B Cell Receptor Regulation of Antigen Processing

B 细胞受体对抗原加工的调节

• 批准号: 7049750
• 负责人: Marcus Ramsay Clark
• 金额: $ 29.08万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049750
• 关键词: B cell receptor; anergy; antigen presentation; artificial chromosomes; binding sites; biological signal transduction; cell migration; enzyme mechanism; genetically modified animals; humoral immunity; immune response; laboratory mouse; leukocyte activation /transformation; nuclear proteins; protein degradation; protein structure function; receptor binding; receptor expression; tissue /cell culture; ubiquitin; ubiquitin protein ligase; vesicle /vacuole

DESCRIPTION (provided by applicant): The ability of B lymphocytes to capture, process and present antigens to T cells is requisite for normal humoral immune responses and contributes to the pathogenesis of both B and T cell mediated autoimmune diseases. B lymphocytes preferentially capture polyvalent antigens which, by aggregating the B cell antigen receptor (BCR) and initiating signaling cascades, elicit a coordinated series of cellular responses that ensure that even low affinity antigens are productively captured. Antigenic polyvalency greatly accelerates both the endocytosis of engaged receptors and their transit through the endocytic pathway to the late endosomal antigen processing compartments. Similar to what has been described in maturing dendritic cells, BCR ligation also induces a remodeling of the receptor targeted antigen processing compartments which enhances their ability to process peptides and load them onto MHC class II. Despite the importance of BCR signaling in determining antigen presentation to T cells, relatively little is known about which signaling pathways contribute to receptor trafficking and what specific cellular processes they regulate. In this grant application, we demonstrate that the BCR constituent Ig? is ubiquitinylated at the cell surface by the E3 ligase Itch and that this is required for normal trafficking from early to late endosomes. In the absence of ubiquitinylation, the receptor recycles back to the cell surface. Farther downstream, the ubiquitin ligase Cbl-b is required for entry into the antigen processing compartments. From these observations, we propose a model in which there are two different checkpoints in BCR endocytic trafficking each controlled by different ubiquitin ligases. Based on this model, we predict that decisions in receptor trafficking made at each checkpoint determine peripheral B cell responses. We propose to test this model in the following Specific Aims: Aim 1. To determine how Itch ubiquitinylates Ig?. Aim 2. To determine the in vivo function of Ig? ubiquitinylation. Aim 3. To determine how BLNK and Cbl-b contribute to receptor trafficking. Aim 4: To determine why BCR trafficking is aberrant in anergic B cells.

描述（由申请人提供）：B 淋巴细胞捕获、加工并向 T 细胞呈递抗原的能力是正常体液免疫反应所必需的，并且有助于 B 和 T 细胞介导的自身免疫性疾病的发病机制。 B 淋巴细胞优先捕获多价抗原，通过聚集 B 细胞抗原受体 (BCR) 并启动信号级联，引发一系列协调的细胞反应，确保即使是低亲和力抗原也能被有效捕获。抗原多价极大地加速了参与受体的内吞作用及其通过内吞途径到达晚期内体抗原加工区室的转运。与成熟树突状细胞中所描述的类似，BCR 连接还诱导受体靶向抗原加工区室的重塑，从而增强它们加工肽并将其加载到 MHC II 类上的能力。尽管 BCR 信号传导在确定向 T 细胞呈递抗原方面非常重要，但对于哪些信号传导途径有助于受体运输以及它们调节哪些特定细胞过程，人们知之甚少。在此资助申请中，我们证明了 BCR 成分 Ig？ E3 连接酶 Itch 在细胞表面泛素化，这是从早期内体到晚期内体正常运输所必需的。在没有泛素化的情况下，受体会循环回到细胞表面。在更下游，需要泛素连接酶 Cbl-b 才能进入抗原加工区室。根据这些观察，我们提出了一个模型，其中 BCR 内吞运输中有两个不同的检查点，每个检查点由不同的泛素连接酶控制。基于这个模型，我们预测每个检查点的受体运输决策决定了外周 B 细胞的反应。我们建议在以下具体目标中测试该模型： 目标 1. 确定 Itch 如何泛素化 Ig？。目标2.确定Ig的体内功能？泛素化。目标 3. 确定 BLNK 和 Cbl-b 如何促进受体运输。目标 4：确定为什么 BCR 运输在无能 B 细胞中异常。