Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8⁺ T-cells during viral infection.

Exhaustion of CD8+ T-cells leads to their reduced immune functionality and is controlled by numerous transcription factors. Here we show that the transcription factor IRF-5 helps to limit functional exhaustion of murine CD8+ T-cells during the chronic stage of LCMV (CL13) viral infection. Our results suggest that T-cell inhibitory receptors and transcription factor TOX, which are implicated in dampening T-cell activation and promoting exhaustion, are upregulated in infected IRF-5-deficient CD8+ T-cells. In addition, these cells display a reduced capacity to produce cytokines and lower survival rates than wild-type cells. Our findings indicate that these effects are mediated by defective lipid metabolism, increased lipid peroxidation, enhanced mitochondrial ROS production, and reduced levels of oxidative phosphorylation in the absence of IRF-5. These results identify IRF-5 as an important regulator of lipid metabolism and mitochondrial function that protects CD8+ T-cells from functional exhaustion during the chronic stage of viral infection. Synopsis: A complex regulatory network is known to promote functional exhaustion of CD8+ T-cells, but less is known about those factors that protect CD8+ T-cells from exhaustion. This study identifies the transcription factor IRF-5 as a metabolic regulator that prevents premature functional exhaustion of LCMV-infected murine CD8+ T-cells by sustaining mitochondrial function and lipid metabolism. T-cell inhibitory receptors and transcription factor TOX are upregulated in infected IRF-5-deficient CD8+ T-cells. IRF-5-deficient CD8+ T-cells exhibit lower cytokine production and survival. IRF-5 regulates remodeling of mitochondrial cristae. IRF-5 maintains normal levels of oxidative phosphorylation. IRF-5 deficiency results in increased ROS production and lipid peroxidation. IRF-5 protects CD8+ T-cells from premature functional exhaustion by preventing excessive lipid peroxidation and mitochondrial defects. [ABSTRACT FROM AUTHOR]