PDF(Pubmed)
Abstract：
BACKGROUND: γ-aminobutyric acid (GABA), known as the main inhibitory neurotransmitter in the brain, exerts immunomodulatory functions by interaction with immune cells, including T cells. Metabolic programs of T cells are closely linked to their effector functions including proliferation, differentiation, and cytokine production. The physiological molecules glucose and insulin may provide environmental cues and guidance, but whether they coordinate to regulate GABA-mediated T cell immunomodulation is still being examined.
METHODS: CD4+ T cells that were isolated from blood samples from healthy individuals and from patients with type 1 diabetes (T1D) were activated in vitro. We carried out metabolic assays, multiple proximity extension assay (PEA), ELISA, qPCR, immunoblotting, immunofluorescence staining, flow cytometry analysis, MS-based proteomics, as well as electrophysiology and live-cell Ca2+ imaging.
RESULTS: We demonstrate that GABA-mediated reduction of metabolic activity and the release of inflammatory proteins, including IFNγ and IL-10, were abolished in human CD4+ T cells from healthy individuals and patients with T1D when the glucose concentration was elevated above levels typically observed in healthy people. Insulin increased GABAA receptor-subunit ρ2 expression, enhanced the GABAA receptors-mediated currents and Ca2+ influx. GABA decreased, whereas insulin sustained, hexokinase activity and glycolysis in a glucose concentration-dependent manner.
CONCLUSIONS: These findings support that metabolic factors, such as glucose and insulin, influence the GABA-mediated immunomodulation of human primary T cells effector functions.
BACKGROUND: The Swedish Children\'s Diabetes Foundation, The Swedish Diabetes Foundation, The Swedish Research Council 2018-02952, EXODIAB, The Ernfors Foundation, The Thurings Foundation and the Science for Life Laboratory.
METHODS: CD4+ T cells that were isolated from blood samples from healthy individuals and from patients with type 1 diabetes (T1D) were activated in vitro. We carried out metabolic assays, multiple proximity extension assay (PEA), ELISA, qPCR, immunoblotting, immunofluorescence staining, flow cytometry analysis, MS-based proteomics, as well as electrophysiology and live-cell Ca2+ imaging.
RESULTS: We demonstrate that GABA-mediated reduction of metabolic activity and the release of inflammatory proteins, including IFNγ and IL-10, were abolished in human CD4+ T cells from healthy individuals and patients with T1D when the glucose concentration was elevated above levels typically observed in healthy people. Insulin increased GABAA receptor-subunit ρ2 expression, enhanced the GABAA receptors-mediated currents and Ca2+ influx. GABA decreased, whereas insulin sustained, hexokinase activity and glycolysis in a glucose concentration-dependent manner.
CONCLUSIONS: These findings support that metabolic factors, such as glucose and insulin, influence the GABA-mediated immunomodulation of human primary T cells effector functions.
BACKGROUND: The Swedish Children\'s Diabetes Foundation, The Swedish Diabetes Foundation, The Swedish Research Council 2018-02952, EXODIAB, The Ernfors Foundation, The Thurings Foundation and the Science for Life Laboratory.
摘要：
背景：γ-氨基丁酸（GABA），被称为大脑中的主要抑制性神经递质，通过与免疫细胞的相互作用发挥免疫调节功能，包括T细胞。T细胞的代谢程序与其效应子功能密切相关，包括增殖，分化,和细胞因子的产生。生理分子葡萄糖和胰岛素可以提供环境线索和指导，但它们是否协调调节GABA介导的T细胞免疫调节仍在研究中。
方法：从健康个体和1型糖尿病（T1D）患者的血液样本中分离的CD4+T细胞在体外被激活。我们进行了代谢测定，多重邻近延伸测定(PEA)，ELISA,qPCR,免疫印迹,免疫荧光染色，流式细胞术分析,基于MS的蛋白质组学，以及电生理学和活细胞Ca2+成像。
结果：我们证明了GABA介导的代谢活性降低和炎症蛋白的释放，当葡萄糖浓度升高到高于健康人中通常观察到的水平时,包括IFNγ和IL-10在来自健康个体和患有T1D的患者的人CD4+T细胞中被废除。胰岛素增加GABAA受体亚基ρ2表达，增强了GABAA受体介导的电流和Ca2流入。GABA下降，而胰岛素持续，己糖激酶活性和糖酵解呈葡萄糖浓度依赖性。
结论：这些发现支持代谢因素，如葡萄糖和胰岛素，影响GABA介导的人原代T细胞效应功能的免疫调节。
背景：瑞典儿童糖尿病基金会，瑞典糖尿病基金会TheSwedishResearchCouncil2018-02952,EXODIAB,Ernfors基金会,图林斯基金会和生命科学实验室。
方法：从健康个体和1型糖尿病（T1D）患者的血液样本中分离的CD4+T细胞在体外被激活。我们进行了代谢测定，多重邻近延伸测定(PEA)，ELISA,qPCR,免疫印迹,免疫荧光染色，流式细胞术分析,基于MS的蛋白质组学，以及电生理学和活细胞Ca2+成像。
结果：我们证明了GABA介导的代谢活性降低和炎症蛋白的释放，当葡萄糖浓度升高到高于健康人中通常观察到的水平时,包括IFNγ和IL-10在来自健康个体和患有T1D的患者的人CD4+T细胞中被废除。胰岛素增加GABAA受体亚基ρ2表达，增强了GABAA受体介导的电流和Ca2流入。GABA下降，而胰岛素持续，己糖激酶活性和糖酵解呈葡萄糖浓度依赖性。
结论：这些发现支持代谢因素，如葡萄糖和胰岛素，影响GABA介导的人原代T细胞效应功能的免疫调节。
背景：瑞典儿童糖尿病基金会，瑞典糖尿病基金会TheSwedishResearchCouncil2018-02952,EXODIAB,Ernfors基金会,图林斯基金会和生命科学实验室。
