高盐(NaCl)饮食破坏机体促炎/抑炎平衡，高浓度盐诱导Th17分化，削弱tTreg的免疫抑制活性，加重T细胞介导的多发性硬化、自身免疫性肠炎等多种小鼠模型的发病。长期高盐饮食损伤机体适应性免疫系统，促进多种自身免疫病的发生发展。课题组前期研究阐述了维生素A活性代谢物atRA在炎症环境中能稳定tTreg，抑制其向Th17细胞转化。我们假设atRA能够抑制高盐对T细胞的炎性修饰，预实验结果也表明atRA具有此功能：1）能抵抗高盐对tTreg稳定性、免疫抑制力的改变；2）显著抑制高盐诱导的Th17分化；3）抑制高盐联合炎症上调的IL-6R的表达。因此，本项目拟在探索维生素A抵抗高盐诱导的tTreg/Th17失衡的细胞生物学特性，及SGK1-FoxO1/IL-23R信号通路在这一过程中发挥的分子机制。该项目研究结果可为高盐饮食人群如何防御盐促进自身免疫病的发生发展提供客观的实验依据。

High dietary salt intake promotes autoimmunity via pro-inflammatory responses. Excessive sodium chloride intake can dampen immune system, as well as boost the differentiation of Th17 cells and attenuate suppressive function of tTreg cells. High salt mobilize CD4+ T cells response that exacerbates the progress of experimental autoimmune encephalomyelitis, a mouse model of human MS. Vitamin A or Vitamin A-like analogs known as retinoids can regulate inflammatory responses and mediate immune tolerance. tTreg primed with all-trans retinoic acid (atRA) are able to restore their stability and functionality. Given that a novel environmental high-salt conditions linking tTreg/Th17 balance to autoimmunity, we will test whether vitamin A- riching diet or atRA treatment can maintain tTreg phenotype and function, meanwhile, suppress the proliferation, migration and cytokine production of Th17 cells in the EAE mice worsened by high dietary salt intake. We propose a set of experiments using GFP-reporter and immunodeficient mice model that will allow us to understand the mechanisms whereby NaCl- aggravated and atRA- attenuated T helper cells crosstalk in the inflammatory condition. We predict that SGK1, IL-23R, FoxO1, molecules that have a key role in this process are crucial for tTreg stability and Th17 differentiation in the presence of inflammation and high salt dual environment. To achieve these aims, we will conduct the strategies with the following four specific aims. Aim 1: examine whether the retinoic acid can weaken the effect of NaCl on the proliferation, migration and cytokine production of tTreg and Th17 in the presence of inflammation and high salt. Aim 2: determine whether retinoic acid maintains the inhibitory activity of tTreg dampened by high salt combined with inflammatory condition. Aim 3: determine whether retinoic acid treated high salt intake EAE mice has inflammation relief. Aim 4: elucidate the possible biological mechanisms in the tTreg/Th17 balance of high salt feeding EAE mice. When successfully completed, this project will help us understand the characteristics of tTreg in autoimmune diease and manipulation of tTreg by vitamin A as therapy may provide a superior approach to combat autoimmune and inflammatory diseases in complicated environmental conditions.