Meningeal regulatory T cells inhibit nociception in female mice

T cells have emerged as orchestrators of pain chronification, but the mechanism by which T cells control pain processing is unresolved. Here, we demonstrate an influence of regulatory T cells (Tregs) on nociception that is distinct from their canonical functions of immune regulation and tissue repair. Site-specific depletion or expansion of meningeal Tregs (mTregs) leads to profound female-specific and sex hormone-dependent modulation of mechanical sensitivity. Specifically, mTregs produce the endogenous opioid enkephalin that exerts an anti-nociceptive action through the delta opioid receptor expressed by MrgprD+ sensory neurons. Although enkephalin restrains nociceptive processing, it is dispensable for Treg-mediated immunomodulation. Together, our findings uncover a fundamental sexually dimorphic immunological circuit that restrains nociception and establish Tregs as sentinels of pain homeostasis.