Feverish temperatures accelerate metabolism, proliferation and immune cell activity, but also (in a particular subset of T cells) cause mitochondrial stress, DNA damage and cell death, researchers at Vanderbilt University Medical Center have discovered.
The findings, published September 20 in the journal Science ImmunologyThey offer a mechanistic understanding of how cells respond to heat and could explain how chronic inflammation contributes to cancer development.
The impact of fever temperatures on cells is a relatively understudied area, said Jeff Rathmell, PhD, the Cornelius Vanderbilt Professor of Immunobiology and corresponding author on the new study. Most of the existing temperature-related research concerns agriculture and how extreme temperatures affect crops and livestock, he noted. It’s challenging to change the temperature of animal models without causing stress, and cells in the lab are typically grown in incubators that are set to human body temperature — 37 degrees Celsius (98.6 degrees Fahrenheit).
“Standard body temperature is not actually the temperature for most inflammatory processes, but few have 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 fevers for personal reasons: Before joining Rathmell’s lab, his father developed an autoimmune disease and had a constant fever for months.
“I started thinking about what a higher setpoint temperature like that could do. I found it fascinating,” Heintzman said.
Heintzman cultured immune system T cells at 39 degrees Celsius (about 102 degrees Fahrenheit). He found that heat increased the metabolism, proliferation, and inflammatory effector activity of helper T cells and reduced the suppressive capacity of regulatory T cells.
“If you think about a normal response to an infection, it makes a lot of sense: You want the effector (helper) T cells to respond better to the pathogen, and you want the suppressor (regulatory) T cells to not suppress the immune response,” Heintzman said.
But the researchers also made an unexpected discovery: A certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was puzzling, the researchers said, because Th1 cells are involved in settings where fever is often present, such as viral infections. Why would cells needed to fight infection die?
The researchers found that only a portion of Th1 cells die and the rest undergo adaptation, changing their mitochondria and becoming more resistant to stress.
“There is a wave of stress and some cells die, but those 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 febrile temperatures. He found that heat rapidly damaged electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. Impairment of ETC1 triggers signaling mechanisms that lead to DNA damage and activation of the tumor suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity. Th1 cells were more sensitive to ETC1 impairment 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 to 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 between tissues and changes all the time, and we don’t really know what it does. If temperature changes change the way cells are forced to perform metabolism because of ETC1, that will have a huge impact. This is fundamental stuff that’s in the textbooks.”
The findings suggest that heat may be mutagenic: when cells responding to mitochondrial stress fail to properly repair DNA damage, they die.
“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 fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism that explains why it’s bad.”
The research was supported by the National Institutes of Health (grants R01DK105550, R01HL136664, R01CA217987, R01HL118979, R01AI153167, R01CA245134, T32AI112541, T32DK101003, T32AR059039, K00CA253718), the Lupus Research Alliance, the Waddell Walker Hancock Cancer Discovery Fund, and the National Science Foundation.