Intracellular Trafficking Of The B cell Antigen Receptor

B 细胞抗原受体的细胞内运输

• 批准号: 6521528
• 负责人: Susan Pierce
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6521528
• 关键词: B lymphocyte; antibody formation; antigen receptors; antigens; intracellular; protein transport; receptor binding; receptor expression; tissue /cell culture

The B cell antigen receptor (BCR) serves dual, interrelated functions in B cell activation. The first is to initiate signal cascades that result in the transcription of a variety of genes associated with B cell activation. However, signaling through the BCR alone is insufficient for full activation and for this the B cell requires the functions of antigen-specific helper T cells. The interaction of the B and T cells is mediated through the T cells' engagement of antigenic peptide-MHC class II complexes on the B cell surface by the T cell antigen receptor (TCR). The peptide MHC complexes expressed by the B cells are assembled in an intracellular compartment from newly synthesized MHC class II molecules and peptides derived from the antigen bound to the BCR. Our previous studies showed that the BCR transports the antigen to the intracellular compartment where the antigen is degraded and the peptide class II complexes are assembled. The signaling and antigen transport functions of the BCR are interdependent in that the BCR signaling is necessary for the correct and rapid targeting of the antigen to the class II containing compartments. Indeed, for signaling defective BCR antigen is either not processed or the rate of antigen delivery is significantly reduced. In turn, the internalization of the BCR may play an important role in regulating signaling by removing activated receptors from the cell surface. Our recent studies showed that the signaling and antigen targeting functions of the BCR may be coordinated by the BCRs association with cholesterol-rich membrane microdomains termed lipid rafts. We showed that the BCR in resting cells is excluded from rafts that concentrate the Src-family kinase Lyn, required for the initiation of signaling. Following antigen binding the BCR translocates into rafts where it associates with Lyn and signaling is initiated. Subsequently, the BCR is internalized and trafficked to the class II peptide-loading compartment. We learned that the internalization of the receptor is controlled during B cell development, by B cell coreceptors that regulate BCR signaling and by infection by Epstein Barr Virus. Studies in progress are focusing on the mechanism by which the BCR is internalized in order to elucidate the precise relationship between rafts and internalization and to uncover points of regulation in the process.

B细胞抗原受体(BCR)在B细胞激活中起着双重的、相互关联的作用。第一个是启动信号级联反应，导致与B细胞激活相关的各种基因的转录。然而，仅通过BCR发出的信号不足以完全激活，为此B细胞需要抗原特异性辅助T细胞的功能。B细胞与T细胞的相互作用是通过T细胞抗原受体(TCR)与B细胞表面抗原肽-MHC-II类复合体结合而实现的。B细胞表达的多肽MHC复合体是由新合成的MHC II类分子和与BCR结合的抗原衍生的多肽组装在细胞内的一个隔室中。我们以前的研究表明，BCR将抗原运送到细胞内的隔室，在那里抗原被降解，并组装成II类多肽复合体。BCR的信号传递功能和抗原运输功能是相互依赖的，因为BCR信号对于正确和快速地将抗原靶向包含II类的间隔是必要的。事实上，对于信号缺陷，bcr抗原要么没有被处理，要么抗原递送速度显著降低。反过来，BCR的内化可能通过从细胞表面移除激活的受体，在调节信号方面发挥重要作用。我们最近的研究表明，BCR的信号和抗原靶向功能可能是通过BCR与富含胆固醇的膜微域(称为脂筏)相结合来协调的。我们发现，静息细胞中的BCR被排除在浓缩了启动信号所需的Src家族激酶Lyn的筏子中。在抗原结合后，BCR移位到与LYN相关联的木筏中，并启动信号传递。随后，BCR被内化并被运送到第二类多肽载荷室。我们了解到，在B细胞发育过程中，受体的内化受到调节BCR信号的B细胞辅助受体和EB病毒感染的控制。正在进行的研究集中于BCR内化的机制，以阐明木筏和内化之间的确切关系，并揭示这一过程中的规律点。