Abstract
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.