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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080769-03
Application #
8306171
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Rothermel, Annette L
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$333,936
Indirect Cost
$111,186
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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Kim, Chang H (2014) Crawling of effector T cells on extracellular matrix: role of integrins in interstitial migration in inflamed tissues. Cell Mol Immunol 11:1-4
Chang, Jinsam; Thangamani, Shankar; Kim, Myung H et al. (2013) Retinoic acid promotes the development of Arg1-expressing dendritic cells for the regulation of T-cell differentiation. Eur J Immunol 43:967-78
Kim, Myung H; Kang, Seung G; Park, Jeong H et al. (2013) Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145:396-406.e1-10
Wang, Chuanwu; Thangamani, Shankar; Kim, Myunghoo et al. (2013) BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid. J Exp Med 210:475-89
Wang, Chuanwu; Lee, Jee H; Kim, Chang H (2012) Optimal population of FoxP3+ T cells in tumors requires an antigen priming-dependent trafficking receptor switch. PLoS One 7:e30793
Kim, Chang H (2011) Retinoic acid, immunity, and inflammation. Vitam Horm 86:83-101
Wang, Chuanwu; Hillsamer, Peter; Kim, Chang H (2011) Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets. BMC Immunol 12:53
Kang, S G; Park, J; Cho, J Y et al. (2011) Complementary roles of retinoic acid and TGF-ýý1 in coordinated expression of mucosal integrins by T cells. Mucosal Immunol 4:66-82
Lee, Jee H; Ulrich, Benjamin; Cho, Jungyoon et al. (2011) Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol 187:1778-87

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