TOX transcriptionally and epigenetically programs CD8 T cell exhaustion.

Exhausted CD8 T (T) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T) or memory (T) CD8 T cells. T cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T cells are a distinct immune subset, with a unique chromatin landscape compared with T and T cells. However, the mechanisms that govern the transcriptional and epigenetic development of T cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T cells in mice. TOX is largely dispensable for the formation of T and T cells, but it is critical for exhaustion: in the absence of TOX, T 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 cells. Robust expression of TOX therefore results in commitment to T cells by translating persistent stimulation into a distinct T cell transcriptional and epigenetic developmental program.