Regulatory T cell-derived enkephalin gates nociception

Abstract

T cells have emerged as sex-dependent orchestrators of pain chronification but the sexually dimorphic mechanisms by which T cells control pain sensitivity is not resolved. Here, we demonstrate an influence of regulatory T cells (Tregs) on pain processing that is distinct from their canonical functions of immune regulation and tissue repair. Specifically, meningeal Tregs (mTregs) express the endogenous opioid, enkephalin, and mTreg-derived enkephalin exerts an antinociceptive action through a presynaptic opioid receptor signaling mechanism that is dispensable for immunosuppression. mTregs are both necessary and sufficient for suppressing mechanical pain sensitivity in female but not male mice. Notably, the mTreg modulation of pain thresholds depends on sex-hormones and expansion of enkephalinergic mTregs during gestation imparts a remarkable pregnancy-induced analgesia in a pre-existing, chronic, unremitting neuropathic pain model. These results uncover a fundamental sex-specific, pregnancy-pronounced, and immunologically-derived endogenous opioid circuit for nociceptive regulation with critical implications for pain biology and maternal health.

Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice

“…Additionally, a similar hypersensitivity to heat has been recently reported in mice lacking Penk in Treg following TMX treatment (Mendoza et al, 2024) but not in another model of bone marrow chimeras, which allows the depletion of Penk-expressing Treg only in the dorsal root ganglion (DRG), a crucial relay of nociception. Instead, an increased mechanical allodynia was observed in that model (Midavaine et al, 2024), a result that we did not observe. This discrepancy might be explained by the relatively low number of animals that we tested for mechanical allodynia.…”

“…Finally, our in vitro and in vivo experiments, along with results from Midavaine and coll. (Midavaine et al, 2024), show that Tregs maintains their suppressive capacities in the absence of Penk , ruling out the possibility that hyperalgesia stems from increased inflammation due to a defect in the immunosuppressive function of Treg. Instead, our results strongly indicate a direct implication of enkephalins produced by Treg in nociception, revealing a novel non-immune intrinsic role of Treg in the endogenous regulation of basal somatic sensitivity.…”

“…Finally, our in vitro and in vivo experiments, along with results from Midavaine and coll (Midavaine et al, 2024),. show that Tregs maintains their suppressive capacities in the absence of Penk, ruling out the possibility that hyperalgesia stems from increased inflammation due to a defect in the immunosuppressive function of Treg.…”