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Unlike the combative immune cells that protect us from pathogens, regulatory T cells (Tregs) are nurturers. They salve inflammation, promote healing of injured tissue, and rein in immune attacks to curb self-inflicted damage, Science reports.
Now, a study of mice suggests some Tregs act also on nerve cells to quell a specific type of pain—but only in females. Why only female rodents seem to benefit remains unclear, but researchers hope they might someday enlist these Tregs to address pain conditions, many of which disproportionately affect women.
“It’s a very impressive paper,” says neuroscientist Gila Moalem-Taylor of the University of New South Wales Sydney, who wasn’t connected to the research. The study “uses elegant, sophisticated methods to conclusively demonstrate the mechanisms” by which the cells reduce one kind of sensitivity to pain, she says.
Tregs, a type of white blood cell, are best known for their role in keeping the immune system in balance and preventing autoimmunity. But researchers have recently found that they also help control pain. For example, a 2025 study by neuroscientist Allan Basbaum of the University of California San Francisco (UCSF) and colleagues showed that Tregs reduce mice’s sensitivity to pain triggered by other immune cells that reside in the brain and spinal cord. That research and additional work suggested Tregs influence pain by targeting various immune cells and tamping down inflammation. But these studies left open the possibility that Tregs might also directly affect pain-sensing nerve cells. Basbaum, his postdoc Élora Midavaine, UCSF dermatologist Sakeen Kashem, and their colleagues launched the new study to nail down how the regulatory cells curb pain.
They focused on Tregs that dwell in the meninges—the membranes that sheathe the brain and spinal cord—and in similar nearby membranes. The cells are much more abundant in these structures than elsewhere in the nervous system. To find out whether the cells affect pain perception, the scientists used genetically engineered mice whose Tregs are vulnerable to a toxin produced by the bacteria that cause diphtheria. Injecting this toxin into the meninges in the lower back killed about 90% of the Tregs in the membranes without harming Tregs in the rest of the body.
The scientists then measured the animals’ responsiveness to pain by prodding their feet with hairlike fibers of varying flexibility. The stiffer the fiber necessary to induce a mouse to pull its foot away, the lower the animal’s presumed sensitivity to pain. In female mice, the researchers found, culling Tregs in the meninges caused pain sensitivity to shoot up. Loss of Tregs did not have the same effect in male mice, however, and it didn’t alter either sex’s responsiveness to heat, cold, and other types of painful stimulation.
Boosting Tregs, on the other hand, appeared to blunt painful stimulation. In mice with higher pain sensitivity because of nerve damage, increasing the number of Tregs with injections of the immune system protein IL-2 counteracted this hypersensitivity—but again, only in females. To further probe this sex-specific effect, the researchers surgically removed the ovaries from female mice or gave them a drug that blocks the effects of estrogen. In both cases, IL-2 did not reduce pain sensitivity. The researchers’ findings suggest female sex hormones somehow help control the pain-reducing functions of Tregs.
Previous work revealed that Tregs pump out pain-suppressing molecules known as enkephalins. By performing bone marrow transplants with genetically engineered stem cells, the researchers produced mice in which the diphtheria toxin could kill blood cells that made enkephalins while sparing other body cells that fashioned the signaling molecules. Shots of the toxin caused the number of Tregs in the animals to fall and their pain sensitivity to rise.
The researchers also explored which cells the rodent Tregs target to quash pain. The enkephalins released by Tregs work by prodding pain-reducing receptors on nerve cells, they reported. “We show a different pathway for how Tregs regulate pain that is independent of how they regulate inflammation and tissue repair,” Basbaum says.
New approaches to pain relief are sorely needed, Basbaum says, particularly for women and people receiving gender-affirming care, who have disproportionately high rates of pain. Researchers are already testing therapies for autoimmune diseases that boost Treg numbers, including infusions of the cells, Kashem notes. He and his colleagues hope to investigate the possibility of harnessing such treatments for pain relief.
Identifying specific Tregs that reduce pain sensitivity is an important step toward these treatments, says neuroimmunologist Michael Burton of the University of Texas at Dallas, who was not involved the research. But scientists would still have to come up with a way to target the cells in the meninges in people, he notes. “Will it be practical? I’m not quite sure.”