Migration and function of Th17 cells in the gut

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Project Summary: 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 Th17 cell-mediated regulation of tissue inflammation and immunity. It is unknown how Th17 cells are induced, maintained and localized in the gut. This is a significant problem in our understanding and control (or utilization) 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 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, a receptor that is characteristically expressed by most Th17 cells and binds the chemokine CCL20 specifically expressed by follicle-associated epithelial cells and other specialized epithelial cells in the intestine. There are three aims: Specific aim #1. Determine the role of CCR6 in Th17 migration in the gut; Specific aim #2. Determine the role of CCR6 in induction, maintenance and propagation of Th17 cells in the gut; Specific aim #3. Determine the mechanism by which Th17 cells regulate the expression of CCR6. 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 pathologies and infection associated with the gut (e.g. inflammatory bowel diseases and bacterial infections) but is important also for inflammatory diseases in other tissue sites as well.