and infection in the gut by regulating the migration, induction and maintenance of gut Th17 cells after the proposed research is completed. Among the trafficking receptors, we will focus our research on CCR6, CCR9 and 1427. CCR6 is the receptor that is characteristically expressed by most Th17 cells and binds the chemokine CCL20 specifically expressed in the inductive sites of the intestine. CCR9 is a retinoic acid-induced trafficking receptor and plays potentially important roles in Th17 cell migration to certain effector sites of the intestine. 1427 is another retinoic-induced receptor potentially important for migration of Th17 cells to both inductive and effector sites. It is likely that the three receptors cooperatively regulate subset-specific distribution of Th17 cells in various anatomic compartments of the intestine. There are three aims: Specific aim #1. Determine the mechanism for coordinated regulation of the expression and/or activity of CCR6, CCR9 and 1427 in Th17 cells. Specific aim #2. Determine the individual and coordinated roles of CCR6, CCR9 and 1427 in Th17 cell migration to various microanatomic sites within the intestine. Specific aim #3. Determine the roles of CCR6, CCR9 and 1427 in induction, maintenance and effector function of Th17 cells in the gut. It is expected to yield novel knowledge regarding the trafficking receptor requirement for migration, induction and maintenance of gut Th17 cells. The project will also provide novel strategies to control the migration of Th17 cells and their differentiation and activities in specific anatomic sites of the gut. This problem has primary importance to the inflammatory pathology and infection associated with the gut (e.g. inflammatory bowel diseases and infection) but is important also for inflammatory diseases in other tissue sites as well. PUBLIC HEALTH RELEVANCE: Th17 cells have recently been recognized as a major lineage of immune cells that regulate inflammation in the body. The research aims to provide novel strategies to control the migration, differentiation and function of Th17 cells in the intestine, which are particularly relevant to inflammatory bowel diseases. The outcomes can also be applied to control of Th17-cell-regulated inflammation and immunity in other tissues.

描述（由申请人提供）：Th17细胞在免疫、组织炎症和自身免疫性疾病中发挥重要作用。肠道是体内Th17细胞富集最多的器官。因此，研究Th17细胞在肠道中的迁移和功能将为Th17细胞在肠道中调节免疫应答和免疫耐受的功能提供重要信息。目前尚不清楚Th17细胞是如何在肠道中被诱导、维持和定位的。这是我们理解和控制这一重要T细胞谱系的一个重要问题。该应用的中心假设是，转运受体在肠内Th17细胞的迁移、诱导和/或维持的调节中发挥重要作用。我们的理由是，在本研究完成后，通过调节肠道Th17细胞的迁移、诱导和维持，将有可能更有效地控制肠道炎症疾病和感染。在贩运受体中，我们将重点研究CCR6、CCR9和1427。CCR6是大多数Th17细胞特征性表达的受体，并结合在肠诱导部位特异性表达的趋化因子CCL20。CCR9是一种维甲酸诱导的转运受体，在Th17细胞迁移到肠道某些效应位点的过程中发挥着潜在的重要作用。1427是另一种视黄酮诱导的受体，对Th17细胞向诱导位点和效应位点的迁移具有潜在的重要作用。这三种受体可能协同调节Th17细胞在肠各解剖区室的亚群特异性分布。有三个目标：具体目标#1。确定Th17细胞中CCR6、CCR9和1427表达和/或活性协同调控的机制。具体目标2。确定CCR6、CCR9和1427在Th17细胞迁移到肠内不同微观解剖部位中的单独和协调作用。具体目标#3。确定CCR6、CCR9和1427在肠道Th17细胞诱导、维持和效应功能中的作用。该研究有望为肠道Th17细胞的迁移、诱导和维持所需的转运受体提供新的知识。该项目还将提供新的策略来控制Th17细胞的迁移及其在肠道特定解剖部位的分化和活动。这个问题对与肠道相关的炎症病理和感染（例如炎症性肠病和感染）具有重要意义，但对其他组织部位的炎症性疾病也很重要。