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-gamma 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 beta-catenin as a key regulator of IFN-gamma and IL-10 expression. The activated beta-catenin signature was enriched in human IFN-gamma(+) T-reg cells, as confirmed in vivo with T-reg-specific beta-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-gamma and IL-10 production under a high-salt environment, with skewed activation of the beta-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-beta-catenin loop in T-reg cells linking environmental high-salt conditions to autoimmunity.