Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells
Amanda L. Hernandez, … , Markus Kleinewietfeld, David A. Hafler
Amanda L. Hernandez, … , Markus Kleinewietfeld, David A. Hafler
Published November 2, 2015; First published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4212-4222. https://doi.org/10.1172/JCI81151.
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Research Article Autoimmunity Immunology Inflammation

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

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.

Authors

Amanda L. Hernandez, Alexandra Kitz, Chuan Wu, Daniel E. Lowther, Donald M. Rodriguez, Nalini Vudattu, Songyan Deng, Kevan C. Herold, Vijay K. Kuchroo, Markus Kleinewietfeld, David A. Hafler

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Figure 1

High-salt conditions block suppressive function in vitro.

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High-salt conditions block suppressive function in vitro. (A) CD4+ naive...
(A) CD4+ naive effector T cells (CD4 effector) were labeled with CFSE, stimulated with αCD2/αCD3/αCD28-coated beads (at 2 beads/cell) and cultured alone or cocultured with CD4+CD25hiCD127lo Tregs at ratios as indicated. Cells were cultured either in media (white) or with an additional 40 mM NaCl (gray) added. CFSE dilution was measured by flow cytometry after 5 days. Histograms depict cellular proliferation and are gated on viable cells. (B) The line graph depicts a summary of experiments at Treg/CD4 effector cell ratios as indicated (n = 10). (C) Tregs were stained with Celltrace Violet and CD4 effector cells with CFSE to track proliferation within the coculture system either in normal media or in media enriched with 40 mM NaC. Cultures were stimulated with αCD2/αCD3/αCD28-coated beads (at 2 beads/cell). (D) Summary of findings (n = 5). Statistical analyses were performed using paired Student’s t test.