Figure 2. Reinforced DNA methylation programming during chronic infection.

Naïve CD8 T cells have a fully methylated PD-1 (Pdcd1) promoter, but upon antigen exposure and differentiation into effector CD8 T cells, the PD-1 locus becomes demethylated. (A) During acute antigen exposure, antigen-specific CD8 T cells that survive to the memory stage of the immune response re-acquire a methylated PD-1 promoter. (B) During the persistent antigen exposure of a chronic infection, the antigen-specific CD8 T cells retain a demethylated PD-1 locus. (C) After control of the chronic pathogen, either by natural mechanisms such as those that occur during elite control of HIV infection or by therapeutic intervention, the antigen-specific CD8 T cells retain a demethylated locus. In the cartoon schematic, methylation at the PD-1 locus (pdcd1) is represented by filled lollipops, and demethylated locus is represented by an open lollipop.