Induction of Foxp3 demethylation increases regulatory CD4+CD25+ T cells and prevents the occurrence of diabetes in mice
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CD4+CD25+ regulatory T cells (Treg), a subpopulation of CD4+ T cells, regulate immune responses. Foxp3 is a key transcription factor for the development and function of Treg cells. During T-cell activation in vitro, a DNA demethylation agent 5-Aza-2′-deoxycytydine (DAC) can induce Foxp3 expression in CD4+CD25− Foxp3− cells via altering methylation status of a conserved element in the 5′-untranslated region of the Foxp3 gene. However, the effects of this agent on the development of Foxp3+ Treg cells in the thymus and in vivo are poorly understood. In the present study, a short-term treatment with a low dose of DAC significantly increased the ratios of thymic CD4+CD8− CD25+ cells or CD4+CD8− Foxp3+ cells to CD4+CD8− cells, and the total numbers of thymic CD4+CD8−Foxp3+ Treg cells or CD4+CD8−CD25+Foxp3+ Treg cells in the thymus in mice. DAC-treatment induced the Foxp3 expression and the significant demethylation of a CpG island in the first intron of the Foxp3 gene in CD4+CD8−CD25+ cells predominantly. Furthermore, CD4+CD8−CD25+ thymocytes in DAC-treated mice exhibited enhanced immunosuppressive function than those in control mice. In addition, DAC treatment in vivo was effective in improving the clinical course of diabetes in cyclophosphamide (CY)-potentiated non-obese diabetic mice (CY-NOD). Thus, the in vivo treatment with DAC can significantly promote the development of natural thymic CD4+CD25+Foxp3+ Treg cells through Foxp3 demethylation, implicating a therapeutic application of DAC in patients suffering from autoimmune diseases.
KeywordsThymocytes Regulatory T cells Epigenetic Development Autoimmune disease
Regulatory T cell
Forkhead box protein 3
Cytotoxic T-lymphocyte-associated protein 4
Glucocorticoid-induced tumor necrosis factor receptor
Peripheral blood mononuclear cells
Median fluorescence intensity
The authors wish to thank Ms. Jing Wang and Ms. Jianxia Peng for their expertise technical assistance, Ms. Qinghuan Li for her excellent laboratory management. This work was supported by grants from National Natural Science Foundation (30630060, 30425026, Y.Z.), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars of State Education Ministry (2005-546, Y.Z.).
Conflict of interest statement
The authors declare that they have no conflicts of interest.
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