Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [day 8 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 terms acute and chronic samples refer to P14 T-cells that were initially activated in acute LCMV (Armstrong) or chronic LCMV (clone-13) infections. 4 weeks later, the P14 T cells were collected, transferred into naive mice, and both then re-expanded in acute LCMV (Armstrong) infection. 8 days later P14 T-cells were collected and analysed. 2*10^3 wt P14 T-cells were transferred into C57BL6 host, infected with 2x10^5 PFU LCMV Armstrong or 2x10^6 PFU LCMV-c13 and collected on day 28. P14 T-cells were isolated and FACS-sorted, before being tranferred in a naive host,infected then with 2x105 PFU LCMV Armstrong. P14 were isolated and FACS-sorted on day 8 and sent to IMGM Laboratories to generate Microarray gene expression profiles.