目的:生酮饮食因其葡萄糖摄入量低而被提议作为1型和2型糖尿病的治疗方法。然而,它们对免疫系统的潜在影响需要调查。本研究旨在探讨葡萄糖浓度和β-羟丁酸(BHB)对T细胞表型的影响,新陈代谢,和功能,重点关注全身炎症反应(T2D)和自身免疫(T1D)。
方法:在有或没有BHB的不同葡萄糖浓度下,在体外培养来自健康供体的T细胞。流式细胞术用于分析T细胞表型的变化,而增殖通过CFSE稀释试验进行评估。此外,我们使用了一种新的流式细胞术方法,可以直接评估T细胞代谢.
结果:在低葡萄糖浓度下培养T细胞显示它们对葡萄糖代谢的依赖性,导致扩散率降低,耗竭标志物的过度表达和对Treg抑制的敏感性增加以及免疫调节药物如雷帕霉素的影响,FK506和MMF。值得注意的是,在低葡萄糖浓度下培养的T细胞增加了BDH1的表达,以利用BHB作为替代燃料来源。最后,向培养物中添加BHB可有效挽救由葡萄糖水平不足引起的T细胞损伤。
结论:T细胞对低葡萄糖水平的适应能力有限,导致严重的功能障碍。然而,通过存在2mMBHB可以有效地恢复T细胞功能。
OBJECTIVE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D).
METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism.
RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels.
CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.