Our research interest is to elucidate mechanisms of TGF-beta regulation of mucosal and systemic T cell immunity and tolerance, in order to offer targets to manipulate T cell immunity versus tolerance in animal models to develop potential therapies for relevant human diseases such as autoimmunity, cancer and infectious diseases. Specifically we would like to understand (1) how TGF-beta is involved in the function and development of CD4+CD25+ T regulatory cells (Treg) in mucosal and other lymphoid tissues, (2) how TGF-beta regulates T programmed cell death and the consequent immune tolerance, (3) how TGF-beta signal transduction and TGF-beta production in mucosal T cells are regulated, and (4) The cellular and molecular mechanisms of TGF-beta regulation of oral mucosal intraepithelial lymphocytes (IELs). Recently, we have focused on the isolation and characterization of CD4+CD25+ T regulatory cells from normal and genetically engineered mice and dissected the involvement of TGF-beta in immunosuppression mediated by T regulatory cells. Importantly, we have also identified that TGF-beta is a critical factor in the conversion of naive CD4+CD25- peripheral T cells to CD4+CD25+ T regulatory cells through induction of Foxp3, a master gene for T regulatory cell development. This finding not only has significant impact on understanding the generation of CD4+CD25+ regulatory T cells, but also makes it possible for the first time to design strategies to embellish the limited and/or inadequate numbers of T regulatory cells in the periphery, as needed, for therapeutic intervention in autoimmune diseases and inflammation. In addition, with the T-cell specific conditional TGF-beta receptor I knockout mice, we have shown that TGF-beta signaling is also critical for the development and generation of natural Foxp3+ Tregs in the thymus. In related studies, we have demonstrated that clearance of apoptotic T cells by macrophages and immature dendritic cells triggers TGF-beta;secretion, which plays a critical role in CD3-specific antibody mediated immune tolerance. We have also discovered that TGF-beta controls the development of mucosal IELs in the gut. Our immediate next steps are to decipher the molecular pathway(s) by which TGF-beta induces Foxp3 expression to define how CD4+CD25+ T cells are developed in and out of mucosal lymphoid systems as well as to begin to resolve the mystery of TGF-beta's role in T regulatory cell mediated immune tolerance. We also intend to apply the knowledge obtained from our basic research to manipulate T cell immunity versus tolerance in animal models to develop potential therapy for relevant human diseases, with special attention to NIDCR mission relevant diseases, such as Sjogrens syndrome and oral and head and neck cancers.

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Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$2,094,154
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
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Luo, Xuerui; Nie, Jia; Wang, Shuaiwei et al. (2016) Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 regulates the function of regulatory T cells. J Biol Chem 291:1201
Meng, Xiao; Yang, Jianmin; Dong, Mei et al. (2016) Regulatory T cells in cardiovascular diseases. Nat Rev Cardiol 13:167-79
Deng, Wei; Chen, Weiwei; Zhang, Zhuoya et al. (2015) Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus. Clin Immunol :
Ding, Xiaoli; Yan, Yaping; Li, Xing et al. (2015) Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity. J Immunol 194:4251-64
Liu, Rui; Li, Xia; Zhang, Zhuoya et al. (2015) Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis. Sci Rep 5:12777
MaruYama, Takashi; Kobayashi, Shuhei; Ogasawara, Kouetsu et al. (2015) Control of IFN-γ production and regulatory function by the inducible nuclear protein IκB-ζ in T cells. J Leukoc Biol 98:385-93
Chen, WanJun; Konkel, Joanne E (2015) Development of thymic Foxp3(+) regulatory T cells: TGF-β matters. Eur J Immunol 45:958-65
Yang, Ruili; Qu, Cunye; Zhou, Yu et al. (2015) Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis. Immunity 43:251-63
Kuang, Ruixia; Perruche, Sylvain; Chen, WanJun (2015) Apoptotic cell-linked immunoregulation: implications for promoting immune tolerance in transplantation. Cell Biosci 5:27
Wu, Tingting; Liu, Yi; Fan, Zhipeng et al. (2015) miR-21 Modulates the Immunoregulatory Function of Bone Marrow Mesenchymal Stem Cells Through the PTEN/Akt/TGF-β1 Pathway. Stem Cells :

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