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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Park, J; Kim, M; Kang, S G et al. (2015) Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 8:80-93
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
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
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
Kim, Chang H (2011) Retinoic acid, immunity, and inflammation. Vitam Horm 86:83-101
Betz, Briana C; Jordan-Williams, Kimberly L; Wang, Chuanwu et al. (2010) Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J Exp Med 207:933-42

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