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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE132028 | GEO | 2019/07/03

REPOSITORIES: GEO

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Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [day 8 acute vs chronic]

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