How heat from fever and inflammation affects immune cells

Fever raises the temperature of the body, and local inflammation can raise the temperature of surrounding tissues. But it’s not clear how these temperature changes affect the immune cells that fight infection and mediate inflammation. Among the most critical cells in the immune response are T cells. A variety of T cell types with different functions help recognize pathogens, control inflammation, and kill infected cells.

A team of researchers, led by Dr. Jeffrey Rathmell at Vanderbilt University Medical Center, carefully examined how higher temperatures affect T cells. The results of the study, which was funded in part by NIH, appeared in Science Immunology on September 20, 2024.

The team cultured mouse T cells at a normal body temperature (37 °C or 98.6 °F) and at fever temperature (39 °C or 102.2 °F). At the higher temperature, T helper cells, which direct other immune cells by releasing signaling molecules called cytokines, produced more cytokines than at the lower temperature. At the same time, regulatory T cells, which suppress immune responses, were less effective at the higher temperature. All the types of T cells evaluated proliferated more at the higher temperature. These led to an enhanced inflammatory state at fever temperature.

Higher temperatures also enhanced metabolism in various types of T cells. The exception was in the T helper 1 (T_H1) cell subset, whose metabolic rate was largely unaffected. T_H1 cells developed stress and DNA damage at high temperature, making them less likely to survive. Those that did survive, however, had more mitochondria—the energy-generating compartments of the cell—and greater activity.

Further experiments showed that higher temperatures impaired a protein called electron transport chain complex 1 (ETC1) in T_H1 cells. ETC1 is part of the process by which mitochondria convert fuel to energy. Impairing ETC1 led to formation of reactive byproducts, mitochondrial stress, and DNA damage. In response, the cells activated mechanisms to repair DNA or, failing that, to self-destruct.

The team wanted to find out if these results were relevant to human inflammation. They examined sequencing data from patients with Crohn’s disease and rheumatoid arthritis, two inflammatory autoimmune diseases. They found signs of increased DNA damage and ETC1 impairment in T_H1 cells like they saw in the cultured cells.

These findings suggest how fever and inflammation can enhance the immune response, but also increase DNA damage. DNA damage results in mutations when the damage isn’t properly repaired. This could explain why chronic inflammation increases the risk of cancer.

“People ask me, ‘Is fever good or bad?’” Rathmell says. “The short answer is, a little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.” 

—by Brian Doctrow, Ph.D.