Membrane Microdomains And B Cell Signaling

膜微区和 B 细胞信号传导

• 批准号: 6521525
• 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/6521525
• 关键词: B lymphocyte; Epstein Barr virus; Herpesviridae disease; antibody formation; antibody receptor; antigen receptors; biological signal transduction; leukopoiesis; membrane lipids; membrane structure; receptor binding; tissue /cell culture

B cell antibody responses are triggered by the binding of antigen to the clonally distributed B cell antigen receptors (BCRs). The BCR serves to initiate signal cascades and to transport antigens into the cell for presentation, both essential processes in B cell activation. Over the last several years a great deal has been learned about the biochemistry of the complex signal cascades triggered by BCR antigen engagement and the intracellular pathway by which antigen is transported for processing. Both signaling and antigen targeting appear to be initiated by phosphorylation of the BCR by a membrane associated member of the Src family kinase, Lyn. However, the initiating event in B cell activation that brings the antigen bound BCR into contact with Lyn is not known. We recently provided evidence that cholesterol- and sphingolipid-rich membrane microdomains, termed lipid rafts, serve as platforms for both BCR signaling and antigen trafficking. In resting cells the BCR is excluded from rafts that concentrate Lyn but upon multivalent antigen binding, the BCR oligomerizes and associates with rafts where it is phosphorylated by Lyn and signaling is initiated. Subsequent studies showed that the translocation of the BCR into rafts did not require two of the earliest events in BCR signaling, namely the phosphorylation of the BCR by Lyn or association of the BCR with the actin cytoskeleton. Thus, the association of the BCR with rafts and the resulting initiation of signaling appear to be dependent only on the oligomerization of the BCR. Following raft association antigen bound to the BCR is internalized for processing. The initiation of signaling in the rafts is followed by raft clustering and ultimately by the formation of a highly organized structure termed an immunological synapse from which BCR signaling may be prolonged. An exciting theme that emerged from our studies of the relationship of the BCR with rafts is one in which BCR raft association is regulated by a variety of factors that control the outcome of the B cell?s encounter with antigen including the developmental state of the B cell, the engagement of coreceptors and viral infection. We have learned that the ability of the BCR to stably associate with lipid rafts changes during development and that the changes correlate with the outcome of antigen engagement by the B cell. Significantly, the BCR does not associate with rafts in immature B cells and BCR antigen binding results in the death of the B cell rather than activation. We also learned that coreceptors that function to enhance BCR response prolong the residency of the BCR in rafts. Conversely, B cell receptors that attenuate BCR signaling destabilize the BCR in rafts. Lastly, Epstein Barr Virus that established a latent infection in human B cells blocks the BCRs access to rafts and thus blocks the ability of antigen to activate infected cells.

B细胞抗体应答是由抗原与克隆分布的B细胞抗原受体（BCR）的结合触发的。BCR用于启动信号级联并将抗原转运到细胞中以进行呈递，这两个过程都是B细胞活化的基本过程。在过去的几年中，已经了解了大量关于由BCR抗原接合触发的复杂信号级联的生物化学和抗原被转运用于加工的细胞内途径。信号传导和抗原靶向似乎都是通过Src家族激酶的膜相关成员林恩对BCR的磷酸化而启动的。然而，使抗原结合的BCR与林恩接触的B细胞活化中的起始事件尚不清楚。我们最近提供的证据表明，胆固醇和鞘脂丰富的膜微区，称为脂筏，作为平台的BCR信号和抗原运输。在静息细胞中，BCR被排除在浓缩林恩的筏之外，但在多价抗原结合后，BCR寡聚化并与筏缔合，在筏中BCR被林恩磷酸化并启动信号传导。随后的研究表明，BCR进入筏的易位并不需要BCR信号传导中最早的两个事件，即BCR被林恩磷酸化或BCR与肌动蛋白细胞骨架的结合。因此，与筏的协会的BCR和由此产生的信号传导的启动似乎是唯一依赖于寡聚化的BCR。在筏结合后，与BCR结合的抗原被内化用于加工。筏中信号的起始之后是筏聚集，并最终形成被称为免疫突触的高度组织化的结构，BCR信号可以从该免疫突触延长。 一个令人兴奋的主题，出现了从我们的研究的关系，BCR与筏是一个在BCR筏协会是由各种因素，控制的结果B细胞？B细胞与抗原的接触包括B细胞的发育状态、辅助受体的参与和病毒感染。我们已经了解到BCR与脂筏稳定结合的能力在发育过程中发生变化，并且这些变化与B细胞抗原结合的结果相关。值得注意的是，BCR不与未成熟B细胞中的筏结合，BCR抗原结合导致B细胞死亡而不是活化。我们还了解到，辅助受体的功能，以提高BCR反应延长驻留的BCR在筏。相反，减弱BCR信号传导的B细胞受体使筏中的BCR不稳定。最后，在人B细胞中建立潜伏感染的爱泼斯坦巴尔病毒阻断BCR进入筏，从而阻断抗原激活感染细胞的能力。