Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception

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 examined whether regulatory T (T_reg) cells, which suppress systemic and local inflammation, can modulate activation of peripheral neurons. Acute T_reg cell "loss of function" increased neuronal activation to noxious stimuli independently of their immunosuppressive function. This activity was mediated by a T_reg cell subset capable of production of enkephalins encoded by the gene Penk, whose expression is facilitated by combined TCR and glucocorticoid receptor signaling. Punctual selective depletion of Penk-expressing T_reg cells or specific ablation of Penk in T_reg cells increased neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of tissular T_reg cells exhibits neuromodulatory activity to restrain local inflammation in the skin.