Neuroscience Graduate Program, University of Vermont, Burlington, VT 05405, USA.
J Neurol Sci. 2011 Jul 15;306(1-2):121-8. doi: 10.1016/j.jns.2011.03.030. Epub 2011 Apr 14.
Immune-neural interactions dictate both lesion formation and repair in multiple sclerosis (MS). MS pathogenesis is mediated by the interplay of invading immune cells, neurons, glia, and endogenous stores of neural stem/progenitor cells (NPCs). However, the signals important in this cross-talk are not well defined. We utilized a co-culture method and flow cytometric analysis capable of detecting outcomes for both cell types. Here we describe the effects of NPCs on three different CD4+ subtypes (Th1, Th2, and Th17) and vice versa. Utilizing lpr (Fas receptor-deficient) and gld (Fas ligand-deficient) NPC lines, we further define the role of Fas in this neuroimmune cross-talk. We show that only the Th1 subtype is capable of inducing NPC cell death, and this is independent of Fas activation. Conversely, NPCs specifically kill pro-inflammatory Th1 and Th17 cells in a contact-dependent manner without affecting Th2 survival. Further investigation into these effects revealed that FasL expressed by NPCs mediates Th17 apoptosis. Additionally NPC/T-cell cross-talk modulates FasL expression in both cell types, while Fas receptor levels remains static. These findings illuminate the direct neuropathogenic effects of T-cells, as well as help define the immunomodulatory capacity of NPCs. We have elucidated novel interactions that may be critical in MS pathogenesis.
免疫-神经相互作用决定了多发性硬化症（MS）中的病变形成和修复。MS 的发病机制是由入侵的免疫细胞、神经元、神经胶质和内源性神经干细胞/祖细胞（NPC）库之间的相互作用介导的。然而，这种交叉对话中重要的信号尚未得到很好的定义。我们利用共培养方法和流式细胞术分析，能够检测到两种细胞类型的结果。在这里，我们描述了 NPC 对三种不同的 CD4+亚型（Th1、Th2 和 Th17）的影响，反之亦然。利用 lpr（Fas 受体缺陷）和 gld（Fas 配体缺陷）NPC 系，我们进一步定义了 Fas 在这种神经免疫交叉对话中的作用。我们表明，只有 Th1 亚型能够诱导 NPC 细胞死亡，而这与 Fas 激活无关。相反，NPC 以接触依赖的方式特异性杀死促炎性 Th1 和 Th17 细胞，而不影响 Th2 的存活。对这些效应的进一步研究表明，NPC 表达的 FasL 介导了 Th17 细胞的凋亡。此外，NPC/T 细胞相互作用调节两种细胞类型中 FasL 的表达，而 Fas 受体水平保持不变。这些发现阐明了 T 细胞的直接神经致病作用，并有助于定义 NPC 的免疫调节能力。我们已经阐明了可能在 MS 发病机制中起关键作用的新的相互作用。
