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., , , # **# Regulatory T cell-derived enkephalin gates nociception**

\[[https://doi.org/10.5061/dryad.9s4mw6msg](https://doi.org/10.5061/dryad.9s4mw6msg)]([https://doi.org/10.5061/dryad.9s4mw6msg](https://doi.org/10.5061/dryad.9s4mw6msg))

## ## Description of the data and file structure

We provide raw data of main figures 1 to 4 organized by figure number.

### Figure 1

Fig 1C: Number of tissue Tregs across organs, in both sexes combined. Treg numbers were normalized to organ weight (g).

Fig 1D: Number of tissue Tregs from male and female mice across organs. Treg numbers were normalized to female Treg numbers.

Fig 1F: Number of tissue Tregs 2 days after a single IT pegDT injection across organs in female mice. Treg numbers were normalized to vehicle-injected Treg numbers.

15 represents mean number of tissue Tregs in IT vehicle-injected mice per organ.

Fig 1G: Nociceptive thresholds following mTreg depletion in female and male mice.

Fig 1H: Behavioral differences between control and m...