Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells

FOXP+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFN gamma-secreting Tregs. It was previously reported that increased NaCI concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCI, either in vitro or in murine models via diet, markedly impairs Treg function. NaCI increased IFN gamma secretion in Tregs, and reducing IFN gamma - either by neutralization with anti-IFN gamma antibodies or shRNA-mediated knockdown - restored suppressive activity in Tregs. The heightened IFN gamma secretion and loss of Treg function were mediated by the serum/glucocorticoid-regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNy-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways.