, Volume 87, Issue 12, pp 1191-1205

Induction of Foxp3 demethylation increases regulatory CD4+CD25+ T cells and prevents the occurrence of diabetes in mice

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Abstract

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+CD8Foxp3+ Treg cells or CD4+CD8CD25+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+CD8CD25+ cells predominantly. Furthermore, CD4+CD8CD25+ 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.