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

CD4⁺CD25⁺Foxp3⁺regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting thatPenkis regulated in part by members of the TNF receptor family and the transcription factor Batf. Using mice in which the promoter activity ofPenkcan be tracked with a fluorescent reporter, we also show thatPenkexpression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient forPenksuppress equally well the proliferation of effector T cellsin vitroand autoimmune colitisin vivo. In contrast, inducible ablation ofPenkin Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.