In vivo role of CTLA-4 in Costimulation and Autoimmunity

CTLA-4 在共刺激和自身免疫中的体内作用

• 批准号: 8630055
• 负责人: Arlene H. Sharpe
• 金额: $ 42.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630055
• 关键词: Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bone Marrow; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell physiology; Cells; Chimera organism; Chronic; Colitis; Data; Development; Effector Cell; Equilibrium; Experimental Autoimmune Encephalomyelitis; Funding; Generations; Genetic; Goals; Hematopoietic; Human; Immune; Immune Tolerance; Immune response; Immunotherapy; Individual; Infection; Inflammation; Injury; Investigation; Knockout Mice; Lead; Leukocytes; Lymphocyte; Lymphoid; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mus; Myelin; Oligodendroglia; Organ; Pathogenicity; Pathology; Pathway interactions; Peripheral; Play; Positioning Attribute; Publishing; Recruitment Activity; Regulatory T-Lymphocyte; Relative (related person); Resolution; Role; Signal Transduction; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Transplantation; Vascular Endothelial Cell; autoreactive T cell; base; cell type; chronic autoimmune disease; exhaustion; genetic manipulation; immunopathology; in vivo; innovation; insight; interest; novel; peripheral tolerance; prevent; public health relevance; receptor; response; success; therapeutic target; tool

Abstract The PD-1:PD-L1 pathway plays multifaceted roles in controlling the balance between pathogenic and protective immune responses in T cell tolerance and autoimmunity. During the current funding period, our studies have revealed critical roles for the PD-1:PD-L1 pathway in regulating T cell activation, tolerance and immune-mediated tissue damage. We have found that PD-L1 not only inhibits the activation and function of pathogenic effector T cells, but also promotes the development and sustains the function of induced regulatory T cells. In addition, we have identified a novel role for PD-L1 on non-hematopoietic cells in protecting target organs from immune-mediated tissue injury. However, we lack a mechanistic understanding of the function of PD-L1 on different cell types. The great interest in PD-L1 and PD-1 as therapeutic targets gives impetus to further investigation of how these important immunoregulatory molecules regulate autoreactive T cells. The overall goal of this project is to elucidate mechanisms by which PD-L1 controls T cell tolerance, prevents autoimmunity, and limits immune-mediated inflammation locally within tissues. Our published and preliminary data lead us to hypothesize that PD-L1 on specific types of hematopoietic and non-hematopoietic cells will regulate T cell activation, tolerance and autoimmunity-related pathology by distinct mechanisms. We will use our newly generated PD-L1 conditional knockout mice crossed to cell type-specific Cre lines to test this hypothesis in the following Specific Aims. Aim 1: To test the hypothesis that there are distinct roles for PD-L1 on specific hematopoietic or non-hematopoietic cell types in regulating the activation, differentiation, and function of potentially pathogenic self-reactive T cells. We will analyze the relative functions of PD-L1 on specific hematopoietic and non-hematopoietic cell types in controlling the activation and differentiation of na¿ve myelin-reactive CD4 T cells and the functions of differentiated myelin-reactive effector cells using the myelin oligodendrocyte (MOG) model of experimental autoimmune encephalomyelitis (EAE). 2) To test the hypothesis that there are distinct roles for PD-L1 on specific cell types in controlling the generation and function of regulatory T cells. We will analyze the relative functions of PD-L1 in controlling natural regulatory T cells (nTreg) and induced regulatory T cells (iTreg). We will use the MOG-induced EAE model to study how PD-L1 regulates nTreg expansion, function and plasticity. We will study how PD-L1 on specific cell types promotes iTreg generation, function, and plasticity using a colitis model, where iTreg are best defined. These studies should further our understanding of mechanisms that control tolerance and autoimmunity, and provide insight into how to modulate PD-L1 and PD-1 therapeutically to control autoimmune diseases, chronic infections and cancer.

摘要 PD-1：PD-L1通路在控制致病性和免疫性之间的平衡中起着多方面的作用。 T细胞耐受性和自身免疫中的保护性免疫应答。在本财政年度内，我们 研究已经揭示了PD-1：PD-L1通路在调节T细胞活化、耐受和免疫应答中的关键作用。 免疫介导的组织损伤。我们已经发现PD-L1不仅抑制了 致病性效应T细胞，而且还促进发展和维持诱导的调节功能， T细胞。此外，我们已经确定了PD-L1在非造血细胞中保护靶细胞的新作用。 免疫介导的组织损伤。然而，我们缺乏一个机械的理解的功能， PD-L1对不同细胞类型的作用。对PD-L1和PD-1作为治疗靶点的极大兴趣推动了 进一步研究这些重要的免疫调节分子如何调节自身反应性T细胞。的 该项目的总体目标是阐明PD-L1控制T细胞耐受性，预防T细胞免疫耐受， 自身免疫，并限制组织内局部的免疫介导的炎症。我们已公布的和初步的 数据使我们假设，特定类型的造血和非造血细胞上的PD-L1将 通过不同的机制调节T细胞活化、耐受性和自身免疫相关的病理。我们将使用 我们新产生的PD-L1条件性敲除小鼠与细胞类型特异性Cre系杂交以测试这一点。 在以下具体目标中的假设。目的1：检验PD-L1具有不同作用的假设 对特定造血或非造血细胞类型在调节活化、分化和 潜在致病性自身反应性T细胞的功能。我们将分析PD-L1的相关功能， 特定的造血和非造血细胞类型在控制幼稚细胞的激活和分化中的作用 髓磷脂反应性CD4 T细胞和使用髓磷脂的分化的髓磷脂反应性效应细胞的功能 实验性自身免疫性脑脊髓炎（EAE）的少突胶质细胞（MOG）模型。2)为了检验这一假设 PD-L1在特定细胞类型中控制细胞的生成和功能方面具有不同的作用， 调节性T细胞我们将分析PD-L1在控制天然调节性T细胞中的相关功能 （nTreg）和诱导的调节性T细胞（iTreg）。我们将使用MOG诱导的EAE模型来研究PD-L1 调节nTreg的扩增、功能和可塑性。我们将研究特定细胞类型上的PD-L1如何促进 使用结肠炎模型的iTreg生成、功能和可塑性，其中iTreg被最好地定义。这些研究 应该进一步了解控制耐受性和自身免疫性的机制， 研究如何在治疗上调节PD-L1和PD-1，以控制自身免疫性疾病、慢性感染和 癌