Figure 1. Antigen stimulation is essential for establishing the progressive epigenetic states of T cell memory differentiation and exhaustion.

A naïve CD8⁺ T cell exposed to its cognate antigen undergoes differentiation which can result in several distinct T cell fates. In the context of acute stimulation, the naïve CD8⁺ T cell proliferates and clonally expands. Multipotent progenitor cells are able to give rise to any of the subsequent cell types. The vast majority of cells generated are terminal effectors (TE), which die fulfilling their duty of antigen clearance. After antigen clearance, a small subset of cells, described as memory precursor effector cells (MPEC – derived from a multipotent progenitor), survive the contraction stage of the immune response and develop into subsets of functional memory (FM) T cells [44]. These functional memory T cells remain poised to rapidly recall effector functions upon antigen reencounter. In the case of chronic stimulation, persistent antigen exposure results in an exhausted (Exh.) fate with T cells unable to illicit an effector response after antigen re-challenge [21]. The question mark indicates a need for further resolution of the branching point among the developmentally plastic cells that give rise to exhausted versus functional memory T cells. The general epigenetic state of effector and stem genes are represented at each of these stages of differentiation. White circles represent an unmethylated CpG and black circles represent a methylated CpG.