In the midst of a flu-induced fever, it’s easy to ask why your own body would subject you to the chills, sweats, and aches that go along with a temperature. New research offers some insight into what’s going on beneath the surface. Fever-like temperatures shift how certain immune cells behave, ramping up activity in some key infection-fighters and dialing down suppression in regulatory cells by modifying their metabolism, according to a study published September 20 in the journal Science Immunology.
The findings offer insight into what’s long been a mysterious biological process, helping to partially explain how fevers fight infection. But the new research may also shed light on the darker side of our immune response. The specific biological pathways that the researchers identified could play a role in the increased cancer risk known to be associated with long-term inflammation. In short: “A little bit of fever is good, but a lot of fever is bad,” says senior study author Jeff Rathmell, a professor of immunobiology at Vanderbilt University Medical Center (VUMC).
A fever is a systemic, full-body rise in temperature–usually associated with infection. Inflammation, which involves a more localized rise in body temperature, resulting from injury or illness is also common. Though it’s long-been known that temperature is an important variable in lots of biological processes, the function of heat and exactly what’s happening to our immune system when the proverbial thermostat is turned up is poorly understood, says Rathmell. “Science doesn’t have a good answer,” he says. Generally, it’s been assumed that heat makes the body less welcoming to invading microbes–the pathogens that make us sick, “but it’s really not known,” he adds.
Reality, it seems, is much more complicated than the basic explanation, according to the new research. There’s a whole other side of the equation to consider: how our own cells respond to extra warmth. Previous research has indicated heat helps the immune system by stimulating activity. This week’s study illustrates how, down to the intracellular level.
Rathmell and his co-authors looked at how a handful of different types of T cells–a subset of white blood cells–react to heat. In multiple experiments of lab-cultured cells, they found that a “moderate fever” of around 102 degrees Fahrenheit increases the metabolism, proliferation, and activity of one group of generalist T cells, which go on to differentiate into multiple immune functions. At the same time, the regulatory T cells that generally suppress immune response were impaired, a double-negative that means loosened reins on the body’s defense system.
Finally and counterintuitively, one type of helper T cells, important for warding off viruses, were stressed by the higher temps. Many of these Th1 cells died in response to the stress. However, the survivors were super-cells–faster-acting and more prolific. “The cells that live have adaptations that allow them to overcome stress. They’re better in the long run but they have to get through this gauntlet in the middle,” says Rathmell.
“That balance makes logical sense in the context of a normal infection,” says lead study author Darren Heintzman, a postdoctoral fellow at VUMC. “You want your suppressors to be worse and your effectors to be better.” But there’s a catch.
In subsequent experiments, the scientists homed in on the mechanism behind many of those observed changes. Cell metabolism and the mitochondria were critically important–particularly one big metabolic protein called Electron Transport Chain 1. This protein complex, which helps to fuel cells, became far less efficient under higher temperature conditions. The same cellular stress occurring in the helper T cells is also likely occurring all over the body–in many different cells’ mitochondria, causing DNA damage that can lead to things like cancerous growth. “When that heat and that inflammation becomes chronic, that is when it becomes a problem–conditions like autoimmune diseases is where this isn’t such a good thing,” explains Heintzman.
Certain cancers, such as colon cancer, are known to be tied to inflammation from bowel diseases like Crohn’s disease. Now, there’s at least one clear hypothesis about why. “The heat that’s associated with local inflammation might be because of this mitochondrial mechanism… and might ultimately be contributing towards [cancer promoting] mutations,” Rathmell tells Popular Science.
Right now though, that’s speculative, he adds. They have the petri dish experiments, and also some data from past mice and human studies to indicate their theories pass muster–but more studies of actual, living systems are needed to confirm the hunch. Studying temperature changes in animals is a challenge because the many variables at play make isolating the effects of any one change near impossible, “but it’s really important, and we’re very interested in doing it,” says Rathmell.
“Everyone gets fevers. Everyone experiences temperature change–they feel the swelling and thumping in an [injured] finger,” says Heintzman. Now, he adds, we have a better understanding of what those thermal processes do to both help and hurt us. That doesn’t mean you should necessarily skip the fever reducer when you’re sick–nor be overly concerned about a swollen sprained ankle, he says. But it does mean even innate biological responses might be best in moderation.
