Taken together, these studies indicate that the core epigenetic and transcriptional program driving CD8 T cell exhaustion in chronic infection and cancer is initiated by the persistent Ag-dependent activation of TCR, which leads to two fundamental events (Figure 3B): (i) continuous induction of TCR-responsive IFR4, BATF and NFAT TFs; (ii) continuous expression of PD-1 and other IRs. Here, CD8A is linked to cancer.