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.
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