Molecular events driving CD8 ⁺ T cell exhaustion. Persistent antigen exposure leads to chronic TCR stimulation of effector (memory) CD8⁺ T cells, which causes dominant NFAT TF activation at the expense of AP-1 TF activity. The NFAT:AP-1 imbalance triggers the expression of TOX, NR4A, and IRF4, which together repress T-bet and TCF-1 and (indirectly) promote elevated EOMES levels. As a result, NFAT, TOX, NR4A, EOMES, and IRF4 control the chromatin landscape of chronically activated CD8⁺ T cells, promoting a transcriptional program that results in exhaustion while suppressing the effector/memory program.