The transcription factor IRF-5 is essential for the metabolic rewiring of CD8 T cells during chronic infection

Mai, L. T.; Swaminathan, S.; Nguyen, T. H.; Charpentier, T.; Loucif, H.; Carmona-Perez, L.; Lamarre, A.; Heinonen, K. M.; Fritz, J. H.; Stager, S.

doi:10.1101/2024.01.29.577789

bioRxiv · 10.1101/2024.01.29.577789

The transcription factor IRF-5 is essential for the metabolic rewiring of CD8 T cells during chronic infection

Mai, L. T.·Swaminathan, S.·Nguyen, T. H.·Charpentier, T.·Loucif, H.·Carmona-Perez, L.·Lamarre, A.·Heinonen, K. M.·Fritz, J. H.·Stager, S.

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Abstract

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 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 a faulty mitochondrial envelope, 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 regulator of the metabolic rewiring that occurs in CD8 T cells during the chronic stages of infection and highlight its role in protecting cells from cell death, possibly by lipid peroxidation. SummaryIRF-5 is critical for regulating mitochondrial functions and oxidative phosphorylation in CD8 T cells during chronic stages of LCMV Cl13 infection.

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Mai, L. T., Swaminathan, S., Nguyen, T. H., Charpentier, T., Loucif, H., Carmona-Perez, L., Lamarre, A., Heinonen, K. M., Fritz, J. H., Stager, S.. 2024-01-31. The transcription factor IRF-5 is essential for the metabolic rewiring of CD8 T cells during chronic infection. https://doi.org/10.1101/2024.01.29.577789

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