CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element
Athmane Teghanemt, Priyanjali Pulipati, Kara Misel‐Wuchter, Kenneth Day, Matthew S. Yorek, Ren Yi, Henry L. Keen, Christy Au, Thorsten Maretzky, Prajwal Gurung, Dan R. Littman, Priya D. Issuree
Abstract
The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of 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 histone H3K4me3 levels during T cell replication, which is critical for preventing 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. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells.