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

Abstract

CD4 + CD25 + Foxp3 + regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, the mechanisms by which Treg hamper pain are still unclear. From a meta-analysis of 11 available transcriptomes, we show that the proenkephalin gene ( Penk) which encodes the precursor of analgesic opioid peptides, is among the top 10 genes enriched in murine Treg relative to conventional T cells (Tconv). We then show that Penk expression in Treg is under the control of TNFR signaling and the transcription factor BATF. Using mice in which Penk mRNA expression can be tracked with a fluorescent reporter, we also show that Penk expression is restricted to Treg and activated Tconv in non-inflammatory conditions in all examined organs and tissues. Furthermore, inducible ablation of Penk in Treg leads to heat hyperalgesia for both male and female mice. Overall, our results indicate that TNFR signaling and BATF regulation of Penk in Treg might play a key role at modulating basal somatic sensitivity in mice.