Th17 cells are highly proinflammatory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases 1 . IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing Th17 cells with pathogenic effector functions 2, 3 . However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we

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... sed transcriptional profiling of developing Th17 cells to construct a model of their signaling network and nominate major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase 4 , as an essential node downstream of IL-23 signaling. SGK1 is critical for regulating IL-23R expression and stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na + transport and salt (NaCl) homeostasis in other cells 5, 6, 7, 8 . We here show that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na + -mediated Th17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation.