Role of CX3CR1 in adaptive immunity during autoimmune encephalomyelitis

CX3CR1在自身免疫性脑脊髓炎适应性免疫中的作用

• 批准号: 8586316
• 负责人: Astrid E Cardona
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-03 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586316
• 关键词: Acute Disease; Address; Adhesions; Affect; Affinity; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Biological Assay; Bone Marrow; Brain; CD 200; CD28 gene; CNS autoimmunity; CSF1R gene; CX3CL1 gene; Cell Adhesion Molecules; Cell Communication; Cell Maturation; Cell membrane; Cell physiology; Cells; Chemotactic Factors; Chronic; Demyelinations; Dendritic Cells; Development; Disease; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Autoimmune Encephalomyelitis; Fractalkine; Generations; Goals; Human; Human Genetics; ITGAX gene; Immigration; Immune response; Inflammation; Knock-in Mouse; Life; Link; Maintenance; Mediating; Microglia; Modeling; Multiple Sclerosis; Mus; Myelin; Natural Killer Cells; Nervous System Trauma; Neuraxis; Neurons; Paralysed; Pathology; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Play; Population; Prevention strategy; Recovery; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Spleen; Staining method; Stains; Symptoms; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Variant; adaptive immunity; base; chemokine; cytokine; enzyme linked immunospot assay; expression vector; genetic variant; human CX3CR1 protein; in vivo; macrophage; migration; monocyte; peripheral blood; receptor; trafficking; treatment strategy

DESCRIPTION (provided by applicant): The transmembrane chemokine fractalkine (CX3CL1) present on neurons and peripheral endothelial cells acts as an adhesion molecule or as a soluble chemoattractant. CX3CL1 signals through its receptor CX3CR1 which is expressed in microglia, monocytes/macrophages and dendritic cells, NK cells and T cells. Notably, multiple sclerosis patients revealed lower expression of CX3CR1 in peripheral NK cells when compared to healthy controls and lack of CX3CR1+ cells in peripheral blood correlated with disease activity. However, the role of CX3CR1 in antigen presenting cells and T cells, and their contribution to CNS pathology are still enigmatic. The hypothesis behind the proposed research is that CX3CR1/CX3CL1 regulates antigen presenting cell (APC) effector functions influencing the development of pathogenic T cells during experimental autoimmune encephalomyelitis (EAE). This hypothesis is based on the following: 1) EAE symptoms are more severe and CNS demyelination is enhanced CX3CR1-deficient mice, 2) absence of CX3CR1 correlated with a selective accumulation of CD115+CD11c+ dendritic cells to CNS tissues, and 3) Bone marrow chimeric mice revealed that absence of CX3CR1 in bone marrow induced an unusual, severe and chronic non-remitting EAE disease with sustained paralysis. The overall goal of this proposal is to elucidate the function of CX3CR1 during EAE and how it regulates pathogenic CNS inflammation. The specific aims are: 1. to determine the role of CX3CR1 for the initiation of EAE via modulation of antigen presentation and T cell priming. We will test the hypothesis that CX3CR1 controls peripherally DC maturation affecting antigen presentation and subsequently peripheral T cell polarization. We will investigate the role of CX3CR1 antigen trafficking and dendritic cell mobilization and effects of CX3CR1-deficiency in generation of encephalitogenic T cells. 2. To determine the role of CX3CR1 deficiency in the effector phase of EAE and protection from neuronal damage and demyelination. We hypothesize that absence of CX3CR1 in bone marrow is critical for the maintenance of T cell mediated inflammation and tissue damage in the EAE brain. We will investigate the role of CX3CR1 in inhibitory signaling, activation, and survival of pathogenic and regulatory T cell subsets within CNS tissues at peak of disease and at time of recovery. 3. To define address how weaker signaling through human CX3CR1I249/M280 replicates the pathology of Cx3cr1-/- mice during EAE. We hypothesize that I249/M280 expressing cells will exhibit effector functions comparable to CX3CR1-deficient cells. We will use knock-in mice expressing the human variant as a low affinity model to investigate the role of the I249/M280 in APC activation and T cell polarization in vivo during CNS autoimmunity.

描述（由申请人提供）：神经元和周围内皮细胞上存在的跨膜趋化因子分裂（CX3CL1）充当粘附分子或可溶性趋化剂。 CX3CL1通过其受体CX3CR1信号，该受体CX3CR1在小胶质细胞，单核细胞/巨噬细胞以及树突状细胞，NK细胞和T细胞中表达。值得注意的是，与健康对照组相比，多发性硬化症患者在外周NK细胞中的CX3CR1表达较低，并且在外周血中缺乏与疾病活性相关的CX3CR1+细胞。但是，CX3CR1在抗原呈现细胞和T细胞中的作用及其对CNS病理学的贡献仍然是神秘的。拟议的研究背后的假设是，CX3CR1/CX3CL1调节抗原呈现细胞（APC）效应子功能会影响实验性自身免疫性脑脊髓炎（EAE）期间致病性T细胞的发展。 This hypothesis is based on the following: 1) EAE symptoms are more severe and CNS demyelination is enhanced CX3CR1-deficient mice, 2) absence of CX3CR1 correlated with a selective accumulation of CD115+CD11c+ dendritic cells to CNS tissues, and 3) Bone marrow chimeric mice revealed that absence of CX3CR1 in bone marrow induced an unusual, severe以及持续麻痹的慢性非恢复EAE疾病。该提案的总体目标是阐明EAE期间CX3CR1的功能以及如何调节致病性中枢神经系统炎症。具体目的是：1。通过调节抗原表现和T细胞启动来确定CX3CR1在EAE启动中的作用。我们将检验以下假设：CX3CR1控制外围DC成熟，影响抗原表现，并随后外周T细胞极化。我们将研究CX3CR1抗原运输和树突状细胞动员的作用以及CX3CR1缺乏性在产生脑源性T细胞中的作用。 2。确定CX3CR1缺乏在EAE效应阶段的作用，并保护神经元损伤和脱髓鞘。我们假设骨髓中缺少CX3CR1对于维持T细胞介导的EAE脑中的炎症和组织损伤至关重要。我们将研究CX3CR1在疾病高峰和恢复时CNS组织中致病和调节性T细胞亚群的抑制信号传导，激活和存活中的作用。 3。定义通过人CX3CR1I249/M280的信号传导如何弱的信号传导如何复制EAE期间CX3CR1 - / - 小鼠的病理。我们假设I249/M280表达细胞将表现出与CX3CR1缺陷细胞相当的效应函数。我们将使用表达人类变体作为低亲和力模型的敲入小鼠研究中枢神经系统自身免疫期间I249/M280在体内的APC激活和T细胞极化的作用。