Activated ß-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity.
Nat Immunol
; 19(12): 1391-1402, 2018 12.
Article
in En
| MEDLINE
| ID: mdl-30374130
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 ß-catenin as a key regulator of IFN-γ and IL-10 expression. The activated ß-catenin signature was enriched in human IFN-γ+ Treg cells, as confirmed in vivo with Treg-specific ß-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 ß-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-ß-catenin loop in Treg cells linking environmental high-salt conditions to autoimmunity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autoimmunity
/
T-Lymphocytes, Regulatory
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Multiple Sclerosis, Relapsing-Remitting
/
Beta Catenin
/
Inflammation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2018
Type:
Article
Affiliation country:
United States