Salt Sensing by Serum/Glucocorticoid-Regulated Kinase 1 Promotes Th17-like Inflammatory Adaptation of Foxp3+ Regulatory T Cells

Abstract

Summary: Regulatory T (Treg) cells integrate diverse environmental signals to modulate their function for optimal suppression. Translational regulation represents a favorable mechanism for Treg cell environmental sensing and adaptation. In this study, we carry out an unbiased screen of the Treg cell translatome and identify serum/glucocorticoid-regulated kinase 1 (SGK1), a known salt sensor in T cells, as being preferentially translated in activated Treg cells. We show that high salt (HS) drives thymic Treg cells to adopt a T helper type 17 (Th17)-like phenotype and enhances generation of Th17-like induced Treg cells in a SGK1-dependent manner, all the while maintaining suppressive function. Salt-mediated Th17-like differentiation of Treg cells was evident in mice fed with HS diet or injected with HS-preconditioned T cells. Overall, SGK1 enables Treg cells to adapt their function in response to environmental cues. By understanding these environmental-sensing mechanisms, we envision targeted approaches to fine-tune Treg cell function for better control of inflammation. : Yang et al. demonstrate that high salt promotes Th17-like functional adaptation of both thymic and induced Foxp3+ Treg cell subsets through a salt-sensor protein, SGK1. The translationally regulated SGK1 pathway enables Treg cells to fine-tune their effector function in response to environmental cues during the dynamic course of inflammation. Keywords: Foxp3+ Treg cell, Treg Adaptation, Treg Reprogramming, salt, SGK1, Treg cell plasticity, mRNA translation regulation, Environmental Sensing, Autoimmunity, RORγt+ Treg, Helios