Developmental epigenetic programming by Tet1/3 determines peripheral CD8 T cell fate.

In response to infections, naive CD8 T cells give rise to effector and memory T cells. However, eliciting long-lived memory CD8 T cells remains a challenge for many infections. DNA demethylation of cytosines within CpG dinucleotides by Tet enzymes is a key epigenetic mechanism that regulates short- and long-term transcriptional programs in cells. Currently, their roles in modulating CD8 T-cell effector and memory differentiation are unclear. Here, we report that developing CD8 T cells lacking Tet1/3 preferentially differentiate into short-lived effector and effector memory cells following acute infection. Using genome-wide analyses, mice in which Tet1/3 were ablated during T-cell development and mature CD8 T cells, respectively, we show that Tet1/3 regulates these cell fates by licensing the chromatin landscape of genes downstream of T-cell receptor activation during thymic T-cell maturation. However, in mature CD8 T cells, Tet1/3 are dispensable for effector and memory cell fates. These findings unveil context-specific roles of DNA demethylation, which are essential for defining pathways that contribute to CD8 memory T-cell generation in response to infections.