A population of Regulatory T cells controls nociception through enkephalins to restrain skin inflammation [fixed scRNA-seq]

The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we questioned whether regulatory T (Treg ) cells, that suppresses systemic and local inflammation, can modulate activation of peripheral neurons. Acute Treg cell “loss-of-function” increased neuronal activation to noxious stimuli independently from immunosuppressive function. We find that a population of activated skin Treg cells is highly enriched for Penk expression, a precursor for endogenous opioid enkephalins. Punctual selective depletion of Penk-expressing Treg cells, or specific ablation of Penk in Treg cells increases neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of tissue Treg cells exhibits neuromodulatory activity to restrain local inflammation. Overall design: Cervical DRGs were isolated from Penkfl/fl;Foxp3creERT2 and littermate control mice treated following 3 day treatment with imiquimod and fixed in 4% PFA. Fixed DRG were dissociated and analyzed by snRNAseq.