The transcription factor IRF-5 is an essential metabolic checkpoint in CD8 T cells during chronic infection

Numerous transcription factors are involved in promoting an intricate gene expression program that leads to CD8 T cell exhaustion. Here, we found that the transcription factor IRF-5 is involved in limiting functional exhaustion of murine CD8 T cells by regulating the cell cycle and contributing to sustaining the mitochondrial functions and oxidative phosphorylation during the chronic stage of LCMV Cl13 infection. CD8 T cells lacking IRF-5 display reduced survival capacity and show increased signs of functional exhaustion during the chronic stage of infection. IRF-5-deficiency also resulted in a severely defective lipid metabolism, in an increased mitochondrial ROS production, and in the reduced capacity to produce ATP. Additionally, we observed increased lipid peroxidation in CD8 T cells lacking IRF-5, when compared with WT cells. These findings identify IRF-5 as a pivotal metabolic checkpoint in CD8 T cells during the chronic stages of infection and highlight its role in protecting cells from lipid peroxidation. RNA-seq profiling of adoptively transferred wildtype and Irf5-/- p14 CD8 T cells from male and female mice 21 days post-infection with LCMV cl13.