Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells

J Clin Invest. 2015 Nov 2;125(11):4212-22. doi: 10.1172/JCI81151. Epub 2015 Oct 20.

Abstract

FOXP3+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNγ-secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCl, either in vitro or in murine models via diet, markedly impairs Treg function. NaCl increased IFNγ secretion in Tregs, and reducing IFNγ - either by neutralization with anti-IFNγ antibodies or shRNA-mediated knockdown - restored suppressive activity in Tregs. The heightened IFNγ secretion and loss of Treg function were mediated by the serum/glucocorticoid-regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNγ-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Neutralizing / immunology
  • Autoimmunity / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Colitis / immunology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Forkhead Transcription Factors / analysis
  • Forkhead Transcription Factors / genetics
  • Gene Expression Profiling
  • Genes, Reporter
  • Graft vs Host Disease / immunology
  • Heterografts
  • Humans
  • Immediate-Early Proteins / physiology
  • Inflammation
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Leukocytes, Mononuclear / transplantation
  • Male
  • Mice
  • Protein-Serine-Threonine Kinases / physiology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Sodium Chloride / pharmacology*
  • Sodium Chloride, Dietary / adverse effects*
  • Sodium Chloride, Dietary / pharmacology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Antibodies, Neutralizing
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Immediate-Early Proteins
  • RNA, Small Interfering
  • Sodium Chloride, Dietary
  • Sodium Chloride
  • Interferon-gamma
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase