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

Nat Immunol. 2018 Dec;19(12):1391-1402. doi: 10.1038/s41590-018-0236-6. Epub 2018 Oct 29.

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • Gene Expression Regulation / immunology
  • Humans
  • Inflammation / immunology*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / immunology
  • Mice, Inbred C57BL
  • Multiple Sclerosis, Relapsing-Remitting / immunology*
  • Receptors, Prostaglandin E, EP2 Subtype / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • beta Catenin / immunology*

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Receptors, Prostaglandin E, EP2 Subtype
  • beta Catenin
  • Interleukin-10
  • Interferon-gamma