UCSF

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 (T_reg 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 T_reg cells (mT_reg cells) in mice led to female-specific and sex hormone-dependent modulation of mechanical sensitivity. Specifically, mT_reg 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 T_reg cell-mediated immunosuppression. Thus, our findings uncovered a sexually dimorphic immunological circuit that restrains nociception, establishing T_reg cells as sentinels of pain homeostasis.