Fever increases immune cell metabolism, proliferation, and activity, but it also causes mitochondrial stress, DNA damage, and cell death in a specific subgroup of T cells, according to Vanderbilt University Medical Centre researchers.
The
study, published in Science Immunology, sheds light on how cells respond to
heat and how persistent inflammation can lead to cancer.
The
impact of fever temperatures on cells is a relatively understudied area, said
Jeff Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and
corresponding author of the new study. Most of the existing temperature-related
research relates to agriculture and how extreme temperatures impact crops and
livestock, he noted. 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 a 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 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 Darren Heintzman was interested in the impact of fevers for personal
reasons: Before he joined the Rathmell lab, his 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.
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 regulatory T
cell suppressive capacity.
"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.
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. Th1 cells were more sensitive to impaired
ETC1 than other T cell subtypes.
The
researchers 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.
"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 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.
"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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