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）：神经元和外周内皮细胞上存在的跨膜趋化因子 fractalkine (CX3CL1) 充当粘附分子或可溶性趋化剂。 CX3CL1 通过其受体 CX3CR1 发出信号，该受体在小胶质细胞、单核细胞/巨噬细胞和树突细胞、NK 细胞和 T 细胞中表达。值得注意的是，与健康对照相比，多发性硬化症患者外周 NK 细胞中 CX3CR1 的表达较低，并且外周血中缺乏与疾病活动相关的 CX3CR1+ 细胞。然而，CX3CR1 在抗原呈递细胞和 T 细胞中的作用及其对 CNS 病理学的贡献仍然是个谜。这项研究背后的假设是，CX3CR1/CX3CL1 调节抗原呈递细胞 (APC) 效应器功能，影响实验性自身免疫性脑脊髓炎 (EAE) 期间致病性 T 细胞的发育。该假设基于以下内容：1) CX3CR1 缺陷小鼠的 EAE 症状更严重，CNS 脱髓鞘增强，2) CX3CR1 缺失与 CD115+CD11c+ 树突状细胞选择性积累到 CNS 组织相关，3) 骨髓嵌合小鼠发现，骨髓中缺乏 CX3CR1 会诱发一种不寻常、严重且慢性的非缓解性 EAE 疾病，并伴有持续瘫痪。该提案的总体目标是阐明 CX3CR1 在 EAE 过程中的功能以及它如何调节致病性 CNS 炎症。具体目标是： 1. 确定 CX3CR1 通过调节抗原呈递和 T 细胞启动来启动 EAE 的作用。我们将检验以下假设：CX3CR1 控制外周 DC 成熟，影响抗原呈递以及随后的外周 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 缺陷对致脑炎 T 细胞生成的影响。 2. 确定CX3CR1缺陷在EAE效应期中的作用以及对神经元损伤和脱髓鞘的保护作用。我们假设骨髓中 CX3CR1 的缺失对于 EAE 大脑中 T 细胞介导的炎症和组织损伤的维持至关重要。我们将研究 CX3CR1 在疾病高峰期和恢复期中枢神经系统组织内致病性和调节性 T 细胞亚群的抑制信号传导、激活和存活中的作用。 3. 明确人类 CX3CR1I249/M280 的较弱信号如何在 EAE 期间复制 Cx3cr1-/- 小鼠的病理学。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功能。我们将使用表达人类变体的敲入小鼠作为低亲和力模型来研究 I249/M280 在中枢神经系统自身免疫期间体内 APC 激活和 T 细胞极化中的作用。