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

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-? 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 ?-catenin as a key regulator of IFN-? and IL-10 expression. The activated ?-catenin signature was enriched in human IFN-?+ Treg cells, as confirmed in vivo with Treg-specific ?-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-? and IL-10 production under a high-salt environment, with skewed activation of the ?-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-?-catenin loop in Treg cells linking environmental high-salt conditions to autoimmunity.

SUBMITTER: Sumida T

PROVIDER: S-EPMC6240373 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Sumida Tomokazu T Lincoln Matthew R MR Ukeje Chinonso M CM Rodriguez Donald M DM Akazawa Hiroshi H Noda Tetsuo T Naito Atsuhiko T AT Komuro Issei I Dominguez-Villar Margarita M Hafler David A DA

Nature immunology 20181029 12

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. R ...[more]

PMID: 30374130

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Project description:Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+ regulatory T (Treg) cell function due to Foxp3 gene mutations, but whether the loss of Foxp3+ Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive Foxp3 deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+ Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+ Treg cell ablation focused on Foxp3DTR NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+ TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+ Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+ Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+ Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+ T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+ Treg cell activity for the control of genetically pre-installed autoimmune diabetes.

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

Publications

Activated β-catenin in Foxp3<sup>+</sup> regulatory T cells links inflammatory environments to autoimmunity.

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