Progressive memory differentiation of CD8 T cells is regulated by de novo DNA methylation (P1426)

Memory CD8 T cells generated from acute infection or vaccination have the potential to provide the host with life-long immunity against re-infection, yet one of the least understood and most remarkable attributes of memory T cells is their ability to progressively regain select naïve cell functions following the effector stage of the response. Presently debated is whether or not CD8 T cell memory arises through progressive modification of effector programs. To ascertain if effector programs are progressively modified during the effector to memory stage of the response, we performed longitudinal analyses of acquired epigenetic programs at the L-selectin (CD62L) promoter in virus-specific CD8 T cells during acute LCMV infection of mice. We observed that the CD62L promoter acquires a repressive de novo DNA methylation program in both terminal (TE) and memory precursor (MP) effector CD8 T cells. Demethylation of the de novo program in MP effector cells results in re-expression of CD62L at the memory stage of differentiation and occurs in the absence of cell division. Conditional deletion of the DNA methyltransferase 3a blocks methylation of the CD62L promoter in effector cells resulting in faster CD62L re-expression during effector to memory cell conversion. These data provide proof-of-principle that progressive modification of epigenetic programs in CD8 T cells undergoing memory differentiation is utilized to re-acquire naïve-like properties to enhance the recall response.