Membrane Microdomains And B Cell Signaling

B细胞抗体反应是由抗原与克隆分布的B细胞抗原受体(BCR)结合而触发的。BCR的作用是启动信号级联，并将抗原运送到细胞内以供呈递，这两个过程都是B细胞激活的基本过程。在过去的几年里，关于BCR抗原结合触发的复杂信号级联的生物化学以及抗原被运输进行处理的细胞内途径，人们已经了解了很多。信号和抗原靶向似乎都是通过膜相关的Src家族成员Lyn对BCR进行磷酸化来启动的。然而，使抗原结合的BCR与LYN接触的B细胞激活的起始事件尚不清楚。我们最近提供的证据表明，富含胆固醇和鞘磷脂的膜微域，称为脂筏，是BCR信号和抗原运输的平台。在静息细胞中，BCR被排除在浓缩LYN的RAFT之外，但在多价抗原结合时，BCR寡聚并与RAFT结合，在那里它被LYN磷酸化，信号被启动。后来的研究表明，BCR的移位到RAFT中不需要BCR信号中的两个最早的事件，即LYN对BCR的磷酸化或BCR与肌动蛋白细胞骨架的结合。因此，BCR与RAFT的结合以及由此产生的信号的启动似乎仅依赖于BCR的寡聚。在RAFT结合后，结合到BCR上的抗原被内化以供处理。在RAFT中信号的起始之后是RAFT聚集，并最终形成一个被称为免疫突触的高度组织化的结构，BCR信号可能从这个突触延长。从我们对B细胞受体与RAFT关系的研究中出现了一个令人兴奋的主题，即BCR RAFT关联受到多种因素的调节，这些因素控制着B细胞的结局-S与抗原的接触，包括B细胞的发育状态，辅助受体的结合和病毒感染。我们已经了解到，BCR稳定地与脂筏结合的能力在发育过程中发生了变化，并且这种变化与B细胞与抗原结合的结果有关。值得注意的是，BCR与未成熟B细胞中的RAFT无关，BCR抗原结合会导致B细胞的死亡而不是激活。我们还了解到，增强BCR反应的辅助受体可以延长BCR在筏子中的驻留时间。相反，减弱bcr信号的B细胞受体会破坏筏子中bcr的稳定性。最后，在人类B细胞中建立潜伏感染的爱泼斯坦-巴尔病毒阻止了BCR进入木筏，从而阻止了抗原激活受感染细胞的能力。

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.