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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 IFN?-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 IFN? secretion in Tregs, and reducing IFN? - either by neutralization with anti-IFN? antibodies or shRNA-mediated knockdown - restored suppressive activity in Tregs. The heightened IFN? 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 IFN?-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.

SUBMITTER: Hernandez AL

PROVIDER: S-EPMC4639983 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Hernandez Amanda L AL Kitz Alexandra A Wu Chuan C Lowther Daniel E DE Rodriguez Donald M DM Vudattu Nalini N Deng Songyan S Herold Kevan C KC Kuchroo Vijay K VK Kleinewietfeld Markus M Hafler David A DA

The Journal of clinical investigation 20151020 11

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 ...[more]

PMID: 26524592

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Project description:ObjectiveThe approximately 45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Idd9.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3.Research design and methodsWe used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive CD8(+) T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP(206-214)), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Idd9.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice.ResultsMost of the protective effect of Idd9 against 8.3-CD8(+) T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive CD8(+) T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the FoxP3(+)CD4(+)CD25(+) T-cell subset in both TCR-transgenic and nontransgenic mice.ConclusionsA gene(s) within Idd9.1 regulates the development and function of FoxP3(+)CD4(+)CD25(+) regulatory T-cells and, in turn, the activation of CD8(+) effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential.

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

Publications

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

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