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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Rothermel, Annette L
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Purdue University
Veterinary Sciences
Schools of Veterinary Medicine
West Lafayette
United States
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Kim, Chang H (2018) Microbiota or short-chain fatty acids: which regulates diabetes? Cell Mol Immunol 15:88-91
Kim, Myunghoo; Friesen, Leon; Park, Jeongho et al. (2018) Microbial metabolites, short-chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice. Eur J Immunol 48:1235-1247
Hashimoto-Hill, Seika; Friesen, Leon; Park, Sungtae et al. (2018) RAR? supports the development of Langerhans cells and langerin-expressing conventional dendritic cells. Nat Commun 9:3896
Park, Jeongho; Lee, Jang-Won; Cooper, Scott C et al. (2017) Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response. J Leukoc Biol 102:1093-1102
Hashimoto-Hill, S; Friesen, L; Kim, M et al. (2017) Contraction of intestinal effector T cells by retinoic acid-induced purinergic receptor P2X7. Mucosal Immunol 10:912-923
Kim, Myunghoo; Kim, Chang H (2016) Colonization and effector functions of innate lymphoid cells in mucosal tissues. Microbes Infect 18:604-614
Park, Jeongho; Goergen, Craig J; HogenEsch, Harm et al. (2016) Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell-Mediated Ureteritis and Hydronephrosis. J Immunol 196:2388-400
Kim, Myunghoo; Qie, Yaqing; Park, Jeongho et al. (2016) Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host Microbe 20:202-14
Kim, Chang H; Hashimoto-Hill, Seika; Kim, Myunghoo (2016) Migration and Tissue Tropism of Innate Lymphoid Cells. Trends Immunol 37:68-79
Kim, Myung H; Taparowsky, Elizabeth J; Kim, Chang H (2015) Retinoic Acid Differentially Regulates the Migration of Innate Lymphoid Cell Subsets to the Gut. Immunity 43:107-19

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