Meningeal regulatory T cells inhibit nociception in female mice

• 成果类型: Article
• 署名作者: Midavaine, Elora; Moraes, Beatriz C.; Benitez, Jorge; Rodriguez, Sian R.; Braz, Joao M.; Kochhar, Nathan P.; Eckalbar, Walter L.; Tian, Lin; Domingos, Ana I.; Pintar, John E.; Basbaum, Allan I.; Kashem, Sakeen W.
• 署名单位: University of California System; University of California San Francisco; Max Planck Society; University of Oxford; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; University of California System; University of California San Francisco; US Department of Veterans Affairs; Veterans Health Administration (VHA)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8486
• DOI: 10.1126/science.adq6531
• 发表日期: 2025-04-04
• 页码: 96-104
• 关键词: delta-opioid receptor; neuropathic pain; hypersensitivity; TRAFFICKING; allodynia; IDENTITY; mouse; MODEL

摘要

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.