Brain-infiltrating inflammatory monocyte responses to acute virus infection

描述（由申请方提供）：目前尚不清楚负责将免疫学相关信息从中枢神经系统（CNS）传递至外周免疫系统的细胞类型。这种细胞的鉴定对于理解 对CNS感染的先天性和适应性免疫应答的发生、CNS自身免疫性疾病中发生的对自身的适应不良免疫应答以及保护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CNS内驱动T细胞再刺激的抗原呈递细胞，但这些细胞将信息传递到淋巴结用于原始T细胞引发的能力是有限的或未研究的。一个长期的目标是识别携带神经抗原到外周淋巴结的细胞，以治疗性地改变、调节或消除它们的功能。本提案的具体目的是测试CD 45 hiCD 11 bhiLy 6 Chi Ly 6 Gneg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。中心假设是响应于特定趋化因子信号而浸润脑的炎性单核细胞是具有离开脑并将抗原携带至颈淋巴结（CLN）的能力的关键抗原呈递细胞。该假设基于初步数据，显示脑浸润炎性单核细胞在感染后的前18-24小时内在脑内获得蛋白抗原和病毒，并将此信息携带至CLN。主要假设将通过追求两个具体目标来检验：1）鉴定负责在病毒感染的前48小时期间炎性单核细胞募集和浸润到脑中的机制;和2）确定脑浸润的炎性单核细胞是否获得树突细胞表型，携带病毒抗原离开脑，并在CLN中充当抗原呈递细胞。实验方法将利用LysM：GFP报告小鼠急性感染Theiler氏鼠脑脊髓炎病毒，并将利用趋化因子、趋化因子受体和粘附因子的遗传和免疫学操作以及过继转移来测试主要假设。这种方法是创新的，因为它使用了一个模型系统，其中脑限制性抗原是通过浸润炎性单核细胞获得的，然后将这些抗原携带到外周，以驱动T细胞反应。这项研究意义重大，因为它确定了一种炎症反应者，这种炎症反应者浸润大脑，获得免疫学信息，并将该信息传递给外周免疫系统，为CNS免疫反应的治疗和药理学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.