Vitamin A (retinol) and its metabolites (called retinoids) play critical roles in the immune system. Retinoids regulate the development and functions of various types of immune cells and are being used as therapeutics for some inflammatory diseases and cancers. There is a strong body of evidence that vitamin A metabolites play both positive and negative roles in regulation of the immune system, and we still do not clearly understand how they function in both ways. The overall objective of this research is to elucidate the role of retinoids in generation of FoxP3+ regulatory T cells in mucosal tissues in vitro and in vivo and to determine the functional significance of this novel biological pathway. FoxP3+ regulatory T cells are a major subset of T cells specialized in suppression of autoimmunity and over-active immune responses. Our central hypothesis is that retinoids are natural inducers of FoxP3+ cells that are specialized in regulation of immune responses in mucosal tissues. This hypothesis is based upon our strong preliminary data showing that retinoids induce the master transcription factor FoxP3 in T cells. We also found that the retinoid-induced FoxP3+ cells are unique in that they express mucosal tissue homing receptors and several effector molecules associated with target cell killing. Our rationale for this project is that its successful completion may well provide a mechanism important for our understanding of the role of retinoids as natural regulators of immune responses. This application has three specific aims:
Specific aim #1 : Establish retinoids as natural inducers of a mucosal FoxP3+ regulatory T-cell subset.
Specific aim #2 : Determine the molecular basis of the tissue tropism of retinoid-induced mucosal homing FoxP3+ T cells.
Specific aim #3 : Investigate the impact of retinoid-induced FoxP3+ T cells on regulation of immune responses and inflammation in mucosal tissues. Following the successful completion of the proposed research, we expect to 1) have identified a novel mechanism by which vitamin A metabolites regulate the immune system;2) have determined the important trafficking receptors of retinoid-induced FoxP3+ T cells;and 3) have identified novel strategies by which we can control inflammatory diseases in selected mucosal tissues through the use of vitamin A/retinoids and retinoid-induced FoxP3+ T cells.

Public Health Relevance

We will study how vitamin A and its metabolites promote the generation of T cells important for regulation of immune responses. The outcomes of this project would significantly advance our understanding of the generation of important regulatory T cell subsets in mucosal tissues and of the roles of vitamin A and retinoids in regulation of the immunity and inflammatory diseases. Since vitamin A is widely consumed by humans, the impact of the project on human health will be high.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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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, 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
Kim, Chang H (2018) Microbiota or short-chain fatty acids: which regulates diabetes? Cell Mol Immunol 15:88-91
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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