The HMG Transcription Factor TOX Induces a Transcriptional and Epigenetic Program of CD8+ T Cell Exhaustion in Chronic Infection and Cancer

Exhausted CD8+ T cells (TEX) in chronic infections and cancer are characterized by loss of optimal function, high co-expression of inhibitory receptors and extensive transcriptional changes compared to functional effector (TEFF) or memory (TMEM) CD8+ T cells. Due to their role in cancer and infections, TEX are now important clinical targets of checkpoint blockade and other immunotherapies. Recent epigenetic studies have demonstrated that TEX are a distinct immune subset, with a unique chromatin landscape compared to naïve CD8+ T cells (TN), TEFF, and TMEM. However, the mechanisms that govern the transcriptional and epigenetic events of TEX development remain unknown. Here, we identify the HMG-box protein TOX as a central regulator of TEX cells. TOX is largely dispensable for TEFF and TMEM formation yet, it is critical for exhaustion, as in the absence of TOX, TEX do not form. TOX is induced by calcineurin and NFAT2 and then operates in a feed-forward loop to become calcineurin independent and durably expressed at a high level in TEX, but not TEFF or TMEM. Lastly, TOX interacts with histone modifying enzymes and other epigenetic regulators including the HBO1 complex and the acetyl-transferase Kat7, providing a mechanism for TEX-specific epigenetic changes. Thus, high and sustained induction of TOX results in commitment to TEX by translating persistent stimulation cues into a distinct TEX transcriptional and epigenetic developmental program