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现细胞（APC）为幼稚T细胞提供的共刺激信号，以调节T细胞抗原受体（TCR）驱动的克隆膨胀和记忆细胞形成。 CD28和CTLA-4偏爱CD86和CD80作为配体，分别是天真T细胞的最有效的阳性和负刺激受体。 CD28的封锁现已被批准用于治疗类风湿关节炎，并且正在人类中测试CTLA-4的抑制以增强肿瘤免疫力。尽管有这些有希望的进步，但关于CD28和CTLA-4如何实际调节免疫力的许多问题仍然存在。例如，在不存在CD28的情况下，TCR信号的后果仍然无法清楚地清楚，死亡和无知所有可行的可能性。此外，我们目前缺乏关于在没有CTLA-4的情况下引起疾病的T细胞的特异性的理解，这是了解该分子如何阻止自身免疫性的障碍。我们建议，这些不确定性中的许多与过去对一个固定亲和力对一种肽固定亲和力的非生理学的体外激活刺激或单克隆T细胞有关：MHC（PMHC）配体。相比之下，我们将使用一种基于PMHCII四聚体和磁珠富集的新方法来研究CD28和CTLA-4对PMHCII伴生范围范围的多克隆CD4+ T细胞的影响。在第一个目的中，我们将测试以下观点：CD28以两种不同模式的信号依赖于TCR共聚类和细胞质尾巴中的YMNM基序，而另一个涉及与TCR共聚类无关的PYAP基序。我们假设共聚类模式对于低亲和力TCR的克隆的PMHCII传感至关重要。这些目标将通过测量克隆膨胀，收缩，表型转换，TCR亲和力和记忆细胞形成，并通过多克隆PMHCII特异性的幼稚CD4+ T细胞在发育过程中缺乏一种或两种信号传导模式和初级免疫反应。第二个目的是确定CTLA-4是否限制了表达具有高亲和力的TCR的CD4+ T细胞的激活。该假设将在CTLA-4缺陷的小鼠中使用候选自我PMHCII进行测试，并通过使用CTLA-4缺陷型小鼠患病器官的CD4+ T细胞克隆和表达克隆系统来识别其TCR配体。这组实验有可能在与TCR亲和力范围的T细胞的生理相关条件下清楚地了解CD28和CTLA-4功能。 叙述：这些研究之所以相关，是因为它们专注于调节T淋巴细胞免疫反应质量的分子（CD28和CTLA-4）。基于对这些分子的封锁的几种有希望的疗法正在使用或开发用于治疗关节炎，移植排斥和癌症。本应用中描述的计划旨在进一步理解CD28和CTLA-4控制免疫反应的机制，以期提高上述治疗的功效并将其扩展到其他T细胞介导的疾病。