Treg cells control female nociception

Abstract

Women experience a higher prevalence of chronic pain, and pain hypersensitivity has been observed in female mice, but that mechanisms that drive sexual dimorphism in nociception remain unclear. In Science, Midavaine et al. find that meningeal regulatory T (mT_reg) cells controlled the responses of female mice to mechanical pain via the endogenous opioid peptide enkephalin. Intrathecal injection of pegylated diphtheria toxin to Foxp3-DTR mice enabled the selective depletion of mT_reg cells, which resulted in decreased mechanical nociceptive thresholds in female, but not male mice. Conversely, intrathecal injection of low-dose IL-2 led to mT_reg cell expansion, and this increased the nociceptive threshold in female, but not male mice. Blocking female sex hormones prevented the mT_reg cell expansion-mediated increases in the nociceptive threshold. mT_reg cells expressed Penk, which encodes proenkephalin, a precursor of analgesic enkephalin peptides. In female mic, the expansion of mT_reg cells resulted in increased levels of enkephalin in the cerebrospinal fluid. During nerve injury, enkephalin decreased pain sensing by activating δ-opioid receptors expressed by sensory neurons. Thus, in female mice, mT_reg cells have an important role in controlling the activation of sensory neurons in response to mechanical pain.

Original reference: Science https://doi.org/10.1126/science.adq6531 (2025)