High glucose promotes regulatory T cell differentiation.
High glucose promotes regulatory T cell differentiation.
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DOI：
10.1371/journal.pone.0280916
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
Wang, Kepeng
中科院分区：
文献类型：
--
作者：
Pitmon, Elise;Meehan, Eileen Victoria;Ahmadi, Elham;Adler, Adam J.;Wang, Kepeng
西方饮食中加工食品和含糖苏打水的消费与肥胖、代谢综合征（如2型糖尿病）、心血管疾病和自身免疫性疾病（包括炎症性肠病和类风湿性关节炎）的发病率增加相关。所有这些疾病都有炎症成分，其中T淋巴细胞在驱动中发挥着关键作用。关于糖，特别是葡萄糖，在为效应T细胞和调节T细胞提供能量方面的重要性已经有了很多了解，效应T细胞和调节T细胞可以分别促进或抑制炎症。特别是，葡萄糖及其代谢分解产物通过糖酵解是必不可少的效应T细胞的分化和功能，而脂肪酸燃料氧化磷酸化支持调节性T细胞的稳态和功能。然而，鉴于糖尿病在西方社会的流行，一个关键的知识差距是葡萄糖浓度升高对效应T细胞与调节T细胞之间平衡的影响。为了开始解决这个问题，我们用不同浓度的葡萄糖培养幼稚的CD 4 + T细胞，并检查它们分化为效应细胞系和调节细胞系。令人惊讶的是，高葡萄糖促进调节性T细胞分化和抑制Th 1效应分化。这种向调节谱系的倾斜是通过依赖于活化的糖酵解T细胞产生的乳酸的间接机制发生的。在T细胞分化过程中添加乳酸盐促进Treg细胞的分化，并激活Akt/mTOR信号级联。因此，我们的研究结果表明，存在一种新的反馈机制，其中乳酸产生的活化，分化T细胞倾斜他们的谱系承诺对监管的命运。
The consumption of processed foods and sugary sodas in Western diets correlates with an increased incidence of obesity, metabolic syndromes such as type 2 diabetes, cardiovascular diseases, and autoimmune diseases including inflammatory bowel disease and rheumatoid arthritis. All these diseases have an inflammatory component, of which T lymphocytes can play a critical role in driving. Much has been learned regarding the importance of sugar, particularly glucose, in fueling effector versus regulatory T cells that can promote or dampen inflammation, respectively. In particular, glucose and its metabolic breakdown products via glycolysis are essential for effector T cell differentiation and function, while fatty acid-fueled oxidative phosphorylation supports homeostasis and function of regulatory T cells. Nevertheless, a critical knowledge gap, given the prevalence of diabetes in Western societies, is the impact of elevated glucose concentrations on the balance between effector versus regulatory T cells. To begin addressing this, we cultured naïve CD4+ T cells with different concentrations of glucose, and examined their differentiation into effector versus regulatory lineages. Surprisingly, high glucose promoted regulatory T cell differentiation and inhibited Th1 effector differentiation. This skewing towards the regulatory lineage occurred via an indirect mechanism that depends on lactate produced by activated glycolytic T cells. Addition of lactate to the T cell differentiation process promotes the differentiation of Treg cells, and activates Akt/mTOR signaling cascade. Hence, our findings suggest the existence of a novel feedback mechanism in which lactate produced by activated, differentiating T cells skews their lineage commitment towards the regulatory fate.
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