Meningeal regulatory T cells inhibit nociception in female mice.

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