B Cell Receptor Regulation of Antigen Processing

B淋巴细胞捕获、加工抗原并将其呈递给T细胞的能力是 正常体液免疫反应，并参与B和T细胞的发病 介导的自身免疫性疾病。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)并启动信号级联反应，引发协调的 一系列细胞反应，确保即使是低亲和力的抗原也能被有效捕获。 抗原性多价极大地加速了参与的受体及其受体的内吞作用 通过内吞途径进入晚期的内体抗原处理隔间。 与在成熟的树突状细胞中所描述的相似，bcr结扎也诱导 重塑受体靶向抗原处理隔间，增强其能力 处理多肽并将它们加载到MHC II类。尽管BCR信号在 确定抗原递呈给T细胞，对哪些信号通路知之甚少 有助于受体贩运及其调控的具体细胞过程。在这笔赠款中 应用，我们证明了BCR组成的IGP在细胞表面泛素化是通过 E3连接酶瘙痒，这是从早期到晚期正常运输内小体所必需的。在 如果没有泛素化，受体就会循环回到细胞表面。在更下游的地方， 泛素连接酶Cbl-b是进入抗原处理隔间所必需的。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 每一种都由不同的泛素连接酶控制。基于这个模型，我们预测 在每个检查点做出的受体转运决定决定了外周B细胞的反应。 我们建议在以下具体目标上测试该模型： 目的1.确定Itch泛素化IGP的途径。 目的2.检测IGP泛素化的体内功能。 目的3.确定BLNK和Cbl-b在受体转运中的作用。 目的4：探讨无能B细胞BCR转运异常的原因。

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.