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Metabolic exhaustion of T cells in chronic infection is mediated by inhibitory receptor PD-1 and T cell receptor dependent transcription factor IRF4

GSE84820 Mus musculus Expression profiling by high throughput sequencing 37 samples Submitted 2018/01/01 Platform GPL13112Platform GPL19057
Summary
During chronic stimulation T cells acquire an exhausted phenotype characterized by expression of multiple inhibitory receptors and down-modulation of effector function. While this is required for the protection of the organism from excessive immunopathology, it also prevents successful immunity against persistent viruses or tumor cells. Here we demonstrate that CD8+ T cell exhaustion is characterized by a progressive decline in cellular metabolism. Exhausted T cells exhibit reduced metabolic reserve, impaired fatty acid oxidation and production of mitochondrial reactive oxygen species (ROS). Blockade of inhibitory PD-1/PD-L1 signaling rescued mitochondrial biogenesis, oxidative phosphorylation and ROS production, which was required for efficient restoration of cellular expansion and effector function. Expression of inhibitory receptors and impaired metabolic function was fuled by high amounts of IRF4, BATF and NFAT, which formed a TCR-responsive transcriptional circuit that sustained the transcriptional network responsible for T cell exhaustion.
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Also filed as BioProject PRJNA335368 and SRA study SRP079900. Searching any of these in the dataset finder brings you back here.

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