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Sex-specific pain suppression by immune cells

Meningeal sheet showing Treg cells (blue) near sensory nerves (green). Midavaine et al., UCSF

For many health conditions, pain is more common in women than in men. Evidence has suggested that immune system T cells may contribute to pain processing differences between women and men. Regulatory T (T_reg) cells, a type of T cell, are controlled by a gene located on the X chromosome. T_reg cells help to repair damaged tissue and to keep inflammation from getting out of control. But it’s not clear if T_reg cells could also affect pain sensing directly.

A research team led by Drs. Élora Midavaine, Allan Basbaum and Sakeen Kashem at the University of California, San Francisco, examined how T_reg cells affect pain sensitivity in mice. To do so, they depleted or increased T_reg cells in the meninges, the membranes that protect the nerves in the spinal cord and associated structures called dorsal root ganglia. The results of the research, which was funded in part by 51��Ƶ, appeared in Science on April 3, 2025.

The team found that depleting meningeal T_reg (mT_reg) cells increased sensitivity to a specific type of pain in female mice, but not male mice. The difference was in nociceptive mechanical pain, or pain caused by mechanical forces on the body, like pressure. Other types of sensitivity—including to heat, cold, or a pinprick—were unaffected. Increasing the number of mT_reg cells, conversely, reduced this type of pain sensitivity in females but not males. Further experiments showed that the effect of mT_reg cells on pain sensitivity was independent of their ability to repair tissue.

The scientists next showed that the pain-suppressing effects of mT_reg cells require the female sex hormones estrogen and progesterone. Blocking estrogen receptors with a drug abolished the effects of mT_reg cells on pain sensitivity. In mice that had their ovaries removed, mT_reg cells also didn’t suppress pain. But supplementation with estrogen and progesterone restored pain suppression by mT_reg cells in these mice.

Some mT_reg cells produced an analgesic compound called enkephalin. The team found that female mice had more enkephalin-producing mT_reg cells than male mice. Depleting mT_reg cells in female mice reduced the level of enkephalin in the cerebrospinal fluid. Increasing the number of mT_reg cells increased enkephalin levels. Female mice whose T_reg cells lacked the gene for enkephalin also had increased pain sensitivity.

Enkephalin primarily activates the delta-opioid receptor (δOR) to decrease pain sensitivity. When δOR was blocked or deleted from peripheral nerve cells in the mice, increasing mT_reg cells had much less of an effect on pain sensitivity. The team found that δOR was produced by certain pain-sensing neurons. Deleting δOR specifically from these neurons increased pain sensitivity, which was not relieved by increasing mT_reg cells.

The results suggest that female sex hormones can induce mT_reg cells to produce enkephalin. Enkephalin, in turn, suppresses pain by activating δOR on a specific group of pain-sensing nerve cells. Thus, mT_reg cells may be key regulators of nociceptive mechanical pain sensation. The role of hormones in this process might explain some of the differences in pain sensitivity between men and women. The findings also highlight the meninges’ role in communication between the immune and nervous systems to regulate pain sensation.

“What we are showing now is that the immune system actually uses the meninges to communicate with distant neurons that detect sensation on the skin,” Kashem says. “This is something we hadn’t known before.”

More research will be needed to confirm these results and better understand how the immune system affects pain sensation.

—by Brian Doctrow, Ph.D.