Induction of Foxp3 demethylation increases regulatory CD4+CD25+ T cells and prevents the occurrence of diabetes in mice.
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.
Zheng
Qanhui
Q
Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang, Beijing, China 100101.
Xu
Yamei
Y
Liu
Yanlong
Y
Zhang
Baojun
B
Li
Xiaokun
X
Guo
Feng
F
Zhao
Yong
Y
D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000077209:Decitabine; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D000077209:Decitabine; D001374:Azacitidine