B Cell Receptor Regulation of Antigen Processing

B淋巴细胞捕获、加工和向T细胞呈递抗原的能力是免疫应答所必需的。 正常的体液免疫反应，并有助于B和T细胞的发病机制 介导的自身免疫性疾病。B淋巴细胞优先捕获多价抗原， 聚集B细胞抗原受体（BCR）并启动信号级联，引起协调的 一系列细胞反应，确保即使是低亲和力抗原也能被有效捕获。 抗原的多价性大大加速了接合受体的内吞作用及其相互作用。 通过内吞途径转运到晚期内体抗原加工区室。 与成熟树突状细胞中所描述的相似，BCR连接也诱导了树突状细胞的凋亡。 受体靶向抗原加工区室的重塑， 来加工多肽并将其装载到MHC II类上。尽管BCR信号传导在 决定抗原呈递给T细胞，相对而言，对哪些信号通路知之甚少 有助于受体运输以及它们调节的特定细胞过程。在这份赠款中， 应用中，我们证明BCR组成型Igp在细胞表面被泛素化， E3连接酶Itch，并且这是从早期到晚期内体的正常运输所必需的。在 在缺乏泛素化的情况下，受体回缩到细胞表面。在下游， 泛素连接酶Cbl-b是进入抗原加工区室所必需的。从这些 观察，我们提出了一个模型，其中有两个不同的检查点在BCR内吞 每种运输都由不同的泛素连接酶控制。基于这个模型，我们预测， 在每个检查点所做的受体运输的决定决定了外周B细胞应答。 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Igp。 目标2.目的：研究人Igp泛素化的体内功能。 目标3。确定BLNK和Cbl-b如何促进受体转运。 目的4：确定在无反应性B细胞中BCR运输异常的原因。

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 constitutent Igp 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 Igp. Aim 2. To determine the in vivo function of Igp 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.