FoxP3+ regulatory T cells play critical roles in maintaining immune tolerance in the intestine. FoxP3+ regulatory T cells migrate not only to the intestine but also to other organs for regulation of immune responses. The mechanisms that direct the migration of FoxP3+ T cells to the intestine and their specificity for the intestine versus other organs are largely unknown. This is a significant problem in developing FoxP3+ T cells into cellular therapeutics specifically targeting inflammatory diseases of the intestine. The objective of this application is to devise strategies by which we can generate gut-homing FoxP3+ T cells specific for normal or inflamed intestine. The central hypothesis of this application is that migration of FoxP3+ T cells to normal and inflamed intestine can be controlled by regulating the expression of gut-homing receptors in FoxP3+ T cells. Our rationale is that it will become possible to more effectively prevent or suppress inflammatory diseases in the intestine by regulating the migration of FoxP3+ T cells to normal or diseased intestine after the proposed research is completed. Also, it will be possible to increase the specificity of FoxP3+ T cells for inflammatory diseases in the intestine but reduce the side effect of the regulatory T cell therapy on necessary immune responses to pathogens or cancer cells in other organs. We propose the following aims to validate the hypothesis and accomplish the goal.
Specific aim #1 : Determine the temporal and spatial origin of gut- homing FoxP3+ T cells;
Specific aim #2 : Establish strategies to generate FoxP3+ regulatory T cells that preferentially migrate to intestine versus other organs;
Specific aim #3 : Establish strategies to generate FoxP3+ regulatory T cells that target inflamed tissue sites within the intestine. As the outcome, we will have the FoxP3+ T cells tailor-made for normal intestine to prevent inflammation or for inflamed intestine to suppress established inflammation. Once the strategy is validated by the proposed studies, it can be applied also to specific suppression of diseases at other tissue sites. Relevance to Public Health: The research will provide strategies for generation of FoxP3+ regulatory T cells that can specifically target normal or inflamed intestine and effectively prevent or suppress inflammation. Therefore, the proposed research will have positive impacts on prevention and control of inflammatory diseases in the intestine. In addition, the outcomes will have far-reaching implications for treatment of other chronic inflammatory disorders.
|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|
|Wang, Chuanwu; Kang, Seung G; HogenEsch, Harm et al. (2010) Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine. J Immunol 184:5519-26|
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