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Exhausted CD8⁺ T (T_ex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T_eff) or memory (T_mem) CD8⁺ T cells. T_ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T_ex cells are a distinct immune subset, with a unique chromatin landscape compared with T_eff and T_mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T_ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T_ex cells in mice. TOX is largely dispensable for the formation of T_eff and T_mem cells, but it is critical for exhaustion: in the absence of TOX, T_ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin …