TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion

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-independent and sustained in T ex cells. Robust expression of TOX therefore results in commitment to T ex cells by translating persistent stimulation into a distinct T ex cell transcriptional and epigenetic developmental program.