Fever temperatures rev up immune cell metabolism, proliferation and exercise, however additionally they — in a specific subset of T cells — trigger mitochondrial stress, DNA injury and cell demise, Vanderbilt College Medical Middle researchers have found.
The findings, printed Sept. 20 within the journal Science Immunology, provide a mechanistic understanding for a way cells reply to warmth and will clarify how power irritation contributes to the event of most cancers.
The influence of fever temperatures on cells is a comparatively understudied space, stated Jeff Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and corresponding creator of the brand new research. A lot of the present temperature-related analysis pertains to agriculture and the way excessive temperatures influence crops and livestock, he famous. It is difficult to alter the temperature of animal fashions with out inflicting stress, and cells within the laboratory are typically cultured in incubators which are set at human physique temperature: 37 levels Celsius (98.6 levels Fahrenheit).
“Customary physique temperature just isn’t truly the temperature for many inflammatory processes, however few have actually gone to the difficulty to see what occurs if you change the temperature,” stated Rathmell, who additionally directs the Vanderbilt Middle for Immunobiology.
Graduate pupil Darren Heintzman was within the influence of fevers for private causes: Earlier than he joined the Rathmell lab, his father developed an autoimmune illness and had a relentless fever for months on finish.
“I began fascinated about what an elevated set level temperature like that may do. It was intriguing,” Heintzman stated.
Heintzman cultured immune system T cells at 39 levels Celsius (about 102 levels Fahrenheit). He discovered that warmth elevated helper T cell metabolism, proliferation and inflammatory effector exercise and decreased regulatory T cell suppressive capability.
“If you consider a standard response to an infection, it makes loads of sense: You need effector (helper) T cells to be higher at responding to the pathogen, and also you need suppressor (regulatory) T cells to not suppress the immune response,” Heintzman stated.
However the researchers additionally made an sudden discovery — {that a} sure subset of helper T cells, referred to as Th1 cells, developed mitochondrial stress and DNA injury, and a few of them died. The discovering was complicated, the researchers stated, as a result of Th1 cells are concerned in settings the place there’s usually fever, like viral infections. Why would the cells which are wanted to battle the an infection die?
The researchers found that solely a portion of the Th1 cells die, and that the remaining bear an adaptation, change their mitochondria, and turn out to be extra immune to stress.
“There is a wave of stress, and a few of the cells die, however the ones that adapt and survive are higher — they proliferate extra and make extra cytokine (immune signaling molecules),” Rathmell stated.
Heintzman was capable of outline the molecular occasions of the cell response to fever temperatures. He discovered that warmth quickly impaired electron transport chain advanced 1 (ETC1), a mitochondrial protein advanced that generates power. ETC1 impairment set off signaling mechanisms that led to DNA injury and activation of the tumor suppressor protein p53, which aids DNA restore or triggers cell demise to keep up genome integrity. Th1 cells have been extra delicate to impaired ETC1 than different T cell subtypes.
The researchers discovered Th1 cells with related modifications in sequencing databases for samples from sufferers with Crohn’s illness and rheumatoid arthritis, including help to the molecular signaling pathway they outlined.
“We expect this response is a elementary manner that cells can sense warmth and reply to stress,” Rathmell stated. “Temperature varies throughout tissues and modifications on a regular basis, and we do not actually know what it does. If temperature modifications shift the best way cells are compelled to do metabolism due to ETC1, that is going to have a huge impact. That is elementary textbook sort of stuff.”
The findings recommend that warmth could be mutagenic — when cells that reply with mitochondrial stress do not correctly restore the DNA injury or die.
“Power irritation with sustained intervals of elevated tissue temperatures may clarify how some cells turn out to be tumorigenic,” Heintzman stated, noting that as much as 25% of cancers are linked to power irritation.
“Folks ask me, ‘Is fever good or unhealthy?’” Rathmell added. “The brief reply is: A bit of little bit of fever is nice, however loads of fever is unhealthy. We already knew that, however now we have now a mechanism for why it is unhealthy.”
The analysis was supported by the Nationwide Institutes of Well being (grants R01DK105550, R01HL136664, R01CA217987, R01HL118979, R01AI153167, R01CA245134, T32AI112541, T32DK101003, T32AR059039, K00CA253718), Lupus Analysis Alliance, Waddell Walker Hancock Most cancers Discovery Fund, and Nationwide Science Basis.
