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.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Sumida T,Lincoln MR,Ukeje CM,Rodriguez DM,Akazawa H,Noda T,Naito AT,Komuro I,Dominguez-Villar M,Hafler DAdoi
10.1038/s41590-018-0236-6subject
Has Abstractpub_date
2018-12-01 00:00:00pages
1391-1402issue
12eissn
1529-2908issn
1529-2916pii
10.1038/s41590-018-0236-6journal_volume
19pub_type
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