Immune Response to CNS Injury

 描述（由申请人提供）：创伤性CNS损伤和许多神经退行性疾病导致神经元持续死亡。这种神经元死亡的扩散被称为继发性神经变性。在过去的二十年里，一些工作已经证明了免疫系统在影响继发性变性中的作用。虽然T细胞和巨噬细胞的一些亚群限制了损伤的扩散，从而有助于神经保护，但其他亚群则使神经变性永久化。我们的目标是更好地了解哪些T细胞亚群介导神经保护，以及哪些分子线索将这些T细胞招募到损伤部位。最终目标是干预这一过程，提高神经保护性免疫力。我们最近已经证明了效应和调节CD4 + T细胞在中枢神经系统损伤中的作用。我们还表明，神经保护性T细胞，通过其生产的IL-4，限制继发性变性的程度;然而，IL-4介导的神经保护的精确的细胞靶点尚未确定日期。CNS损伤后T细胞的活化发生在CNS引流的颈深淋巴结（dCLN）中，并且dCLN的手术切除导致CNS损伤后神经元存活受损。虽然已经认识到脑脊液（CSF）和dCLN之间的联系，但这两个区域之间细胞运输的确切路径尚未完全了解。在寻找细胞进入和离开CNS的途径时，我们偶然发现了位于沿着硬脑膜窦的脑膜中的经典淋巴管，其携带淋巴细胞和骨髓细胞并将CSF和免疫细胞直接引流到dCLN。这些血管的特征可能使我们能够控制细胞和可溶性CSF成分的引流，从而可能改变对脑抗原的免疫反应。我们的目标是解决这个建议的首要假设是，脑膜淋巴管调节免疫反应的中枢神经系统损伤的脑膜空间和募集的T细胞获得Th2表型之前，他们进入损伤部位。Th2偏斜和随后的IL-4产生介导损伤部位的神经保护。本研究的三个具体目标是：（1）验证脑膜淋巴管调节损伤后脑膜T细胞免疫的假设;（2）验证少突胶质细胞来源的IL-33和ILC2来源的IL-13的联合作用使脑膜T细胞偏向Th2的假设;（3）确定IL-4介导的神经保护作用的细胞靶点。成功完成本提案的目标将提高我们对CNS损伤后驱动保护性免疫反应的分子事件的理解，并将揭示CNS损伤和其他神经退行性疾病的新治疗靶点。

 DESCRIPTION (provided by applicant): Traumatic CNS injuries and many neurodegenerative diseases result in the continuous death of neurons. This spread of neuronal death is termed secondary neurodegeneration. Several works over the last two decades have demonstrated the role of the immune system in affecting secondary degeneration. While some subsets of T cells and macrophages are limiting the spread of damage and thus contributing to neuroprotection, others are perpetuating neurodegeneration. Our goal is to better understand what subsets of T cells mediate neuroprotection and what molecular cues recruit these T cells to the site of injury. The ultimate goal is to intervene with this process and boost neuroprotective immunity. We have recently demonstrated a role for both effector and regulatory CD4+ T cells in response to CNS injury. We also showed that neuroprotective T cells, through their production of IL-4, limit the degree of secondary degeneration; however, the precise cellular targets of IL-4-mediated neuroprotection have not been identified to date. Activation of T cells after CNS injury takes place in the CNS-draining deep cervical lymph nodes (dCLNs), and surgical resection of dCLNs results in impaired neuronal survival after CNS injury. Although the connection between cerebrospinal fluid (CSF) and the dCLNs has been appreciated, the exact path of cell trafficking between the two regions was not completely understood. In search for the routes of cell entry and exit to/from the CNS, we serendipitously discovered classical lymphatic vessels in the brain meninges located along the dural sinuses, which carry lymphocytes and myeloid cells and drain CSF and immune cells directly to the dCLNs. Characterization of these vessels may allow us to gain a control over drainage of cellular and soluble CSF constituents and thus possibly alter the immune response to brain antigens. The overarching hypothesis that we aim to address in this proposal is that meningeal lymphatic vessels regulate immune response to CNS injury within the meningeal spaces and the recruited T cells acquire there a Th2 phenotype prior to their entry into the site of injury. Th2 skew and a subsequent IL-4 production mediate neuroprotection at the site of injury. The three specific aims to be addressed in this proposal are: (1) To test th hypothesis that meningeal lymphatic vessels are regulating post-injury meningeal T cell immunity; (2) To test the hypothesis that the combined action of oligodendrocyte-derived IL-33 and ILC2-derived IL-13, skew meningeal T cells to Th2; (3) To define the cellular targets of IL-4-mediated neuroprotection. A successful completion of the aims of this proposal will enhance our understanding of the molecular events that drive a protective immune response after CNS injury and will shed a light on new therapeutic targets for CNS injuries and other neurodegenerative disorders.