Closing in on a century-old mystery, scientists are figuring out what the body’s ‘tuft cells’ do

While poring over tissue slides in the 1920s, a Soviet microscopist spotted an oddball cell squeezed into the intestinal lining. With its bulbous shape and bristly top knot, it didn't look like any of its neighbors. He was baffled—and so were later researchers who spotted the same kind of cells in the following decades. What they did was a mystery. "It was amazing to me that this huge piece of biology was out there undiscovered," says mucosal immunologist Michael Howitt of Stanford University in Palo Alto, California, who began to study those tuft cells, as they are called, in 2011.

What was known about them only made the mystery more tantalizing. Some tuft cells display the same chemical-sensing surface proteins that act as taste receptors on the tongue. And the cells station themselves in the linings of many body structures and organs—not only the intestines, but also the lungs, pancreas, gallbladder, urethra, and nasal passages. "Almost any hollow tube in the body has something like a tuft cell," says immunologist Mark Anderson of the University of California, San Francisco (UCSF). But why would the pancreas or urethra possibly need a sense of taste?

Now, a wave of recent research reveals a reason. Tuft cells serve as sentinels along the body's invasion routes, relying on their sensory capabilities to detect pathogens and allergens that are inhaled or trying to infiltrate in other ways. Although not part of the immune or nervous system—they are a type of epithelial cell—tuft cells interact with those systems to help coordinate protective responses in many parts of the body, scientists have found.

Through their interplay with other cell types, tuft cells may confer other benefits as well, such as healing damaged tissues, forestalling cancer, and priming the maturation of certain immune system cells. But tuft cells can also betray us. They foster some cancers; offer a foothold to norovirus, the stomach-churning pathogen that causes more than 600 million cases of food poisoning each year; and help instigate inflammatory conditions such as asthma.

The cells haven't shed all their mysteries. What pathogen molecules tuft cells recognize, which chemical-sensing receptors they deploy, and how much they contribute to certain diseases remain uncertain, for example. Still, their role in defending the body and marshaling other cells suggests that "potentially, they are very important cells," says UCSF immunologist Richard Locksley.

Policing parasites

A clue to their function comes from their resemblance to tufted cells on the skin of fish that detect chemicals in the water, alerting the animals to nearby food or predators. "As mammals went ashore, these cells became internalized," Locksley says. Besides their signature plume, tuft cells share with their forebears details of their internal structure and an aptitude for detection. They are well equipped to sample their surroundings, carrying receptors for the tastes of bitter, sweet, and umami as well as for other molecules.

But researchers knew little about what tuft cells perceive and what benefits they provide until 2016. One study that helped clarify the cells' function began when Howitt made a disturbing observation. Two years into his postdoc at Harvard University, he was probing potential interactions between tuft cells and intestinal bacteria. If tuft cells were attuned to those microbes, Howitt reasoned, the cells' numbers might change in germ-free mice. To test that possibility, he counted tuft cells in the intestines of mice born and raised at Harvard's animal facility in what was intended to be an environment free of infectious microbes and even the natural, helpful bacterial residents of the gut. As he examined intestinal tissue from the mice, however, Howitt noticed single-celled parasitic protozoa called Tritrichomonas muris sculling through the microscope's field of view. The mice weren't free of pathogens after all.

"My response was not one of glee," Howitt says. Tuft cells were about 20 times more abundant in the supposedly germ-free mice than in normal rodents. He worried that contamination by the parasite had affected the result and that he would have to start over. But when he and colleagues fed the protozoa-rich intestinal contents of their homegrown mice to parasite-free mice, tuft cell numbers surged. And when the researchers introduced the parasite into germ-free mice whose tuft cells couldn't sense chemicals, that increase did not occur, implying that tuft cells normally act to detect protozoa, a potential threat, and proliferate.

version="1.0" encoding="utf-8"? Tuft enough Tuft cells are odd-looking cells that use taste receptors and other surface proteins to sense pathogens, then release chemical messengers that trigger multiple responses. Weep and sweep Tuft cells help eliminate gut pathogens by releasing interleukin-25 (IL-25), which stimulates mucus-producing goblet cells, recruits immune cells, and leads to muscle contractions. Tuftless Mice whose tuft cells are missing or impaired produce less IL-25 than normal mice and have trouble clearing para- sites from the intestines. IL-25 IL-25 Gut interior Goblet cell Parasite Immune cells Mucus Tuft cell Epithelial cells Villus

At about the same time, Locksley and colleagues serendipitously arrived at the same conclusion. He and the other scientists hadn't even heard of tuft cells when they began their experiments, recalls immunologist Jakob von Moltke, a former UCSF postdoc with Locksley who now runs a lab studying the cells at the University of Washington School of Medicine in Seattle. The group was trying to pin down which cells in the intestinal lining pump out interleukin-25 (IL-25), a protein signal that helps the body defend against parasites but also promotes allergy symptoms and asthma.

The researchers analyzed intestinal tissues from mice genetically modified so that any cells making IL-25 also produced a red fluorescent protein. A few bright cells stood out, and antibodies specific for different kinds of intestinal cells revealed their identity. "That's when we went and looked up what a tuft cell is," von Moltke says. A third group led by researchers from France simultaneously discovered an antiparasite role for tuft cells in the intestine.

The teams ultimately demonstrated that tuft cells are crucial for the body's "weep and sweep" defense against parasites. In that mechanism, mucus-producing goblet cells in the intestinal lining divide rapidly and secrete copiously while muscle cells in the intestinal walls step up their contractions—all to help force the invaders from the body. Tuft cells that sense parasites discharge IL-25 to unleash those responses and stimulate immune cells; genetically altering mice to remove or disable their tuft cells impairs their ability to eliminate parasitic worms, the groups found.

The cells strengthen gut defenses against parasites in a second way, as Locksley, von Moltke, and colleagues revealed last year. The responses of tuft cells to one kind of parasite help make it harder for additional parasites to infect the animals.

How tuft cells in the intestines detect parasites remained unclear until 2018. It would be fitting if the interlopers tasted bitter to the cells, but intestinal tuft cells don't rely on bitter taste receptors. Instead, three papers—including two on which von Moltke and Locksley are authors—showed the cells react to succinate, a metabolic molecule that worms and other parasites secrete. Tuft cells have receptors for succinate, but other, unidentified detectors also seem to be involved. Even giving the mice succinate in their water girds their defenses: "When we put the animals on succinate diets, they didn't get colonized" by parasitic worms, Locksley says.

Tuft cells also fend off invaders elsewhere in the body. Studies on rodents have shown that when tuft cells in the urethra recognize bitter or umami molecules or bacterial cells, they activate nerves that spur urination, flushing away potentially harmful microbes. Otolaryngologist Noam Cohen of the University of Pennsylvania and colleagues determined that tuft cells in the nasal passages respond to bitter chemicals and spur neighboring cells to pump out bactericidal proteins. In rodents, but not people, nasal tuft cells can even temporarily halt breathing by stimulating a nerve that connects to the part of the brain that controls respiration. That might help stop inhalation of pathogens—a handy adaptation for animals constantly sticking their noses into dirty corners.

The cells' responsibilities appear to go beyond guard duty. In 2014, Timothy Wang, a gastrointestinal and cancer researcher at Columbia University Medical Center, and colleagues were probing tuft cells' function by testing genetically modified mice whose tuft cells die when exposed to the diphtheria toxin. To their surprise, dosing the animals with the toxin to eliminate their intestinal tuft cells produced no obvious ill effects. But when the researchers stimulated colitis or triggered other types of intestinal injury in mice lacking tuft cells, the animals quickly perished. Unlike unaltered rodents, those animals could not refurbish their damaged intestines, indicating the cells help orchestrate tissue repair.

Another organ in which the cells may perform unexpected jobs is the thymus, where some kinds of immune cells mature and learn not to attack the body's own tissues. Anderson and colleagues were tracking the varieties of epithelial cells in the part of the thymus where that education takes place when they found "goofy cells with taste receptors" that they didn't recognize. Anderson then ran into Locksley in a hallway at UCSF, who had a pretty good idea what they were. The cells had a tuft, and an analysis of gene activity confirmed them as the enigmatic cells.

After teaming with Locksley and von Moltke, Anderson's group showed that the thymus's tuft cells carry surface proteins that are key to teaching young immune cells not to target the body's own proteins. The team reported its finding in Nature last year, along with a second group that had independently found similar results. The researchers aren't sure what tuft cells are sensing in the thymus, however.

Cancer concerns

Much about the cells remains fuzzy—including the function of the namesake tuft. The cells are most abundant in the gallbladder, but nobody knows what they are doing there. And researchers are still trying to understand the cells' roles—protective or harmful—in disease. Cancer biologist Kathleen DelGiorno of the Salk Institute for Biological Studies in San Diego, California, notes that in mice, tuft cells appear in the pancreas after it is injured and seem to promote healing. They may prevent lesions, which some patients harbor for many years, from becoming aggressive tumors. "Tuft cells inhibiting the immune system might be one reason why these lesions persist but don't progress," DelGiorno says.

Yet some work suggests tuft cells in the pancreas are themselves the source of tumors there. And stronger evidence reveals the cells can help instigate tumors in other organs. In their 2014 study, Wang and colleagues studied genetically modified mice whose tuft cells lack the tumor-suppressor gene APC, which is faulty in most people with colon cancer. When the researchers gave the rodents a noxious compound that spurred colitis, the tuft cells began to proliferate and formed colon tumors.

"I don't think tuft cells are the primary source of colon cancer" in humans, Wang says, but they may on occasion spark the growths. The cells may also promote stomach cancer. When Wang and his team gave mice a chemical that induces stomach tumors, the number of tuft cells in the organ surged. Those cells poured out acetylcholine, which serves as a neurotransmitter in the nervous system but also stokes the initial growth of the tumors, the scientists reported in 2017.

Other work is now hinting that tuft cells in our respiratory system drive conditions such as asthma, sinus inflammation, and nasal polyps, perhaps by releasing the same immune-stimulating molecules that trigger defenses against parasites.

Tuft cells aren't about to become a major target of medical treatments, but researchers are thinking about ways to harness them. In the nasal passages, for example, prodding tuft cells with bitter molecules might help combat sinus infections. Recent work shows that in mice with Crohn disease, tuft cells are less abundant in the most inflamed portions of the intestine, so stimulating the cells to divide might promote healing. In the airways, by contrast, blocking the cells might help ease asthma and allergy symptoms.

It's too early to say whether discoveries about tuft cells will pay off in medicine. But the recent revelations have dispelled the old view that tuft cells are, as Anderson puts it, just oddities that "medical students get quizzed about."

*Correction, 3 April, 2 p.m.: This story has been edited to remove the statement that tuft cells in nasal passages use IL-25 to stimulate other cells to release antimicrobial production (They appear to use calcium instead)