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.

T细胞已被证实为疼痛慢性化的核心调控因子，但T细胞调控伤害性感受加工的具体机制仍未阐明。本研究揭示了调节性T细胞（regulatory T cells, Tregs）对伤害性感受的调控作用，该作用与其经典的免疫调节、组织修复功能截然不同。对脑膜调节性T细胞（meningeal Tregs, mTregs）进行位点特异性耗竭或扩增，可引发显著的雌性特异性且依赖性激素的机械痛敏感性调控效应。具体而言，脑膜调节性T细胞可分泌内源性阿片样脑啡肽，该物质通过MrgprD阳性感觉神经元（MrgprD+ sensory neurons）表达的δ阿片受体（delta opioid receptor）发挥抗伤害性感受作用。尽管脑啡肽可抑制伤害性感受加工，但它并非Treg介导的免疫调节所必需的分子。综上，本研究首次揭示了一条基础性的性二态性免疫环路，该环路可抑制伤害性感受加工，并确立了调节性T细胞作为疼痛稳态守护哨兵的全新功能定位。