Fever’s link with specialized immunity is surprisingly ancient

Cold-blooded creatures like fish typically move to warmer environments to help fight infections. In one fish species, Nile tilapia, that behavioral — or sought-out — fever triggers the adaptive immune system, known for its acquired memory of specific bodily invaders, researchers report in the Dec. 24 Proceedings of the National Academy of Sciences. The finding hints that the link between fever and adaptive immunity arose long ago in animals’ evolutionary history, with a truly archaic common ancestor. 

“It was really exciting to see a concrete link between fever and adaptive immunity [in fish]. That’s something that hadn’t been solidified before,” says comparative immunologist Daniel Barreda of the University of Alberta in Edmonton, Canada, who was not involved in the study. The results, he says, nicely show that this is something that had evolved before our ancestors went through the transition from water to land.

Researchers already knew that cold-blooded animals’ behavioral fevers kick-start a fast-acting, general immune response called innate immunity. But it remained unclear whether fever’s tie to specialized adaptive immunity evolved independently in warm-blooded animals (mammals and birds) or was a strategy shared by all vertebrates.

So comparative immunologist Jialong Yang of East China Normal University in Shanghai and colleagues investigated immune responses in Nile tilapia (Oreochromis niloticus). Fish are special because they’re the evolutionarily oldest living animals with T cells — key players in the adaptive immune system, Yang says.

After tilapia were infected with the bacterium Edwardsiella piscicida, they preferred to swim in a water chamber kept at 34° Celsius, about 5 degrees above their typical temperature, for five days. Compared with sick fish kept at their usual temperature, those that sought warmer water had less bacteria in their livers four to six days after infection, and more of them survived.

Unlike fevers in warm-blooded animals, fish fevers did not cause T cells to multiply into a large number of cells that recognize and attack the specific invader.

But examining fish spleens five days after infection revealed that fever improved T cell survival and ability to kill infected cells. The researchers found the survival benefit comes from upping T cells’ production of a protein that stops programmed cell death, a response not found in animals before. This effect disappeared eight days after infection, suggesting that disease-fighting T cells were dying off to maintain immune homeostasis.

“It is becoming increasingly clear that fever is not simply a symptom of infection … it actually plays an important role in the protection against infection,” Barreda says. “We might take Tylenol or fever [reducers] to make us feel better when we have an infection. The question is, what are we giving up?”