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, and (3) how TGF-beta signal transduction and TGF-beta production in mucosal T cells are regulated. 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-βsecretion, which plays a critical role in CD3-specific antibody mediated immune tolerance. 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-betas 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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National Institute of Dental & Craniofacial Research
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Placek, Katarzyna; Hu, Gangqing; Cui, Kairong et al. (2017) MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping. Nat Immunol 18:1035-1045
Konkel, Joanne E; Zhang, Dunfang; Zanvit, Peter et al. (2017) Transforming Growth Factor-? Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses. Immunity 46:660-674
Zhang, Dunfang; Chia, Cheryl; Jiao, Xue et al. (2017) D-mannose induces regulatory T cells and suppresses immunopathology. Nat Med :
Meng, Xiao; Yang, Jianmin; Dong, Mei et al. (2016) Regulatory T cells in cardiovascular diseases. Nat Rev Cardiol 13:167-79
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
Chen, WanJun; Ten Dijke, Peter (2016) Immunoregulation by members of the TGF? superfamily. Nat Rev Immunol 16:723-740
Kuang, Ruixia; Perruche, Sylvain; Chen, WanJun (2015) Apoptotic cell-linked immunoregulation: implications for promoting immune tolerance in transplantation. Cell Biosci 5:27
Zhang, Dunfang; Tu, Eric; Kasagi, Shimpei et al. (2015) Manipulating regulatory T cells: a promising strategy to treat autoimmunity. Immunotherapy 7:1201-11
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
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-?1 Pathway. Stem Cells :

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