PD-1 expression and HIV specific T cell dysfunction

PD-1 表达和 HIV 特异性 T 细胞功能障碍

• 批准号: 8318852
• 负责人: Bruce D Walker
• 金额: $ 50.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318852
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Acute; Address; Animal Model; Animals; Antigens; Antiviral Agents; Avidity; Blood; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Complex; Cytoplasmic Granules; Defect; Disease Progression; Epigenetic Process; Exocytosis; Failure; Functional disorder; Genes; Genetic Polymorphism; Goals; Grant; HIV; HIV Infections; Human; Imaging Techniques; Immune; Immune System Diseases; Immune system; Impairment; In Vitro; Infection; Intervention; Laboratories; Ligands; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Pathway interactions; Persons; Play; Production; Proteins; Public Health; Publishing; Regulation; Regulatory Element; Relative (related person); Research Personnel; Role; Signal Pathway; Signal Transduction; Specificity; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic Intervention; Viral; Virus; Virus Diseases; Work; cytokine; cytotoxicity; design; exhaustion; interest; killings; knock-down; neoplastic cell; peripheral blood; prevent; programs; receptor; response; synaptogenesis

T cell dysfunction upon ongoing antigen exposure is a cardinal feature of chronic infections and cancer in animals and humans, leading to T cell impairment and failure to eliminate virus or tumor cells. These defective T cell responses are thought to play a major role in HIV infection and progression to AIDS. Previous work performed at our center and by other investigators of this program grant has shown in both HIV infection and animal models that the Programmed Death-1 (PD-1) pathway is a crucial mediator of T cell dysfunction, and that blocking this pathway can reinvigorate CD8 (CTL) and CD4 T cell responses. PD-1, its ligands PD-L1 and PD-L2, and the PD-L1 ligand CD80 participate in a network of pathways that modulate T cell function The goal of this proposal is to elucidate the role of PD-1 and its ligands in AIDS-related T cell dysfunction; successful achievement of these aims will help guide the design of new clinical interventions to reverse immune failure in HIV-infected subjects. In Aim 1, building on previous results correlating PD-1 expression by HIV-specific CD8 and CD4 T cells with disease progression, we will compare the expression and functional impact of PD-1 on T cells from subjects with acute infection, chronic infection, or spontaneous viral control (elite controllers). Using state-of-the-art imaging techniques from Core C, we will determine the role of PD-1 in modulating exocytosis of cytolytic granules by HIV-specific CTL. We will also investigate PD-1 expression and function in elite controllers who present a polymorphism in the PD-1 gene or in PD-1 regulatory elements, as identified in Projects 2 and 4. In Aim 2, we will determine qualitative differences between HIV-specific CTL expanded in the presence or absence of PD-1 blockade, with respect to immunodominance, cytokine production, and cytotoxicity. We will determine the roles of PD- 1 expression and TCR avidity in the response of HIV-specific CTL to PD-1 blockade. In Aim 3, we will determine the relative contributions of multiple pathways engaged by PD-1, PD-L1, and CD80 a key antiviral CTL function, namely the ability to suppress HIV replication in vitro. Starting from established methods to measure viral suppression, we will systematically knock down or block various PD-L1-mediated pathways to determine the role of each pathway in antiviral function. We will determine the relative roles of CTL proliferation, survival, cytokine secretion, and killing of infected targets in PD-L1 modulated antiviral activity. Relevance to public health: The immune system of HIV-infected people includes cells (T cells) that recognize HIV, but fail to block the virus and to prevent progression to AIDS. Our previous studies have shown that these T cells express a protein, called PD-1, which inhibits their function. We are studying the role of PD-1 in preventing proper T cell responses, and looking for ways to rescue the ability of T cells to control HIV.

持续抗原暴露后的T细胞功能障碍是慢性感染和癌症的主要特征， 动物和人类，导致T细胞损伤和无法消除病毒或肿瘤细胞。这些 有缺陷的T细胞应答被认为在HIV感染和发展为AIDS中起主要作用。 先前在我们中心和其他研究人员的研究工作表明， HIV感染和动物模型表明，程序性死亡-1（PD-1）途径是T细胞免疫的关键介质， 该研究表明，CD 8（CTL）和CD 4 T细胞的功能障碍，并且阻断该途径可以重振CD 8（CTL）和CD 4 T细胞应答。PD-1，其 配体PD-L1和PD-L2以及PD-L1配体CD 80参与调节T细胞凋亡的途径网络。 本研究的目的是阐明PD-1及其配体在艾滋病相关T细胞中的作用。 细胞功能障碍;这些目标的成功实现将有助于指导新的临床 逆转HIV感染者免疫失败的干预措施。在目标1中，基于先前的结果 将HIV特异性CD 8和CD 4 T细胞的PD-1表达与疾病进展相关联，我们将比较 PD-1对来自急性感染，慢性感染， 或自发病毒控制（精英控制者）。使用核心C的最先进的成像技术，我们 将确定PD-1在调节HIV特异性CTL对溶细胞颗粒的胞吐作用中的作用。我们将 还研究了PD-1多态性的精英控制者的PD-1表达和功能。 基因或PD-1调控元件，如项目2和4中所确定的。在目标2中，我们将确定 在存在或不存在PD-1阻断的情况下扩增的HIV特异性CTL之间的定性差异， 关于免疫优势、细胞因子产生和细胞毒性。我们将决定警察的角色- 1表达和TCR亲合力在HIV特异性CTL对PD-1阻断的应答中的作用。在目标3中，我们 确定PD-1、PD-L1和CD 80参与的多个途径的相对贡献， CTL功能，即在体外抑制HIV复制的能力。从既定方法出发， 测量病毒抑制，我们将系统地敲低或阻断各种PD-L1介导的途径， 确定每个途径在抗病毒功能中的作用。我们将确定CTL的相对作用 PD-L1调节的抗病毒活性中的增殖、存活、细胞因子分泌和杀死感染的靶标。 与公共卫生的相关性：艾滋病毒感染者的免疫系统包括细胞（T细胞）， 认识到艾滋病毒，但未能阻止病毒和防止发展为艾滋病。我们以往的研究 这些T细胞表达一种名为PD-1的蛋白质，这种蛋白质会抑制它们的功能。我们正在研究 PD-1在防止适当的T细胞反应中的作用，并寻找方法来拯救T细胞的能力， 控制艾滋病毒。