Context-specific requirements of Tet enzymes in the modulation of CD8 effector and memory cell fates during acute viral infection [EM-seq]

In response to infections, naïve CD8 T cells give rise effector and memory T cells. However, eliciting long-lived memory CD8T cells remains a challenge for many infections. DNA demethylation of cytosines within CpG dinucleotides by Tet enzymes is a key epigenetic mechanism that regulate transcriptional programs. However, their roles in CD8 T cell memory differentiation is unclear. We report that following viral infection, Tet1/3-deficient CD8 T cells preferentially differentiate into short-lived effectors and effector memory cells. Using genome-wide DNA methylation and mice, in which Tet1/3 were ablated during T cell development and in mature CD8 T cells, respectively, we established that Tet1/3 regulate these cell fates by licensing the chromatin landscape of genes downstream of T cell receptor signaling during thymic T cell maturation. These findings unveil the context-specific roles of DNA demethylation, which is essential for defining pathways that contribute to CD8 memory T cell generation against infectious diseases. Overall design: To assess changes in methylation following T cell activation, FACs-sorted Naïve CD8 T cells were stimulated with plate-bound anti-cd3/cd28 and 18hrs later, cells were harvested for EM-Seq processing