Dnmt3a-mediated methylation balances memory Th1 and Tfh cell plasticity and functionality.

Following acute viral infection, naïve CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory cells. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. Here we demonstrate that Tfh and Th1 lineages acquire distinct DNA methylation programs that are preserved into memory. Using whole genome methylation analyses and deletion of DNA methyltransferase 3a, we found that DNA methylation is required for generating epigenetic programing to enforce lineage commitment and preserve lineage-specific functions during a recall response to infection. Importantly, partial inhibition of methylation using the methyltransferase inhibitor decitabine during priming enhances Tfh cell functionality in primary and secondary responses to viral infection. Together, these findings demonstrate that DNA methylation is critical to balance lineage commitment and functionality of memory CD4+ T cell subsets and reveal novel potential strategies to modulate immune responses to infectious diseases.