Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Brain. 2013 Nov;136(Pt 11):3427-40. doi: 10.1093/brain/awt259. Epub 2013 Oct 1.
Infiltrating T cells and monocyte-derived macrophages support central nervous system repair. Although infiltration of leucocytes to the injured central nervous system has recently been shown to be orchestrated by the brain's choroid plexus, the immunological mechanism that maintains this barrier and regulates its activity as a selective gate is poorly understood. Here, we hypothesized that CD4(+) effector memory T cells, recently shown to reside at the choroid plexus stroma, regulate leucocyte trafficking through this portal through their interactions with the choroid plexus epithelium. We found that the naïve choroid plexus is populated by T helper 1, T helper 2 and regulatory T cells, but not by encephalitogenic T cells. In vitro findings revealed that the expression of immune cell trafficking determinants by the choroid plexus epithelium is specifically induced by interferon-γ. Tumour necrosis factor-α and interferon-γ reciprocally controlled the expression of their receptors by the choroid plexus epithelium, and had a synergistic effect in inducing the epithelial expression of trafficking molecules. In vivo, interferon-γ-dependent signalling controlled trafficking through the choroid plexus; interferon-γ receptor knockout mice exhibited reduced levels of T cells and monocyte entry to the cerebrospinal fluid and impaired recovery following spinal cord injury. Moreover, reduced expression of trafficking molecules by the choroid plexus was correlated with reduced CD4(+) T cells in the choroid plexus and cerebrospinal fluid of interferon-γ receptor knockout mice. Similar effect on the expression of trafficking molecules by the choroid plexus was found in bone-marrow chimeric mice lacking interferon-γ receptor in the central nervous system, or reciprocally, lacking interferon-γ in the circulation. Collectively, our findings attribute a novel immunological plasticity to the choroid plexus epithelium, allowing it to serve, through interferon-γ signalling, as a tightly regulated entry gate into the central nervous system for circulating leucocytes immune surveillance under physiological conditions, and for repair following acute injury.
浸润 T 细胞和单核细胞衍生的巨噬细胞支持中枢神经系统修复。尽管最近已经证明，白细胞浸润到受损的中枢神经系统是由大脑脉络丛协调的，但维持这种屏障并调节其作为选择性门的活性的免疫机制还知之甚少。在这里，我们假设最近在脉络丛基质中发现的 CD4+效应记忆 T 细胞通过与脉络丛上皮细胞的相互作用来调节白细胞的迁移，从而调节这种屏障。我们发现，幼稚的脉络丛被 T 辅助 1、T 辅助 2 和调节性 T 细胞所占据，但没有致脑炎 T 细胞。体外研究结果表明，脉络丛上皮细胞免疫细胞迁移决定因素的表达是由干扰素-γ特异性诱导的。肿瘤坏死因子-α和干扰素-γ通过脉络丛上皮细胞相互控制其受体的表达，并在诱导上皮细胞表达迁移分子方面具有协同作用。在体内，干扰素-γ依赖性信号控制着脉络丛的迁移；干扰素-γ受体敲除小鼠表现出 T 细胞和单核细胞进入脑脊液的水平降低，并且脊髓损伤后的恢复受损。此外，脉络丛表达的迁移分子减少与干扰素-γ受体敲除小鼠脉络丛和脑脊液中 CD4+T 细胞减少相关。在缺乏中枢神经系统干扰素-γ受体的骨髓嵌合小鼠或循环中缺乏干扰素-γ的反向小鼠中，也发现了对脉络丛表达迁移分子的类似影响。总的来说，我们的研究结果赋予脉络丛上皮细胞一种新的免疫可塑性，使其能够通过干扰素-γ信号，作为循环白细胞免疫监视的中枢神经系统内的一个紧密调节的进入门，在生理条件下，并在急性损伤后进行修复。
