Fever leads to increased mitochondrial activity and damage in a subset of T cells, study finds

High temperatures accelerate the metabolism, proliferation and activity of immune cells, but they also cause – in a particular subset of T cells – mitochondrial stress, DNA damage and cell death, researchers at Vanderbilt University Medical Center have found.

The results, published in the journal Sciences Immunologyprovide a mechanistic understanding of how cells respond to heat and could explain how chronic inflammation contributes to cancer development.

The impact of high temperatures on cells is a relatively understudied area, said Jeff Rathmell, Ph.D., the Cornelius Vanderbilt Professor of Immunobiology and corresponding author of the new study. Most of the existing research on temperature focuses on agriculture and the impact of extreme temperatures on crops and livestock, he noted. It’s difficult to alter the temperature of animal models without causing stress, and cells in the lab are typically grown in incubators set to human body temperature: 37 degrees Celsius (98.6 degrees Fahrenheit).

“Standard body temperature is not actually the temperature of most inflammatory processes, but few people have actually bothered to look at what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology.

Graduate student Darren Heintzman was interested in the impact of fever for personal reasons: Before joining Rathmell’s lab, his father developed an autoimmune disease and had constant fevers for months.

“I started thinking about what such an increase in setpoint temperature might do. It was intriguing,” Heintzman said.

Heintzman cultured immune system T cells at 39 degrees Celsius (about 102 degrees Fahrenheit). He found that heat increased helper T cell metabolism, proliferation, and inflammatory effector activity and decreased the suppressive capacity of regulatory T cells.

“If you think about a normal response to infection, this makes a lot of sense: You want effector (helper) T cells to respond better to the pathogen, and you want suppressor (regulatory) T cells not to suppress the immune response,” Heintzman said.

But the researchers also made an unexpected discovery: A subset of helper T cells, called Th1 cells, experienced mitochondrial stress and DNA damage, and some of them died. This finding is puzzling, the researchers explained, because Th1 cells are involved in situations where there is often fever, such as viral infections. Why would the cells needed to fight infection die?

The researchers found that only a portion of Th1 cells die and the rest undergo adaptation, modifying their mitochondria and becoming more resistant to stress.

“There’s a wave of stress, and some cells die, but the ones that adapt and survive are better: they proliferate more and produce more cytokines (immune signaling molecules),” Rathmell said.

Heintzman was able to define the molecular events of the cellular response to high temperatures. He found that heat rapidly alters the electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. Alteration of ETC1 triggers signaling mechanisms that lead to DNA damage and activation of the tumor suppressor protein p53, which aids in DNA repair or triggers cell death to maintain genome integrity. Th1 cells are more sensitive to altered ETC1 than other T cell subtypes.

The researchers found Th1 cells with similar changes in sequencing databases of samples from patients with Crohn’s disease and rheumatoid arthritis, adding support for the molecular signaling pathway they defined.

“We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said. “Temperature varies across tissues and changes all the time, and we don’t really know what that’s doing. If temperature changes are changing the way cells are forced to do metabolism because of ETC1, that’s going to have a big impact. It’s a textbook staple.”

The results suggest that heat may be mutagenic: when cells responding to mitochondrial stress fail to properly repair DNA damage or die.

“Chronic inflammation accompanied by prolonged periods of elevated tissue temperatures could explain how some cells become tumors,” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation.

“People often ask me if fever is good or bad,” Rathmell adds. “The answer is simple: a little fever is good, but a high fever is bad. We knew that already, but now we have a mechanism to explain why it’s bad.”