Costimulatory Signals in CD4+ T Cell Activation

CD4 T 细胞激活中的共刺激信号

• 批准号: 8036059
• 负责人: Marc Kevin Jenkins
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036059
• 关键词: Affinity; Antibodies; Antigen-Presenting Cells; Antigens; Arthritis; Autoimmune Diseases; Autoimmunity; CD28 Antigens; CD28 gene; CD4 Positive T Lymphocytes; CD80 gene; Cell Survival; Cells; Cessation of life; Chronic; Clinical Treatment; Clonal Expansion; Complex; Cytoplasmic Tail; Detection; Development; Disease; Exposure to; Family; Family member; Frequencies; Funding; Goals; Graft Rejection; Human; Immune response; Immunity; In Vitro; Interleukin-2; Knock-in Mouse; Ligands; Malignant Neoplasms; Measures; Mediating; Memory; Methods; Mus; Mutation; Normal Range; Organ; Pathway interactions; Peptide/MHC Complex; Peripheral; Phenotype; Production; Reagent; Receptor Signaling; Reliance; Rheumatoid Arthritis; Role; Self Tolerance; Signal Transduction; Site; Stimulus; System; T-Cell Activation; T-Cell Antigen Receptor Specificity; T-Cell Immunologic Specificity; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Tail; Testing; Tumor Immunity; Uncertainty; Virus Diseases; allograft rejection; anergy; base; design; disorder prevention; expression cloning; improved; in vivo; mRNA Stability; magnetic beads; novel; prevent; receptor; research study; therapy development; tumor

DESCRIPTION (provided by applicant): The long-term goal of this project is an understanding of the costimulatory signals that antigen-presenting cells (APC) provide to naive T cells to regulate T cell antigen receptor (TCR)-driven clonal expansion and memory cell formation. CD28 and CTLA-4, which prefer CD86 and CD80 as ligands, are the most potent positive and negative costimulatory receptors for naive T cells, respectively. Blockade of CD28 is now approved for the treatment of rheumatoid arthritis, and inhibition of CTLA-4 is being tested in humans to enhance tumor immunity. Despite these promising advances, many questions remain as to how CD28 and CTLA-4 actually regulate immunity. For example, the consequences of TCR signaling in the absence of CD28 are still not clear with anergy, death, and ignorance all viable possibilities. In addition, our current lack of understanding concerning the specificity of the T cells that cause disease in the absence of CTLA-4 is a barrier to understanding how this molecule prevents autoimmunity. We suggest that many of these uncertainties are related to a past reliance on unphysiologic in vitro activation stimuli or monoclonal T cells with fixed affinity for one peptide:MHC (pMHC) ligand. In contrast, we will use a new method based on pMHCII tetramers and magnetic bead enrichment to study CD28 and CTLA-4 effects on polyclonal CD4+ T cells with a normal range of affinities for a pMHCII. In the first aim, we will test the idea that CD28 signals in two distinct modes, one relying on TCR co-clustering and a YMNM motif in the cytoplasmic tail and another involving a PYAP motif that is independent of TCR co-clustering. We hypothesize that the co-clustering mode is critical for pMHCII sensing by clones with low affinity TCRs. These aims will be pursued by measuring clonal expansion, contraction, phenotype conversion, TCR affinity, and memory cell formation by polyclonal pMHCII-specific naive CD4+ T cells lacking one or both of the signaling modes during development and the primary immune response. The second aim is to determine if CTLA-4 constrains the activation of CD4+ T cells expressing TCRs with high affinities for self pMHCII. The hypothesis will be tested in CTLA-4-deficient mice with candidate self pMHCII and by using CD4+ T cell clones from the diseased organs of CTLA-4-deficient mice and an expression cloning system to identify their TCR ligands. This set of experiments has the potential to provide a clear picture of CD28 and CTLA-4 function under physiologically-relevant conditions for T cells with a range of TCR affinities. Narrative: These studies are relevant because they focus on molecules (CD28 and CTLA-4) that regulate the quality of the immune response by T lymphocytes. Several promising therapies based on blockade of these molecules are in use or development for the treatment of arthritis, transplant rejection, and cancer. The plan described in this application is designed to further the understanding of the mechanisms by which CD28 and CTLA-4 control the immune response with the hope of improving the efficacy of the aforementioned treatments and extending them to other T cell-mediated diseases.

描述（由申请人提供）：该项目的长期目标是了解抗原呈递细胞 (APC) 向初始 T 细胞提供的共刺激信号，以调节 T 细胞抗原受体 (TCR) 驱动的克隆扩张和记忆细胞形成。 CD28 和 CTLA-4 更喜欢 CD86 和 CD80 作为配体，分别是初始 T 细胞最有效的正和负共刺激受体。 CD28 的阻断现已被批准用于治疗类风湿性关节炎，并且正在人体中测试 CTLA-4 的抑制以增强肿瘤免疫力。尽管取得了这些有希望的进展，但关于 CD28 和 CTLA-4 如何实际调节免疫仍存在许多问题。例如，在缺乏 CD28 的情况下 TCR 信号传导的后果仍不清楚，无反应、死亡和无知都是可行的可能性。此外，我们目前对在缺乏 CTLA-4 的情况下引起疾病的 T 细胞的特异性缺乏了解，这也是了解该分子如何预防自身免疫的障碍。我们认为，许多不确定性与过去对非生理性体外激活刺激或对一种肽：MHC (pMHC) 配体具有固定亲和力的单克隆 T 细胞的依赖有关。相比之下，我们将使用基于 pMHCII 四聚体和磁珠富集的新方法来研究 CD28 和 CTLA-4 对 pMHCII 具有正常亲和力范围的多克隆 CD4+ T 细胞的影响。在第一个目标中，我们将测试 CD28 以两种不同模式发出信号的想法，一种依赖于 TCR 共聚类和细胞质尾部中的 YMNM 基序，另一种涉及独立于 TCR 共聚类的 PYAP 基序。我们假设共聚类模式对于低亲和力 TCR 克隆的 pMHCII 传感至关重要。这些目标将通过测量多克隆 pMHCII 特异性幼稚 CD4+ T 细胞的克隆扩张、收缩、表型转换、TCR 亲和力和记忆细胞形成来实现，这些细胞在发育和初级免疫反应过程中缺乏一种或两种信号传导模式。第二个目的是确定 CTLA-4 是否限制表达与自身 pMHCII 具有高亲和力的 TCR 的 CD4+ T 细胞的激活。该假设将在具有候选自身 pMHCII 的 CTLA-4 缺陷小鼠中进行测试，并使用来自 CTLA-4 缺陷小鼠患病器官的 CD4+ T 细胞克隆和表达克隆系统来鉴定其 TCR 配体。这组实验有可能为具有一系列 TCR 亲和力的 T 细胞在生理相关条件下提供 CD28 和 CTLA-4 功能的清晰图像。 叙述：这些研究具有相关性，因为它们关注的是调节 T 淋巴细胞免疫反应质量的分子（CD28 和 CTLA-4）。几种基于阻断这些分子的有前途的疗法正在使用或开发用于治疗关节炎、移植排斥和癌症。本申请中描述的计划旨在进一步了解CD28和CTLA-4控制免疫反应的机制，希望提高上述治疗的疗效并将其扩展到其他T细胞介导的疾病。