Excitotoxic neuronal cell death during an oligodendrocyte-directed CD8+ T cell attack in the CNS gray matter

Journal of Neuroinflammation

Sven G Meuth¹  Heinz Wiendl²  Alexander M Herrmann²  Kerstin Göbel²  Nicole Bobak²  Stefan Bittner²  Gordon Hicking²  Nico Melzer² 

[1] Department of Physiology I - Neuropathophysiology, University of Münster, Robert-Koch-Straße 27a, Münster 48149, Germany;Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, Münster 48149, Germany

关键词: CD8⁺ T cells;    CNS tissue damage;    Neuronal cell death;    Glutamate excitotoxicity;   

Others  :  1151875
DOI  :  10.1186/1742-2094-10-121

 received in 2013-08-04, accepted in 2013-09-24,  发布年份 2013

【 摘 要 】

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, CD25^high CD8⁺ T effector cells exhibit higher estimated single cell glutamate release rates than CD25^low CD8⁺ T memory cells. Moreover, glutamate liberation by oligodendrocyte-reactive CD25^high 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.

【 授权许可】

   
2013 Melzer et al.; licensee BioMed Central Ltd.

【 图 表 】

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