RT Journal Article SR Electronic T1 PTGER2-β-Catenin Axis Links High Salt Environments to Autoimmunity by Balancing IFNγ and IL-10 in FoxP3+ Regulatory T cells JF bioRxiv FD Cold Spring Harbor Laboratory SP 379453 DO 10.1101/379453 A1 Tomokazu Sumida A1 Matthew R. Lincoln A1 Chinonso M. Ukeje A1 Donald M. Rodriguez A1 Hiroshi Akazawa A1 Tetsuo Noda A1 Atsuhiko T. Naito A1 Issei Komuro A1 Margarita Dominguez-Villar A1 David A. Hafler YR 2018 UL http://biorxiv.org/content/early/2018/08/02/379453.abstract AB Foxp3+ regulatory T cells (Tregs) are the central component of peripheral immune tolerance. While dysregulation of the Treg cytokine signature has been observed in autoimmune diseases such as multiple sclerosis (MS) and type 1 diabetes, the regulatory mechanisms balancing pro- and anti-inflammatory cytokine production are not known. Here, we identify imbalance between IFNγ and IL-10 as a shared Treg signature, present in patients with MS and under high salt conditions. By performing RNA-seq analysis on human Treg subpopulations, we identify β-catenin as a key regulator that controls the expression of IFNγ and IL-10. The activated β-catenin signature is enriched specifically in IFNγ+Tregs in humans, and this was confirmed in vivo with Treg-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional, IFNγ-producing, Treg phenotype. Moreover, we identify PTGER2 as a major factor balancing IFNγ and IL-10 production in the context of a high salt environment, with skewed activation of the β-catenin/SGK1/Foxo axis in IFNγ+Tregs. These findings identify a novel molecular mechanism underlying inflammatory Tregs in human autoimmune disease and reveal a new role for a PTGER2-β-catenin loop in Tregs linking environmental high salt conditions to autoimmunity.