Unlike their more aggressive immune counterparts that attack pathogens, regulatory T cells (Tregs) are the immune system’s caretakers. These specialized white blood cells calm inflammation, promote healing, and restrain immune responses to prevent damage to the body’s own tissues. Now, a new study in Science reveals a surprising role for Tregs: dampening a specific type of pain in mice—though notably, only in females.
Why this pain relief occurs exclusively in female mice remains unknown, but researchers hope this discovery may eventually lead to new treatments for chronic pain conditions, many of which disproportionately affect women.
“This is a very impressive paper,” says neuroscientist Gila Moalem-Taylor of the University of New South Wales Sydney, who was not involved in the research. “It uses elegant, sophisticated methods to conclusively demonstrate how these cells reduce a specific form of pain sensitivity.”
Tregs are primarily known for regulating the immune system and preventing autoimmune diseases. However, recent studies have shown they also play a role in modulating pain. In 2021, a team led by neuroscientist Allan Basbaum of the University of California, San Francisco (UCSF) found that Tregs reduce pain sensitivity in mice by calming immune cells in the brain and spinal cord. That earlier work left open the question of whether Tregs might also act directly on nerve cells responsible for sensing pain.
In the new study, Basbaum and his team—including postdoctoral researcher Élora Midavaine and dermatologist Sakeen Kashem—sought to clarify how Tregs influence pain perception.
They focused on Tregs located in the meninges, the protective membranes surrounding the brain and spinal cord. These regions harbor unusually high numbers of Tregs compared to other parts of the nervous system. To determine the cells’ role in pain, the team used genetically engineered mice with Tregs that could be selectively destroyed by a diphtheria toxin. By injecting the toxin into the lower back meninges, the scientists eliminated about 90 percent of local Tregs without affecting those elsewhere in the body.
To assess pain sensitivity, the researchers used fine, hairlike filaments of varying stiffness to gently prod the mice’s feet. The softer the filament that triggered a withdrawal, the more sensitive the mouse was to pain. When Tregs were removed from female mice, their sensitivity to mechanical pain increased dramatically. In contrast, removing Tregs had no effect on pain responses in male mice, nor did it influence sensitivity to heat, cold, or other pain types in either sex.
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Conversely, increasing Treg levels reduced pain sensitivity—but again, only in females. In mice experiencing nerve pain, injections of the immune molecule IL-2 boosted Treg numbers and reversed hypersensitivity in females. This effect disappeared when female mice were treated with a drug that blocked estrogen or had their ovaries removed, suggesting that female hormones play a key role in regulating Tregs’ pain-dampening actions.
To better understand how Tregs ease pain, the team turned to enkephalins—natural pain-relieving molecules the cells are known to release. By engineering mice in which only enkephalin-producing blood cells could be killed by the toxin, they showed that loss of these cells increased pain sensitivity. This confirmed that enkephalins produced by Tregs help control pain.
Further experiments revealed that Tregs suppress pain by acting directly on nerve cells. Enkephalins bind to pain-dampening receptors on these cells, triggering relief. “We’ve identified a completely distinct pathway through which Tregs reduce pain, separate from their known roles in inflammation and tissue healing,” says Basbaum.
The findings open the door to new avenues for pain management that consider both immune cell function and sex-specific biology—especially important in light of the fact that many chronic pain disorders more often affect women.
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