Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [day28 acute vs chronic]

Chronic CD8 T-cell stimulation in persisting infections or tumors can induce a stable gene expression program, known as T-cell dysfunction or exhaustion, that limits the cell’s effector functions and anti-viral and anti-tumor immunity. Thus far, the underlaying molecular mechanisms that induce and stabilize this phenotype are vaguely understood. We report here that establishing this program requires the thymocyte selection-associated high mobility group-box protein (Tox). Genetic disruption of Tox augments effector function, decreases the expression of PD-1, and significantly enhances immunopathology. These changes are linked to a failure in fixing the dysfunctional phenotype in the critical Tcf1+ progenitor population and to impaired epigenetic programing. Surprisingly, the gains in effector function co-incide with declining numbers of Tcf1+ cells and result ultimately in reduced total numbers of pathogen-specific T-cells. Thus, we establish Tox as a critical factor for the development of T-cell dysfunction and establish a clear link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology. The term 'chronic' refers to P14 T-cells isolated from mice chronically infected with LCMV clone-13. 'Acute' are P14 T cells that were primed by in a specific LCMV-clone-13 infection setup in which P14 T cells are exposed to low antigen levels. In this setup, T cells retain a phenotype that resembles T-cells found in acutely resolved infection. Both samples were side by side compared. 2*10^3 wt P14 T-cells were transferred into C57BL6 host, infected with 2x10^6 PFU LCMV c13 wt or 0.4x10^6 PFU wt clone-13 mixed with 1.6x106 PFU gp33-deficient LCMV clone-13 mutant strain and collected on day 28. P14 T-cells were isolated and FACS-sorted and sent to IMGM Laboratories to generate Microarray gene expression profiles.