Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation
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<sub>H</sub>1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many T<sub>H</sub>1 cells subjected to such temperatures died, surviving T<sub>H</sub>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<sub>H</sub>1 cells. T<sub>H</sub>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<sub>H</sub>1 cells to maintain genomic integrity and enhance effector functions.
Authors
- Wasay Khan
- Alexander G. Bick (ORCID: https://orcid.org/0000-0001-5824-9595)
- Lana M. Olson (ORCID: https://orcid.org/0000-0003-1315-380X)
- Emilie L. Fisher (ORCID: https://orcid.org/0000-0001-9186-7512)
- Lindsay E Bass (ORCID: https://orcid.org/0000-0002-3940-5633)
- Emily N. Arner (ORCID: https://orcid.org/0000-0003-3589-8829)
- Hanna S. Hong (ORCID: https://orcid.org/0000-0003-1202-2808)
- John T. Wilson (ORCID: https://orcid.org/0000-0002-9144-2634)
- Angela Jones (ORCID: https://orcid.org/0000-0002-1565-4360)
- Nowrin U. Chowdhury (ORCID: https://orcid.org/0000-0002-4621-1423)
- Ayaka Sugiura (ORCID: https://orcid.org/0000-0001-5326-5019)
- Channing Chi (ORCID: https://orcid.org/0000-0003-4987-4764)
- Jeffrey C. Rathmell (ORCID: https://orcid.org/0000-0002-4106-3396)
- Katherine L. Beier
- Frank M. Mason (ORCID: https://orcid.org/0000-0003-1338-494X)
- Dawn C. Newcomb (ORCID: https://orcid.org/0000-0003-2592-9433)
- KayLee K. Steiner (ORCID: https://orcid.org/0000-0003-2188-6376)
- Wentao Deng (ORCID: https://orcid.org/0009-0004-9903-9702)
- Kelsey Voss (ORCID: https://orcid.org/0000-0003-1732-2682)
- W. Kimryn Rathmell (ORCID: https://orcid.org/0000-0002-4984-0225)
- Costas Andreas Lyssiotis (ORCID: https://orcid.org/0000-0001-9309-6141)
- Darren R. Heintzman (ORCID: https://orcid.org/0000-0002-4903-758X)
- Andrew R. Patterson (ORCID: https://orcid.org/0000-0002-5177-5055)
- Yasmine T. Toudji
- Gabriel J Rodriguez-Garcia (ORCID: https://orcid.org/0000-0003-4143-8669)
- Evan S. Krystoviak
- Joel H. Elasy
- Xiang Ye (ORCID: https://orcid.org/0000-0002-8694-8710)
- Rachael C. Sinard
Institutions
- Vanderbilt University (US)
- University of Michigan (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1126/sciimmunol.adp3475
- Citations
- 26
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 6.25
Funders
- National Science Foundation
- Vanderbilt University
- Lupus Research Alliance
- Vanderbilt University Medical Center
- National Institutes of Health
- Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
- National Cancer Institute