Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States of America.
PLoS One. 2023 Feb 2;18(2):e0280916. doi: 10.1371/journal.pone.0280916. eCollection 2023.
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.
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）、心血管疾病以及包括炎症性肠病和类风湿关节炎在内的自身免疫性疾病的发病率增加有关。所有这些疾病都具有炎症成分，其中 T 淋巴细胞在驱动炎症方面可以发挥关键作用。人们已经了解到糖（尤其是葡萄糖）在促进或抑制炎症的效应 T 细胞和调节 T 细胞方面的重要性。特别是，葡萄糖及其通过糖酵解代谢分解产物对于效应 T 细胞的分化和功能至关重要，而脂肪酸供能的氧化磷酸化则支持调节 T 细胞的稳态和功能。然而，鉴于西方社会糖尿病的普遍存在，一个关键的知识空白是高葡萄糖浓度对效应 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 CD4+T 细胞，并研究它们向效应 T 细胞与调节 T 细胞谱系的分化。令人惊讶的是，高葡萄糖促进了调节 T 细胞的分化，并抑制了 Th1 效应细胞的分化。这种向调节谱系的倾斜是通过一种间接机制发生的，该机制依赖于激活的糖酵解 T 细胞产生的乳酸。将乳酸添加到 T 细胞分化过程中可促进 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，即激活、分化的 T 细胞产生的乳酸会使它们的谱系向调节命运倾斜。
