Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.

Autor: Heintzman, Darren R., Sinard, Rachael C., Fisher, Emilie L., Ye, Xiang, Patterson, Andrew R., Elasy, Joel H., Voss, Kelsey, Chi, Channing, Sugiura, Ayaka, Rodriguez-Garcia, Gabriel J., Chowdhury, Nowrin U., Arner, Emily N., Krystoviak, Evan S., Mason, Frank M., Toudji, Yasmine T., Steiner, KayLee K., Khan, Wasay, Olson, Lana M., Jones, Angela L., Hong, Hanna S.
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Zdroj: Science Immunology; 2024, Vol. 9 Issue 99, p1-18, 18p
Abstrakt: Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions. Editor's summary: Heat is one of the hallmarks of inflammation, but its effect on immune cells is not well understood. Heintzman et al. report that temperatures associated with moderate-grade fevers (39°C) both enhance the metabolism, proliferation, and effector function of mouse CD4 T cells and dampen regulatory T cell suppressive potential. In addition, febrile temperatures disrupt electron transport chain complex 1, which selectively drives apoptosis and elimination of a substantial number of mouse and human T helper 1 (TH1) cells. Those TH1 cells that can adapt by increasing their mitochondrial mass and DNA damage responses, however, exhibit genomic integrity and augmented effector functions. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index