Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid
Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid
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DOI：
10.1038/nature16939
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发表时间：
2016-02-18
期刊：
影响因子：
64.8
通讯作者：
Fluegel, Alexander
中科院分区：
文献类型：
--
作者：
Schlaeger, Christian;Koerner, Henrike;Fluegel, Alexander
在多发性硬化症中，脑反应性T细胞侵入中枢神经系统（CNS）并诱导自我破坏性炎症过程。T细胞浸润不仅存在于脑实质和脑膜中，而且存在于浸润整个CNS组织的脑脊液（CSF）中（1，2）。T细胞如何到达CSF、它们的功能以及它们是否在CSF和其他中枢神经系统隔室之间交通仍然是假设的（3-6）。在这里，我们表明，效应T细胞进入脑脊液从软脑膜在刘易斯大鼠实验性自身免疫性脑脊髓炎（EAE），多发性硬化症的模型。当T细胞以随机布朗行走的方式穿过胶原纤维的三维软脑膜网络时，T细胞被CSF的流动从表面冲走。与来自软脑膜和CNS实质的T细胞相比，分离的细胞显示出显著较低的活化水平。然而，它们并不代表专门的非致病性细胞亚组分，因为它们的基因表达谱与组织来源的T细胞的基因表达谱非常相似，并且它们完全保留了它们的致脑炎潜力。从软脑膜的T细胞脱离被整合素VLA-4和LFA-1结合到由驻留的巨噬细胞产生的它们各自的配体抵消。通过CCR 5/CXCR 3的趋化因子信号传导和与软脑膜巨噬细胞接触的T细胞的抗原刺激加强了它们的免疫。漂浮在CSF中的T细胞能够通过使人联想到CNS血管中的血管粘附的步骤重新附着到软脑膜，并侵入实质。T细胞再附着的分子/细胞条件与从软脑膜环境中脱离的要求相同。我们的数据表明，软脑膜代表了一个检查点，在该检查点处，活化的T细胞被许可进入CNS实质，而非活化的T细胞优先释放到CSF中，从那里它们可以到达抗原可用性和组织损伤的区域。
In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue(1,2). How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical(3-6). Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.