A first step in this direction was the recent identification of the HMG-box transcription factor TOX that regulates the epigenetic and transcriptional program in exhausted T cells in mouse models of chronic LCMV infection and cancer [60,61,62] and that is also associated with the exhausted phenotype of HCV-specific CD8+ T cells [60] and PD1+ T cells in HCC [78]. The gene discussed is CD8A; the disease is cancer.