Meningeal regulatory T cells inhibit nociception in female mice, 2025, Midavaine+

Abstract:
T cells have emerged as orchestrators of pain amplification, but the mechanism by which T cells control pain processing is unresolved. We found that regulatory T cells (Treg cells) could inhibit nociception through a mechanism that was not dependent on their ability to regulate immune activation and tissue repair. Site-specific depletion or expansion of meningeal Treg cells (mTreg cells) in mice led to female-specific and sex hormone–dependent modulation of mechanical sensitivity. Specifically, mTreg cells produced the endogenous opioid enkephalin that exerted an antinociceptive action through the delta opioid receptor expressed by MrgprD+ sensory neurons. Although enkephalin restrains nociceptive processing, it was dispensable for Treg cell–mediated immunosuppression. Thus, our findings uncovered a sexually dimorphic immunological circuit that restrains nociception, establishing Treg cells as sentinels of pain homeostasis.

Editor's summary:
Regulatory T (Treg) cells play a well-defined role in restraining inflammatory immune responses. Midavaine et al. found that depleting Treg cells specifically localized to the meninges of the central nervous system (mTreg cells) increased the responses of female, but not male, mice to mechanical pain stimuli. These mTreg cells were a source of enkephalin, an endogenous opioid peptide, within the cerebrospinal fluid. In the context of nerve injury, the enkephalin associated with mTreg cells could decrease pain sensing by activating the δ-opioid receptor expressed by a subset of nociceptive neurons involved in mechanical pain sensing. Injecting the cytokine interleukin-2 (IL-2) into the spinal fluid increased mTreg cell numbers and decreased mechanical pain sensing in female mice after nerve injury. The analgesic effect of IL-2 in female mice could be prevented by blocking female sex hormones.

Link (Science, April 2025)
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"Immune cells have unexpected role in fighting pain" (Science News)