Subset-specific mitochondrial and DNA damage shapes T cell responses to fever and inflammation

Heat is a cardinal feature of inflammation that affects enzymes and molecular complexes, yet the effects on immune cells remain uncertain. We show heat broadly increased inflammatory activity of CD4+ T cell subsets and decreased Treg suppressive function. Heat-exposed Th1 cells, however, selectively developed mitochondrial stress with elevated reactive oxygen species and DNA damage driven by dependence on electron transport chain complex 1 (ETC1), which rapidly decreased activity. While Tp53 and Sting eliminated damaged Th1 cells, those that adapted showed improved long-term activity. Th1 cells with DNA damage and ETC1 signatures were also detected in Crohn’s disease and rheumatoid arthritis. Fever-relevant heat thus selectively induces mitochondrial stress in Th1 cells that drives apoptosis or adaptation to maintain genomic integrity and improve T cell function. To investigate the effects of heat on T cells, we cultured Naïve, Th0, Th17, and iTreg cells in differentiating cytokine media for 4 days at 37˚C or 39˚C. 6 replicates of each T cell subset are available. Naïve cells serve as the control cell group.