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. 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 Sjogren?s syndrome and oral and head and neck cancers.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Intramural Research (Z01)
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Dental & Craniofacial Research
United States
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Perruche, Sylvain; Saas, Philippe; Chen, Wanjun (2009) Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T-cell increase: a potential cell-based therapy? Arthritis Res Ther 11:R104
Chen, Wanjun; Konkel, Joanne E (2009) TGF-{beta} and 'Adaptive' Foxp3+ Regulatory T cells. J Mol Cell Biol :
Yamaza, Takayoshi; Miura, Yasuo; Bi, Yanming et al. (2008) Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents. PLoS One 3:e2615
Liu, Yongzhong; Zhang, Pin; Li, Jun et al. (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9:632-40
Perruche, Sylvain; Zhang, Pin; Liu, Yongzhong et al. (2008) CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 14:528-35
Nandula, Seshagiri R; Amarnath, Shoba; Molinolo, Alfredo et al. (2007) Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor beta signaling in salivary glands. Arthritis Rheum 56:1798-805
Amarnath, Shoba; Dong, Li; Li, Jun et al. (2007) Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells. Retrovirology 4:57
Chen, Wanjun (2006) Dendritic cells and (CD4+)CD25+ T regulatory cells: crosstalk between two professionals in immunity versus tolerance. Front Biosci 11:1360-70
Liu, Yongzhong; Amarnath, Shoba; Chen, WanJun (2006) Requirement of CD28 signaling in homeostasis/survival of TGF-beta converted CD4+CD25+ Tregs from thymic CD4+CD25- single positive T cells. Transplantation 82:953-64
Miura, Yasuo; Gao, Zhigang; Miura, Masako et al. (2006) Mesenchymal stem cell-organized bone marrow elements: an alternative hematopoietic progenitor resource. Stem Cells 24:2428-36

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