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

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

SUBMITTER: Sumida T 

PROVIDER: S-EPMC6240373 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature