The skin is one of the body’s largest barrier tissues and is exposed to a wide range of mechanical, chemical, thermal and infectious threats. A tightly regulated network of sensory nerve endings and immune cells functions together to respond to these stimuli and maintain homeostasis. For example, sensory neurons can promote the recruitment and activation of immune cells through the release of soluble mediators, and regulatory T (Treg) cells can reduce the activation of sensory neurons indirectly by reducing levels of proinflammatory mediators. Mendoza et al. now add to this regulatory network by showing that, in addition to modulating inflammatory tone, Treg cells also regulate neuronal activity in the skin directly through their production of the opioid enkephalin.

Using previously generated gene expression datasets, Mendoza et al. identified Penk, which encodes the precursor proenkephalin, as being highly upregulated in a subset of activated Treg cells. Penk-expressing Treg cells were highly prevalent in the skin, being slightly enriched in the proximity of axons and increased by IMQ treatment, but scarce in lymphoid organs and circulation. Single-cell RNA-sequencing analysis of skin Treg cells showed that Penk-expressing cells were enriched for gene signatures of T cell receptor signalling and activation, and expressed Ccr2, which might support their colocalization with CCL2-producing axons. T cell receptor stimulation was required but not sufficient for Penk expression. An additional role in facilitating Penk expression was shown for signalling through glucocorticoid receptor — which is highly expressed by skin Treg cells, with keratinocytes being a major source of glucocorticoids in response to various stressors — both in vitro and in vivo.