Activated β-catenin in Foxp3⁺ regulatory T cells links inflammatory environments to autoimmunity

Foxp3⁺ regulatory T cells (T_reg cells) are the central component of peripheral immune tolerance. Whereas a 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 an imbalance between the cytokines IFN-γ and IL-10 as a shared T_reg signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human T_reg subpopulations revealed β-catenin as a key regulator of IFN-γ and IL-10 expression. The activated β-catenin signature was enriched in human IFN-γ⁺ T_reg cells, as confirmed in vivo with T_reg-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional T_reg phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-γ and IL-10 production under a 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.