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Foxp3 + regulatory T cells (T reg cells) are the central component of peripheral immune tolerance. While dysregulated T reg cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify imbalance between IFN-γ and IL-10 as a shared T reg signature, present in patients with multiple sclerosis (MS) and under high salt conditions. RNA-sequencing analysis on human T reg subpopulations reveals β-catenin as a key regulator of IFN-γ and IL-10 expression. The activated β-catenin signature is enriched in human IFN-γ + T reg cells, which is confirmed in vivo with T reg specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional T reg phenotype. Moreover, we identify prostaglandin E receptor 2 (PTGER2) as a regulator for IFN-γ and IL-10 production under high salt environment, with skewed activation of the β-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-β-catenin loop in T reg cells linking environmental high salt conditions to autoimmunity.

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