Inhibition of IFN‐γ transcription by site‐specific methylation during T helper cell development

Polarization of naïve CD4 T cells into T helper type 2 (T H 2) cells is characterized by expression of IL‐4 and silencing of IFN‐γ. Here we show that during T H 2 polarization, the DNA methyltransferase Dnmt3a is recruited to the IFN‐γ promoter and correspondingly the promoter undergoes progressive de novo methylation. Notably, the CpG located at the −53 position becomes methylated rapidly and this methylation inhibits ATF2/c‐Jun and CREB transcription factor binding in vitro . In vivo , the same factors bind to the unmethylated IFN‐γ promoter in T helper type 1 (T H 1) cells but not the methylated IFN‐γ promoter in T H 2 cells. Furthermore, methylation at the −53 CpG alone is sufficient to inhibit the IFN‐γ promoter‐driven reporter gene expression in a T H 1 cell line. These findings suggest that rapid methylation of the evolutionarily conserved −53 CpG by Dnmt3a may suppress IFN‐γ transcription in developing T H 2 cells by directly inhibiting transcription factor binding.