Fever temperatures rev up immune cell metabolism, proliferation and activity, but they also—in a particular subset of T cells—cause mitochondrial stress, DNA damage and cell death, Vanderbilt University Medical Center researchers have discovered.

Findings from the team’s primarily in vitro studies offer a mechanistic understanding for how cells respond to heat and could explain how chronic inflammation contributes to the development of cancer. Jeff Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology, is corresponding author of the scientists’ report in Science ImmunologySubset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation,” in which they concluded “One major implication of our study is that a source of mutagenesis to initiate inflammation-associated cancers may derive from heat-dysregulated mitochondria in inflammatory environments.”

Heat is a cardinal feature of inflammation, yet it’s not known how heat impacts immune cells, the authors suggested. “Temperature change is a common physiological characteristic of immune responses yet is poorly understood in the context of T cell metabolism and function,” they wrote.

Moreover, the impact of fever temperatures on cells is a relatively understudied area, suggested Rathmell, who noted that most of the existing temperature-related research relates to agriculture and how extreme temperatures impact crops and livestock. It’s challenging to change the temperature of animal models without causing stress, and cells in the laboratory are generally cultured in incubators that are set at human body temperature: 37°C (98.6°F).

“Standard body temperature is not actually the temperature for most inflammatory processes, but few have really gone to the trouble to see what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology.

Graduate student and first author Darren Heintzman, PhD, was also interested in the impact of fevers.  Before joining the Rathmell lab Heintzman’s father developed an autoimmune disease and had a constant fever for months on end. “I started thinking about what an increased set point temperature like that might do. It was intriguing,” Heintzman said.

As part of their reported research the team cultured mouse immune system T cells at 39°C (about 102°F). They found that heat increased helper T cell metabolism, proliferation and inflammatory effector activity and decreased regulatory T cell suppressive capacity. “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 (Treg) suppressive capacity,” they wrote.

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

But the researchers also made an unexpected discovery—that a certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was confusing, the researchers said, because Th1 cells are involved in settings where there is often fever, like viral infections. Why would the cells that are needed to fight the infection die?

The researchers discovered that only a portion of the Th1 cells die, and that the rest undergo an adaptation, change their mitochondria, and become more resistant to stress. “There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better—they proliferate more and make more cytokine (immune signaling molecules),” Rathmell said.

Heat selectively induces mitochondrial dysfunction in Th1 cells. [Jeffrey C. Rathmell]
Heat selectively induces mitochondrial dysfunction in Th1 cells. [Jeffrey C. Rathmell]

Heintzman was able to define the molecular events of the cell response to fever temperatures. He found that heat rapidly impaired electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. ETC1 impairment set off signaling mechanisms that led to DNA damage and activation of the tumor suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity, and stimulator of interferon genes (STING). Th1 cells were more sensitive to impaired ETC1 than other T cell subtypes.  “Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to Th1 cells,” the team stated. “.… heat-exposed T helper 1 (Th1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and STING pathways.”

The researchers also found Th1 cells with similar changes in sequencing databases for samples from patients with Crohn’s disease and rheumatoid arthritis, adding support to the molecular signaling pathway they defined. “Th1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation,” the team stated. “scRNAseq analysis of Th1-like CD4 T cells in two different human disease suggests the presence of heat-sensitive Th1 cells in vivo that correlate with our in vitro mechanistic studies.”

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

The findings suggest that heat can be mutagenic—when cells that respond with mitochondrial stress don’t properly repair the DNA damage or die. “One major implication of our study is that a source of mutagenesis to initiate inflammation-associated cancers may derive from heat-dysregulated mitochondria in inflammatory environments,” the authors concluded. “Chronic inflammation with sustained periods of elevated tissue temperatures could explain how some cells become tumorigenic” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation.

“People ask me, ‘Is fever good or bad?’” Rathmell added. “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.”

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