When you’re sick, you might develop a fever. It can be part of the body’s response to an infection. But exactly how that fever helps the body fight infections has long been a mystery. A new study in mice shows that it helps immune cells more quickly reach and attack harmful germs.
JianFeng Chen works at the Shanghai Institute of Biochemistry and Cell Biology in China. His team studied how immune cells travel from a blood vessel to the site of an infection. A fever gives the cells a superpower that speeds up that trip, his team found.
The body’s main infection fighters are T cells. They’re a type of white blood cell. When they aren’t killing germs, these cells serve as a patrol squad. Millions of T cells flow through the blood on the lookout for harmful bacteria and viruses. Most of the time, they flow along in a quiet, monitoring mode. But as soon as they detect potential danger, they kick into high gear.
Now they head for the nearest lymph node. Hundreds of these small, bean-shaped glands are scattered throughout our bodies. Their job is to trap disease-causing microbes near the site of an infection. That helps the T cells home in to attack the invaders and clear them out. (You may have felt swollen lymph nodes in your neck, under your jaw or behind your ears. That’s a sign that your immune system is busy fighting a cold or other infection.)
The immune system is similar in people and mice. So Chen’s group used cells from mice to study how fever might work in people. They found that fever's heat boosts two molecules that help T cells get from blood vessels into lymph nodes. One is alpha-4 integrin (INT-eh-grin). It’s part of a group of proteins on the surface of T cells that help these cells chat with each other. The other is known as heat shock protein 90, or Hsp90.
As body temps climb, T cells make more Hsp90 molecules. As these molecules accumulate, the cells switch their α4 integrin to an active state. This makes them sticky. It also allows each Hsp90 molecule to attach itself to the tail ends of two α4-integrin molecules.
Chen and his coworkers described their new findings January 15 in Immunity.
Feeling the heat
In their active state, the alpha-4-integrin molecules stick out from a T cell’s surface. They resemble the hook side of hook-and-loop tape (such as Velcro). Cells that line walls of the blood vessels act as the loops on such tape. With their extra sticking power, T cells now can grab hold of the blood vessel wall near a lymph node.
That’s helpful because the blood vessel is like a fire hose.
“Blood is gushing through at high speed, pushing along any cells that float in it, including the T cells,” explains Sharon Evans. She was not involved in the new study. But she is an immune-system expert at the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.
Grabbing onto the vessel wall helps T cells withstand the blood’s strong current. That means more can quickly squeeze through the wall into a lymph node. There, they team up with other immune cells to attack and destroy infectious germs.
The researchers first showed in a lab dish how feverish heat causes Hsp90 to bind to alpha-4 integrin. Then they moved on to animals. Chen’s group infected mice with a germ that makes their stomach and intestines sick. It also triggers a fever.
When their immune system doesn’t work well, this infection risks killing the mice.
In one group of animals, the researchers prevented αlpha-4 integrin and Hsp90 from sticking together. In the other mice, known as a control group, the two molecules worked normally. In both groups, the team measured how many T cells were in the lymph nodes. Fewer of those cells reached their target in the mice with a blocked pathway. More of these mice also died.
“To me, this was the most exciting part,” says Leonie Schittenhelm. She was not part of the new study. She does, however, study the immune system at Newcastle University in England. The new findings show “these two molecules are relevant in living mice with a fever,” she says. “That’s strong evidence that they may help the T cells get to the right place for clearing the infection."
Confirming that the same two molecules are at work in mice was important. Many animals raise their body temperature to help fight infections. Researchers have observed this in fish, reptiles and mammals. That suggests the process has been maintained throughout evolution. So it’s likely that people use the same molecules as mice.
But researchers still need to prove it. And if they do, this could point toward new treatments for disease. “Eventually,” Evans explains, “we may be able to treat cancer patients with their own T cells after improving [the cells’] ability to travel from the bloodstream to the cancer site.”
Fever: friend or foe?
If fevers help fight infection, should people take fever-reducing drugs when they get sick?
“Waiting a few hours before taking these drugs may boost the immune system of an otherwise healthy person,” says Chen.
But he also notes that whether it’s safe to ride out a fever depends on what’s causing it. So if you’re unsure, he says, seek a doctor’s advice.
bacteria (singular: bacterium) Single-celled organisms. These dwell nearly everywhere on Earth, from the bottom of the sea to inside other living organisms (such as plants and animals). Bacteria are one of the three domains of life on Earth.
biochemistry A field that marries biology and chemistry to investigate the reactions that underpin how cells and organs function. People who work in this field are known as biochemists.
biology The study of living things. The scientists who study them are known as biologists.
blood vessel A tubular structure that carries blood through the tissues and organs.
cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.
control A part of an experiment where there is no change from normal conditions. The control is essential to scientific experiments. It shows that any new effect is likely due only to the part of the test that a researcher has altered. For example, if scientists were testing different types of fertilizer in a garden, they would want one section of it to remain unfertilized, as the control. Its area would show how plants in this garden grow under normal conditions. And that gives scientists something against which they can compare their experimental data.
evolution (v. to evolve) A process by which species undergo changes over time, usually through genetic variation and natural selection. These changes usually result in a new type of organism better suited for its environment than the earlier type. The newer type is not necessarily more “advanced,” just better adapted to the particular conditions in which it developed. Or the term can refer to changes that occur as some natural progression within the non-living world (such as computer chips evolving to smaller devices which operate at an ever faster speed).
germ Any one-celled microorganism, such as a bacterium or fungal species, or a virus particle. Some germs cause disease. Others can promote the health of more complex organisms, including birds and mammals. The health effects of most germs, however, remain unknown.
gland A cell, a group of cells or an organ that produces and discharges a substance (or “secretion”) for use elsewhere in the body or in a body cavity, or for elimination from the body.
immune system The collection of cells and their responses that help the body fight off infections and deal with foreign substances that may provoke allergies.
immunity The ability of an organism to resist a particular infection or poison by providing cells to remove, kill or disarm the dangerous substance or infectious germ. Or, when used colloquially, it means the ability to avoid some other type of adverse impact (such as firing from a job or being bullied).
infection (adj. infectious) A disease that can spread from one organism to another. It’s usually caused by some type of germ.
lymph A colorless fluid produced by lymph glands known as nodes. This secretion, which contains white blood cells, bathes the tissues and eventually drains into the bloodstream.
microbe Short for microorganism. A living thing that is too small to see with the unaided eye, including bacteria, some fungi and many other organisms such as amoebas. Most consist of a single cell.
molecule An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).
protein A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.
T cells A family of white blood cells, also known as lymphocytes, that are primary actors in the immune system. They fight disease and can help the body deal with harmful substances.
Velcro The commercial name for a widely known hook-and-loop type adhesive.
Journal: C. Lin et al. Fever promotes T lymphocyte trafficking via a thermal sensory pathway involving heat shock protein 90 and α4 integrins. Immunity. Vol. 50, January 2019, p. 137. doi:10.1016/j.immuni.2018.11.013.