A Distinct Region of the Murine IFN-gamma Promoter Is Hypomethylated from Early T Cell Development through Mature Naive and Thl Cell Differentiation,but Is Hypermethylated in Th2 Cells

摘要

Reports on the status of DNA methylation of the IFN-gamma gene during T cell development in human and mouse have presented somewhat contradictory results.In this study we demonstrate in the mouse that methylation of the IFN-gamma promoter inhibits its transcriptional activity,and define a small hypomethylated region in T cells that correlates with transcription.The IFN-gamma promoter was also hypomethylated in NK cells,but not in B cells or nonhemopoietic tissues.Surprisingly,unlike the promoters of the IL-2 and IL-4 genes,the IFN-gamma promoter was hypomethylated in naive CD4~+ and CD8~+ T cells,and in this form from very early in T cell development.A population of non-B,non-T,non-NK cells containing the hypomethylated promoter was also found in the bone marrow.The hypomethylated state appears stable until peripheral CD4~+ T cells differentiate in response to Ag and APC.After T cell stimulation in vitro under Th2 conditions,but far less so under Thl conditions,CD4~+ cells display a more methylated IFN-gamma promoter,which may contribute to the lack of expression of IFN-gamma in these preactivated cells.Our experiments support a new model of IFN-gamma chromatin structural changes in murine T cell development that differs from what has been previously published for human T cells.