Subset-specific mitochondrial and DNA damage shapes T cell responses to fever and inflammation
Heintzman, D.; Elasy, J. H.; Chi, C.; Ye, X.; Krystoviak, E.; Khan, W.; Olson, L. M.; Jones, A.; Voss, K.; Patterson, A.; Sugiura, A.; Mason, F. M.; Hong, H.; Bass, L. E.; Beier, K. L.; Deng, W.; Lyssiotis, C. A.; Bick, A. G.; Rathmell, W. K.; Rathmell, J.
Show abstract
Heat is a cardinal feature of inflammation. Despite temperature variability and dependence of enzymes and complexes, how heat and fever affect immune cells remains uncertain. We found that heat broadly increased inflammatory activity of CD4+ T cell subsets and decreased Treg suppressive function. Th1 cells, however, also selectively developed mitochondrial dysfunction with high levels of ROS production and DNA damage. This led Th1 cells to undergo Tp53-dependent death, which was required to minimize the accumulation of mutations in heat and inflammation. Th1 cells with similar DNA damage signatures were also detected in Crohns disease and rheumatoid arthritis. Fever and inflammation-associated heat thus selectively induce mitochondrial stress and DNA damage in activated Th1 cells that requires p53 to maintain genomic integrity of the T cell repertoire. One Sentence SummaryFever temperatures augment CD4+ T cell-mediated inflammation but induce differential metabolic stress and DNA damage in T cell subsets, with Th1 cells selectively sensitive and dependent on p53 to induce apoptosis and maintain genomic integrity.
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