(a) The cross-linked BCR is endocytosed along with bound antigen and membrane rafts. (b) Early endosomes fuse with late endosomes for antigen processing and loading of antigenic peptides onto MHC-II molecules within the membrane raft milieu. (c) Peptide-MHC (pMHC) complexes traffic to the surface and are displayed in association with membrane rafts. Specific peptide-MHC complexes are presented within membrane rafts to cognate TCRs in an immunological synapse (IS) with T cells. Membrane rafts are depicted by grey arrows, and signal transduction via BCR and TCR is indicated by lightning signs.

(a) Upon binding to complement-coated antigen, the BCR associates with membrane rafts, and comes in proximity to Src family kinases (SFKs) that phosphorylate ITAM tyrosine residues (red filled circles) in the Igα/Igβ chains. Phosphorylated ITAMs recruit Syk which phosphorylates many signaling substrates resulting in B cell activation. The co-receptor CR2/CD21 recognizes the complement component of the antigen and associates with CD19 and CD81, which provide an adaptor function and promote membrane raft association, respectively. (b) Feedback inhibition of B cell responses occurs upon immune complex-mediated co-ligation of the BCR with the inhibitory FcγRIIB receptor. In this circumstance, FcγRIIB is phosphorylated on ITIM tyrosine by the SFK Lyn and recruits SHIP which is a cytosolic inositol phosphatase that abrogates PI 3′-kinase and Ras signaling, thus dampening B cell activation.

(a) Membrane rafts are small, dynamic structures dispersed randomly on the cell surface, and tethered to the cortical actin cytoskeleton by protein pickets composed of the raft-associated protein PAG and the linker protein ezrin. In the absence of BCR stimulation, ezrin is phosphorylated (red filled circles) on T567 and exists in its open conformation. The ezrin-based pickets may also create membrane compartments (black rectangle) in which protein and lipid components of membrane rafts are trapped with limited diffusion between adjacent compartments. The Src family kinases (SFKs) are pre-associated with the membrane rafts, while the BCR is excluded from these domains in the absence of antigen resulting in low tonic signaling. (b) Oligomerization of the BCR by multivalent antigen results in its association with membrane rafts, increased proximity to SFKs and greatly amplified signal transduction. Among the effects of BCR signaling is dephosphorylation of ezrin on T567 with concomitant dissociation from PAG and actin, resulting in a break in the diffusion barriers, allowing coalescence of individual membrane rafts into bigger entities. At later times (not shown), ezrin becomes rephosphorylated and again binds to membrane rafts. These reconnections may allow for active actin-myosin-based movement of large rafts to one pole of the cell.