Cytotoxic T lymphocytes are essential mediators of protective immunity against viral infections and malignancies and are a key target for immunotherapy approaches. However, prolonged exposure to an apparent antigen often attenuates the effector capacity of T cells and limits their therapeutic potential.1-4. This process, called depletion or dysfunction of T cells1, is manifested by epigenetic modifications of gene regulation that reduce the expression of cytokines and effector molecules and positively regulate the expression of inhibitory receptors such as Programmed Cell-Death 1 (PD-1)5-8. Up to now, the underlying molecular mechanisms that induce and stabilize the phenotypic and functional characteristics of exhausted T cells are vaguely understood.9-12. Here we report that the development and maintenance of depleted T cell populations requires the high mobility group box protein associated with thymocyte selection (Tox).13,14. Tox is induced by T cell receptor stimulation with high antigen concentration and is correlated with the presence of an "exhausted" phenotype during chronic exposure Lymphocyte choriomeningitis virus and human hepatitis C virus infection. The elimination of its DNA binding domain reduces the expression of PD-1, increases the production of cytokines and gives a more multifunctional phenotype of T cells. These mutated T cells initially induce an increase effector function and cause a more serious immunopathology, but end up experiencing a massive decrease in their quantity, especially in the subset of Tcf1.+ self-renewing T cells. Overall, we establish Tox as a critical factor in the normal progression of T cell dysfunction, maintenance of depleted T cells in chronic infection, and document a link between intrinsic suppression of CD8 T cells and protection against immune system. -pathology.