TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion

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.