Control of T cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis
Control of T cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis
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DOI：
10.1074/jbc.m701890200
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发表时间：
2007-07-06
影响因子：
4.8
通讯作者：
Demetriou, Michael
中科院分区：
文献类型：
--
作者：
Grigorian, Ani;Lee, Sung-Uk;Demetriou, Michael
自身免疫是一种复杂的性状疾病，其中环境通过不清楚的机制影响疾病的易感性。免疫突触处的T细胞受体聚集和信号传导、T细胞增殖、CTLA-4内吞作用、TH 1分化和自身免疫由附着于细胞表面糖蛋白的β 1，6 GlcNAc分支的N-聚糖负调节。T细胞中β 1，6 GlcNAc分支N-聚糖的表达依赖于对UDP-GlcNAc生物合成（己糖胺途径）以及进而对高尔基体N-乙酰葡糖胺基转移酶Mgat 1、Mgat-2、Mgat-4和Mgat-5的代谢物供应。在Jurkat T细胞中，N-聚糖中的β 1，6 GlcNAc-分支被供应己糖胺途径的代谢物刺激，包括葡萄糖、GlcNAc、乙酰乙酸、谷氨酰胺、氨或尿苷，但不被对照代谢物甘露糖胺、半乳糖、甘露糖、琥珀酸或丙酮酸刺激。在体外和体内补充己糖胺还增加幼稚小鼠T细胞中的β 1，6 GlcNAc-分支的N-聚糖，并抑制非肥胖糖尿病小鼠中的T细胞受体信号传导、T细胞增殖、CTLA-4内吞作用、TH 1分化、实验性自身免疫性脑脊髓炎和自身免疫性糖尿病。我们的结果表明，通过己糖胺和N-聚糖途径的代谢物通量通过调节β 1，6 GlcNAc分支的N-聚糖下游的多种T细胞功能来有条件地调节自身免疫。这表明代谢疗法作为自身免疫性疾病的潜在治疗。
Autoimmunity is a complex trait disease where the environment influences susceptibility to disease by unclear mechanisms. T cell receptor clustering and signaling at the immune synapse, T cell proliferation, CTLA-4 endocytosis, TH1 differentiation, and autoimmunity are negatively regulated by beta 1,6GlcNAc-branched N-glycans attached to cell surface glycoproteins. beta 1,6GlcNAc-branched N-glycan expression in T cells is dependent on metabolite supply to UDP-GlcNAc biosynthesis ( hexosamine pathway) and in turn to Golgi N-acetylglucosaminyltransferases Mgat1,-2, -4, and -5. In Jurkat T cells, beta 1,6GlcNAc- branching in N-glycans is stimulated by metabolites supplying the hexosamine pathway including glucose, GlcNAc, acetoacetate, glutamine, ammonia, or uridine but not by control metabolites mannosamine, galactose, mannose, succinate, or pyruvate. Hexosamine supplementation in vitro and in vivo also increases beta 1,6GlcNAc- branched N-glycans in naive mouse T cells and suppresses T cell receptor signaling, T cell proliferation, CTLA-4 endocytosis, TH1 differentiation, experimental autoimmune encephalomyelitis, and autoimmune diabetes in non-obese diabetic mice. Our results indicate that metabolite flux through the hexosamine and N-glycan pathways conditionally regulates autoimmunity by modulating multiple T cell functionalities downstream of beta 1,6GlcNAc- branched N-glycans. This suggests metabolic therapy as a potential treatment for autoimmune disease.