TOX transcriptionally and epigenetically programs CD8 ⁺ T cell exhaustion

SUMMARY

Exhausted CD8 ⁺ T cells (T _EX) in chronic infections and cancer have limited effector function, high inhibitory receptor co-expression and extensive transcriptional changes compared to effector (T _EFF) or memory (T _MEM) CD8 ⁺ T cells. T _EX are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T _EX are a distinct immune subset, with a unique chromatin landscape compared to T _EFF and T _MEM. However, the mechanisms governing the transcriptional and epigenetic development of T _EX remain unknown. Here, we identify the HMG-box transcription factor TOX as a central regulator of T _EX. TOX is largely dispensable for T _EFF and T _MEM formation, but is critical for exhaustion and without TOX T _EX do not form. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin independent and sustained in T _EX. Thus, robust TOX expression results in commitment to T _EX by translating persistent stimulation into a distinct T _EX transcriptional and epigenetic developmental program.