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首页> 外文期刊>Journal of neuroinflammation >Excitotoxic neuronal cell death during an oligodendrocyte-directed CD8+ T cell attack in the CNS gray matter
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Excitotoxic neuronal cell death during an oligodendrocyte-directed CD8+ T cell attack in the CNS gray matter

机译：中枢神经系统灰质中少突胶质细胞定向CD8 + T细胞攻击过程中兴奋性神经元细胞死亡

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Background Neural-antigen reactive cytotoxic CD8+ T cells contribute to neuronal dysfunction and degeneration in a variety of inflammatory CNS disorders. Facing excess numbers of target cells, CNS-invading CD8+ T cells cause neuronal cell death either via confined release of cytotoxic effector molecules towards neurons, or via spillover of cytotoxic effector molecules from 'leaky’ immunological synapses and non-confined release by CD8+ T cells themselves during serial and simultaneous killing of oligodendrocytes or astrocytes. Methods Wild-type and T cell receptor transgenic CD8+ T cells were stimulated in vitro, their activation status was assessed by flow cytometry, and supernatant glutamate levels were determined using an enzymatic assay. Expression regulation of molecules involved in vesicular glutamate release was examined by quantitative real-time PCR, and mechanisms of non-vesicular glutamate release were studied by pharmacological blocking experiments. The impact of CD8+ T cell-mediated glutamate liberation on neuronal viability was studied in acute brain slice preparations. Results Following T cell receptor stimulation, CD8+ T cells acquire the molecular repertoire for vesicular glutamate release: (i) they upregulate expression of glutaminase required to generate glutamate via deamination of glutamine and (ii) they upregulate expression of vesicular proton-ATPase and vesicular glutamate transporters required for filling of vesicles with glutamate. Subsequently, CD8+ T cells release glutamate in a strictly stimulus-dependent manner. Upon repetitive T cell receptor stimulation, CD25high CD8+ T effector cells exhibit higher estimated single cell glutamate release rates than CD25low CD8+ T memory cells. Moreover, glutamate liberation by oligodendrocyte-reactive CD25high CD8+ T effector cells is capable of eliciting collateral excitotoxic cell death of neurons (despite glutamate re-uptake by glia cells and neurons) in intact CNS gray matter. Conclusion Glutamate release may represent a crucial effector pathway of neural-antigen reactive CD8+ T cells, contributing to excitotoxicity in CNS inflammation.
机译：背景神经抗原反应性细胞毒性CD8 + T细胞在多种炎性CNS疾病中导致神经元功能障碍和变性。面对过量的靶细胞，侵袭中枢神经系统的CD8 + T细胞通过细胞毒性效应分子向神经元的有限释放或细胞毒性效应分子从“漏出”的免疫突触中溢出和CD8 + T细胞的无限制释放而引起神经元细胞死亡。自身同时或同时杀死少突胶质细胞或星形胶质细胞。方法在体外刺激野生型和T细胞受体转基因CD8 + T细胞，通过流式细胞仪评估其激活状态，并通过酶法测定上清液中的谷氨酸水平。通过定量实时PCR检测参与水泡谷氨酸释放的分子的表达调控，并通过药理阻断实验研究非水泡谷氨酸释放的机制。在急性脑切片制剂中研究了CD8 + T细胞介导的谷氨酸释放对神经元生存力的影响。结果在T细胞受体刺激后，CD8 + T细胞获得了囊泡谷氨酸释放的分子库：（i）上调通过谷氨酰胺脱氨产生谷氨酸所需的谷氨酰胺酶的表达，（ii）上调囊泡质子-ATPase和囊泡谷氨酸的表达谷氨酸填充囊泡所需的转运蛋白。随后，CD8 + T细胞以严格的刺激依赖性方式释放谷氨酸。在重复性T细胞受体刺激下，CD25高CD8 + T效应细胞比CD25低CD8 + T记忆细胞显示更高的估计单细胞谷氨酸释放速率。此外，少突胶质细胞反应性CD25high CD8 + T效应细胞释放的谷氨酸能够引发完整的CNS灰质中神经元的副兴奋性细胞毒性死亡（尽管神经胶质细胞和神经元重新吸收谷氨酸）。结论谷氨酸释放可能是神经抗原反应性CD8 + T细胞的重要效应途径，有助于中枢神经系统炎症的兴奋性毒性。

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