Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception
Alejandra Mendoza, Regina Bou-Puerto, Juan Sebastián Jara, Stanislav Dikiy, Paolo Giovanelli, Daiana Correa, Susanna Manenti, Emma S. Andretta, Chitra Lekha Dahia, Alexander Y. Rudensky
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.