Epigenetic Programming during thymic development sets the stage for optimal function in effector T cells via DNA demethylation

Abstract The potential for early thymic developmental events to program epigenetic states that influence adult T cell physiology remains an important question in health. Herein using the Cd4 locus as a paradigm for early developmental programming, we demonstrate that DNA demethylation during thymic development is critical for the licensing of a novel stimulus-responsive element that serves to maintain CD4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of H3K4me3 levels during T cell replication, which is critical for repelling de novo DNA methylation at the Cd4 promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication, thus providing evidence that early development can program stimulus-responsive elements to propagate a stable epigenetic state in effector T cells, with important biological consequences.