Mechanisms of T cell inhibitory pathways

T细胞抑制途径的机制

• 批准号: 7660601
• 负责人: MANISH J BUTTE
• 金额: $ 13.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660601
• 关键词: Accounting; Affect; Agonist; Antibodies; Antigen-Presenting Cells; Area; Attenuated; Autoimmune Diabetes; Autoimmune Process; Autoimmune Responses; Autoimmunity; Award; Basic Science; Binding; CD28 gene; CD80 gene; CD8B1 gene; Calcium; Cells; Cellular biology; Cessation of life; Chronic; Clinical Medicine; Communicable Diseases; Complement; Cytoskeleton; Diabetes Mellitus; Diabetes prevention; Equilibrium; Event; Family; Family member; Genes; Goals; Hematopoietic; Human; Imagery; Immune; Immune system; Immunity; Immunoprecipitation; Infection; Knowledge; Learning; Ligands; Ligation; Mediating; Mediator of activation protein; Mentors; Microscopy; Modeling; Molecular; Mus; Pathogenesis; Pathway interactions; Phosphotransferases; Physicians; Play; Research Personnel; Role; Scientist; Self Tolerance; Self-control as a personality trait; Signal Pathway; Signal Transduction; Synapses; T cell regulation; T-Cell Activation; T-Lymphocyte; Tail; Techniques; Testing; Therapeutic; Tumor Immunity; career; cell type; clinically relevant; immunological synapse; in vivo; insight; medical schools; microbial; mutant; prevent; programs; receptor; response; skills; therapeutic target; tool; trafficking; transcription factor

DESCRIPTION (provided by applicant): The main goal of this K08 Award is to study a new T cell inhibitory pathway in the B7:CD28 family of costimulatory molecules that regulates T cell activation and tolerance. The PI will be mentored at Harvard Medical School by Dr. Arlene Sharpe, an expert in the area of T cell costimulation. We have found that Programmed Death-1 Ligand 1 (PD-L1) on T cells can interact with B7-1, and that this interaction can inhibit T cell responses. We will test the hypothesis that PD-L1 on T cells plays an important role in controlling T cell activation, effector responses, and autoimmunity. We have a number of unique tools, including gene-deficient mice and PD-L1 antibodies that enable us to dissect the molecular mechanisms of PD-L1 signaling on T cells and investigate its roles in controlling in vivo responses. Our specific aims are: 1. Establish the mechanisms by which PD-L1 on T cells exerts inhibitory effects in mice and humans. In this Aim, we will test whether PD-L1 on T cells exerts an inhibitory effect by 1) modifying TCR signaling pathways, and/or by 2) utilizing a signaling partner or second chain to enact inhibitory effects. We will also test if ligation of PD-L1 on human T cells is inhibitory. These subaims will provide insight into the mechanisms by which PD-L1 on T cells inhibits responses and the potential for therapeutic manipulation of PD-L1 on human T cells. 2. Determine the roles of PD-L1 on T cells and its partners at the immunological synapse (IS). T cells are activated and regulated by contact with APCs at the IS. B7-1 on APCs can interact with CD28, CTLA-4, or PD-L1 on the T cell, raising the question: how does PD-L1 compete with CD28 and CTLA-4 for B7-1 interactions? We will focus on how PD-L1 on T cells competes with CD28 for binding to B7-1 in the early synapse (microclusters) and the late synapse (T cell-DC synapse). These studies will complement those in Aim 1 to investigate another means by which PD-L1 on T cells may exert its inhibitory effects. 3. Characterize in vivo effects of PD-L1 on T cells: activation and autoimmunity. I will examine the in vivo role of PD-L1 on CD4 and CD8 T cells during activation and effector responses. This aim will test the hypothesis that the PD-L1 pathway may control self-reactive T cells during autoimmune responses in vivo, using an autoimmune model of diabetes. In this proposal, I plan to acquire new skills in areas of T cell biology, including microscopy and in vivo studies of autoimmunity. My long-term goal is to combine my background in basic science and clinical medicine to be an academic physician-scientist and independent investigator, examining the fundamental roles of inhibitory T cell pathways as they regulate autoimmunity and infectious diseases. RELEVANCE: Blockade of PD-L1 has become an important therapeutic target. These studies will provide insights into new mechanisms to control T cell responses in microbial immunity, tumor immunity, and autoimmunity, and will provide fundamental insights into mechanisms of inhibition of T cells.

描述（由申请人提供）：本次 K08 奖的主要目标是研究 B7:CD28 共刺激分子家族中调节 T 细胞活化和耐受的新 T 细胞抑制途径。 PI 将在哈佛医学院接受 T 细胞共刺激领域专家 Arlene Sharpe 博士的指导。我们发现T细胞上的程序性死亡1配体1（PD-L1）可以与B7-1相互作用，并且这种相互作用可以抑制T细胞反应。我们将检验 T 细胞上的 PD-L1 在控制 T 细胞激活、效应反应和自身免疫方面发挥重要作用的假设。我们拥有许多独特的工具，包括基因缺陷小鼠和 PD-L1 抗体，使我们能够剖析 T 细胞上 PD-L1 信号传导的分子机制，并研究其在控制体内反应中的作用。我们的具体目标是： 1. 建立 T 细胞上的 PD-L1 在小鼠和人类中发挥抑制作用的机制。在此目标中，我们将测试 T 细胞上的 PD-L1 是否通过 1) 修改 TCR 信号传导途径和/或 2) 利用信号传导伴侣或第二条链来发挥抑制作用。我们还将测试 PD-L1 在人类 T 细胞上的连接是否具有抑制作用。这些子目标将深入了解 T 细胞上的 PD-L1 抑制反应的机制以及人类 T 细胞上的 PD-L1 的治疗操作潜力。 2. 确定 PD-L1 对 T 细胞及其免疫突触 (IS) 伙伴的作用。 T 细胞通过与 IS 处的 APC 接触而被激活和调节。 APC 上的 B7-1 可以与 T 细胞上的 CD28、CTLA-4 或 PD-L1 相互作用，这就提出了一个问题：PD-L1 如何与 CD28 和 CTLA-4 竞争 B7-1 相互作用？我们将重点关注 T 细胞上的 PD-L1 如何与 CD28 竞争结合早期突触（微簇）和晚期突触（T 细胞-DC 突触）中的 B7-1。这些研究将补充目标 1 中的研究，以研究 T 细胞上的 PD-L1 发挥其抑制作用的另一种方式。 3. 表征 PD-L1 对 T 细胞的体内作用：激活和自身免疫。我将研究 PD-L1 在激活和效应反应期间对 CD4 和 CD8 T 细胞的体内作用。该目标将使用糖尿病自身免疫模型来测试 PD-L1 通路可能在体内自身免疫反应期间控制自身反应性 T 细胞的假设。在这个提案中，我计划获得 T 细胞生物学领域的新技能，包括显微镜和自身免疫的体内研究。我的长期目标是将基础科学和临床医学的背景结合起来，成为一名学术医师科学家和独立研究者，研究抑制性 T 细胞途径在调节自身免疫和传染病方面的基本作用。 相关性：PD-L1 阻断已成为重要的治疗靶点。这些研究将为控制微生物免疫、肿瘤免疫和自身免疫中 T 细胞反应的新机制提供见解，并将为 T 细胞抑制机制提供基本见解。