Defining post-transcriptional mechanisms that control CD8 T cell longevity, proliferation and differentiation

定义控制 CD8 T 细胞寿命、增殖和分化的转录后机制

• 批准号: 10308478
• 负责人: Leonid Pobezinskiy
• 金额: $ 54.07万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-06 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308478
• 关键词: Ablation; Acute; Address; Adoptive Immunotherapy; Antigens; Antitumor Response; Apoptotic; BCL2 gene; CD8-Positive T-Lymphocytes; Cancerous; Cell Differentiation process; Cell Maintenance; Cells; Chronic; Clinical; Clonal Expansion; Cytotoxic T-Lymphocytes; Data; Defect; Effector Cell; Environment; Equilibrium; Exhibits; Family; Generations; Genetic; Genetic Transcription; Goals; Granzyme; Homeostasis; Immune response; Immunologic Memory; Immunotherapy; Infection; Inflammation; Interferon Type II; Laboratories; Lead; Longevity; Lymphocyte; Maintenance; Malignant Neoplasms; Mediating; Memory; Metabolic; MicroRNAs; Modeling; Molecular; Outcome; Pathologic; Performance; Play; Post-Transcriptional Regulation; Production; Publishing; Regulation; Role; T cell differentiation; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Transcriptional Regulation; Tumor-Derived; Viral; base; cell mediated immune response; chronic infection; cytokine; cytotoxic; effector T cell; exhaust; exhaustion; experimental study; improved; in vivo; insight; loss of function; new therapeutic target; novel; pathogen; perforin; prevent; programs; success; transcription factor; tumor; tumor growth

PROJECT SUMMARY CD8 T cells play a critical role in the elimination of infected and cancerous host cells. The success of these immune responses depends on the proper maintenance (survival and proliferation) and precise differentiation of CD8 T cells. Upon antigen stimulation, activated antigen-specific CD8 T cells undergo clonal expansion and differentiate into effector lymphocytes with cytolytic function. Although the majority of effector cells die after antigen clearance, a few antigen-specific cells survive and form long-lived protective memory CD8 T cells. However, during chronic infection and cancer, the immune response is often compromised: CD8 T cells exhibit defects in survival and proliferation, fail to form memory cells and instead are diverted to differentiate into exhausted cells which are characterized by the loss of effector function. Thus, it is of utmost importance to understand the underlying mechanisms that regulate the maintenance and differentiation of CD8 T cells. We have already demonstrated that let-7-mediated posttranscriptional mechanism controls the differentiation and function of effector T cells. Furthermore, our preliminary results suggest that modulation of let-7 levels have a profound impact on the maintenance of T cells, memory formation and diversion into exhaustion. To investigate the molecular mechanisms of let-7 regulation in CD8 T cells we propose the following aims: Aim-1 will determine the molecular basis of let-7-mediated effects on CD8 T cell maintenance: bcl-2-dependent survival and cdc34-driven proliferation. Aim-2 will dissect let-7-mediated mechanisms that guide CD8 T cell differentiation: Eomes-dependent and Eomes-independent molecular programs. To address these aims we will analyze the maintenance and differentiation of CD8 T cells with different levels of let-7 microRNAs into effector, memory and exhausted T lymphocytes using infection and tumor models. We expect to identify novel posttranscriptional mechanisms that regulate the outcome of CD8 T cell-mediated immune responses. It is anticipated that these experiments will define let-7 as a new therapeutic target.

项目概要 CD8 T 细胞在消除受感染和癌性宿主细胞中发挥着关键作用。这些的成功 免疫反应取决于适当的维持（生存和增殖）和精确分化 CD8 T 细胞。抗原刺激后，活化的抗原特异性 CD8 T 细胞进行克隆扩增并 分化为具有溶细胞功能的效应淋巴细胞。尽管大多数效应细胞在 抗原清除后，一些抗原特异性细胞存活并形成长寿命的保护性记忆 CD8 T 细胞。 然而，在慢性感染和癌症期间，免疫反应常常受到损害：CD8 T 细胞表现出 生存和增殖缺陷，无法形成记忆细胞，而是转向分化为 疲惫的细胞，其特征是效应器功能丧失。因此，至关重要的是 了解调节 CD8 T 细胞维持和分化的潜在机制。我们 已经证明let-7介导的转录后机制控制分化和 效应T细胞的功能。此外，我们的初步结果表明，let-7 水平的调节具有 对 T 细胞的维持、记忆的形成和疲劳的转移产生深远的影响。调查 针对 CD8 T 细胞中 let-7 调节的分子机制，我们提出以下目标： Aim-1 将确定 let-7 介导的 CD8 T 细胞维持作用的分子基础：bcl-2 依赖性 生存和 cdc34 驱动的增殖。 Aim-2 将剖析 let-7 介导的引导 CD8 T 细胞的机制 分化：依赖于 Eomes 和不依赖于 Eomes 的分子程序。为了实现这些目标，我们将 分析具有不同水平let-7 microRNA的CD8 T细胞维持和分化为效应细胞的情况， 使用感染和肿瘤模型进行记忆和耗尽的 T 淋巴细胞。我们期望识别出新颖的 调节 CD8 T 细胞介导的免疫反应结果的转录后机制。这是 预计这些实验将把let-7定义为新的治疗靶点。