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

Foxp3+ regulatory T cells (Treg cells) are the central component of peripheral immune tolerance. Whereas a dysregulated Treg 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 Treg signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human Treg 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+ Treg cells, as confirmed in vivo with Treg-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg 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 Treg cells linking environmental high-salt conditions to autoimmunity. Regulatory T cells (Treg cells) can destabilize in inflammatory environments. Sumida et al. show that β-catenin signaling perturbs Treg cell function in patients with multiple sclerosis and under experimental high-salt conditions.