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摘要 : Alexander Flügel及同事,利用大鼠的 “实验性自身免疫性脑脊髓炎”(EAE, 多发性硬化的一个模型),研究了能诱发炎症的自体反应性T-细胞在 “过继性转移” (adoptive transfer)过程中从外周血液被交换到大脑的机制。

 Alexander Flügel及同事,利用大鼠的 “实验性自身免疫性脑脊髓炎”(EAE, 多发性硬化的一个模型),研究了能诱发炎症的自体反应性T-细胞在 “过继性转移” (adoptive transfer)过程中从外周血液被交换到大脑的机制。他们显示,T-细胞从柔脑膜空间进入脑脊髓液(CSF),而不是像人们曾经提出的那样从脉络丛(choroid plexus)进入。被交换的T-细胞保持了它们全部的抗原响应性和致病潜力,这说明对在CSF中容易接触到的T-细胞的表征,对于了解致病性T-细胞在多发性硬化中的性质和功能可能会有用。


Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid


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. How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical. 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 wher they can reach areas of antigen availability and tissue damage.

来源: Nature 浏览次数:0


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