Brain-infiltrating inflammatory monocyte responses to acute virus infection

描述(申请人提供)：负责将免疫相关信息从中枢神经系统(CNS)传递到外周免疫系统的细胞类型目前尚不清楚。对这种细胞的识别是理解 CNS感染的先天和获得性免疫反应的发生，CNS自身免疫性疾病中发生的对自身的不适应性免疫反应，以及保护CNS肿瘤的免疫攻击的逃避。该领域主要集中在树突状细胞和小胶质细胞作为中枢神经系统内驱动T细胞再刺激的抗原提呈细胞，但这些细胞向淋巴结传递信息以进行原始T细胞启动的能力有限或未被研究。一个长期的目标是识别携带神经抗原到周围淋巴结的细胞，以便在治疗上改变、调节或取消它们的功能。这项建议的具体目标是测试CD45hiCD11bhiLy6chi Ly6Gneg炎性单核细胞将抗原从急性感染的大脑传递到外周免疫系统的能力。中心假说是炎性单核细胞在特定的趋化因子信号作用下渗入大脑，是一种关键的抗原提呈细胞，具有离开大脑并将抗原携带到颈部淋巴结(CLN)的能力。这一假说是基于初步数据，该数据显示，大脑浸润性炎症单核细胞在感染后的头18-24小时内获得大脑内的蛋白质抗原和病毒，并将这些信息传递给CLN。主要假说将通过追求两个特定的目标来验证：1)确定在病毒感染的头48小时内炎性单核细胞招募和渗透到脑内的机制；2)确定脑浸润性炎性单核细胞是否获得树突状细胞表型，退出携带病毒抗原的脑，并在CLN中作为抗原递呈细胞发挥作用。实验方法将利用急性感染泰勒氏小鼠脑脊髓炎病毒的LysM：GFP报告小鼠，并将利用对趋化因子、趋化因子受体和黏附因子的遗传和免疫操作以及过继转移来检验主要假设。这种方法是创新的，因为它使用了一个模型系统，在这个系统中，大脑限制性抗原是通过渗透炎性单核细胞获得的，然后炎症单核细胞将这些抗原携带到外周，以驱动T细胞反应。这项拟议的研究具有重要意义，因为它识别了一种炎症反应因子，它渗透到大脑，获得免疫学信息，并将这些信息传递到外周免疫系统，为中枢神经系统免疫反应的治疗和药物调节提供了一个全新的靶点。

DESCRIPTION (provided by applicant): The cell type responsible for transmission of immunologically relevant information from the central nervous system (CNS) to the peripheral immune system is currently unclear. The identification of this cell is central to understanding the genesis of innate and adaptive immune responses to CNS infection, the maladaptive immunological response to self that occurs in CNS autoimmune disease, and the escape from immunological assault that protects CNS tumors. The field has largely focused on dendritic cells and microglia as antigen presenting cells within the CNS that drive T cell restimulation, but the capacity of these cells to transmit information to the lymph nodes for original T cell priming is limited or unstudied. A long-term goal is to identify cells that carry neural antigens to the peripheral lymph nodes in order to therapeutically modify, modulate, or abrogate their function. The specific objective of this proposal is to test the ability of CD45hiCD11bhiLy6Chi Ly6Gneg inflammatory monocytes to transmit antigens from the acutely infected brain to the peripheral immune system. The central hypothesis is that inflammatory monocytes which infiltrate the brain in response to specific chemokine signals are a critical antigen-presenting cell with the capacity to exit the brain and carry antigen to the cervical lymph nodes (CLNs). The hypothesis is based upon preliminary data showing that brain-infiltrating inflammatory monocytes acquire protein antigens and virus within the brain in the first 18-24 hours after infection and carry this information to the CLNs. The main hypothesis will be tested by pursuing two specific aims: 1) To identify the mechanisms responsible for recruitment and infiltration of inflammatory monocytes into the brain during the first 48 hours of virus infection; and 2) To determine if brain-infiltratng inflammatory monocytes acquire a dendritic cell phenotype, exit the brain carrying viral antigens, and function as antigen- presenting cells in the CLNs. The experimental approach will utilize LysM:GFP reporter mice acutely infected with the Theiler's murine encephalomyelitis virus and will exploit genetic and immunological manipulation of chemokines, chemokine receptors and adhesion factors as well as adoptive transfers to test the main hypothesis. The approach is innovative because it uses a model system in which brain-restricted antigens are acquired by infiltrating inflammatory monocytes that then carry these antigens to the periphery to drive T cell responses. The proposed research is significant because it identifies an inflammatory responder that infiltrates the brain, acquires immunological information, and transmits that information to the peripheral immune system, providing an entirely new target for therapeutic and pharmacological modulation of CNS immune responses.