Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation
Darren R. Heintzman, Rachael C. Sinard, Emilie L. Fisher, Xiang Ye, Andrew R. Patterson, Joel H. Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J Rodriguez-Garcia, Nowrin U. Chowdhury, Emily N. Arner, Evan S. Krystoviak, Frank M. Mason, Yasmine T. Toudji, KayLee K. Steiner, Wasay Khan, Lana M. Olson, Angela Jones, Hanna S. Hong, Lindsay E Bass, Katherine L. Beier, Wentao Deng, Costas A. Lyssiotis, Dawn C. Newcomb, Alexander G. Bick, W. Kimryn Rathmell, John T. Wilson, Jeffrey C. Rathmell
Abstract
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 (T H 1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many T H 1 cells subjected to such temperatures died, surviving T H 1 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 T H 1 cells. T H 1 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 T H 1 cells to maintain genomic integrity and enhance effector functions.