Down-regulation of Tet2 is associated with Foxp3 TSDR hypermethylation in regulatory T cell of allergic rhinitis

Abstract

AimsTen-eleven-translocation (Tet) proteins are 5-methylcytosine oxidases and have profound impact on DNA methylation and genes expression. This study aimed to investigate the role of Tet2 and its association with Foxp3 DNA methylation in regulatory T (Treg) cell of allergic rhinitis (AR). Materials and methodsCD4+CD25+Treg cells were sorted from peripheral blood lymphocytes drawn from AR patients and spleen lymphocytes drawn from OVA-exposed mice by flow cytometry. Tet2 and Foxp3 expressions were studied in sorted Treg cells. DNA methylation of CpG sites in Foxp3 in Treg cells was analyzed by pyrosequencing. TET2 protein binding to Foxp3 DNA in Treg cells was detected by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR). Key findingsTreg cells drawn from AR patients and OVA-exposed mice showed reduction in cells counts, expression of Foxp3 mRNA and protein and down-regulation of Tet2, compared with the controls. Hypermethylation of Foxp3 TSDR and decline of TET2 binding to Foxp3 TSDR, but not promoter, were noted in Treg cells of OVA-exposed mice. Significant negative correlations between Tet2 expression and Foxp3 TSDR methylation, Foxp3 TSDR methylation and Foxp3 expression, and positive correlation between Foxp3 expression and Treg cells percentage were demonstrated by correlation analysis. SignificanceThis study demonstrated that down-regulation of Tet2 was associated with higher methylation level of Foxp3 TSDR, reduction in Foxp3 expression and Treg cells percentage in AR, suggesting that Tet2 probably modulated the function of Treg cells in AR through Foxp3 methylation.