Cutting Edge: Differential Sequestration of Plasma Membrane-Associated B Cell Antigen Receptor in Mature and Immature B Cells into Glycosphingolipid-Enriched Domains

Abstract

Glycosphingolipid-enriched domains (GEDs) are believed to act as platforms for transduction of B cell Ag receptor (BCR)-induced signals from the cell surface. We sought to study whether differential sequestration of BCR into GEDs may contribute to the described intrinsic signaling differences between mature and immature B cells. In this study we found that mature B cells copolarize the BCR with GEDs following BCR aggregation, whereas transitional immature B cells do not. Although anti-BCR treatment leads to receptor aggregation by immature stage B cells, the aggregated complexes do not colocalize with GEDs. We found this difference to be independent of the isotype of the receptor, thereby associating this difference in BCR-GED colocalization to the developmental stage of the B cell. These findings suggest a structural basis for the developmentally regulated differences observed in Ag receptor-mediated signal transduction.

Transitional Type 1 and 2 B Lymphocyte Subsets Are Differentially Responsive to Antigen Receptor Signaling

“…These structures have been suggested to serve as platforms for initiating downstream BCR signaling cascades (63). Indeed, the BCR is poorly co-localized with lipid rafts in immature B cells compared with M B cells (64).…”

Lipid Rafts Associate with Intracellular B Cell Receptors and Exhibit a B Cell Stage-Specific Protein Composition

“…These events have been correlated with the limited entry of the BCR into lipid rafts (5,8,9). In contrast, the BCR in mature B cells gains rapid access to lipid rafts after activation with anti-HC F(ab)2 (5,10,11).…”

B Cell Antigen Receptor-Induced Rac1 Activation and Rac1-Dependent Spreading Are Impaired in Transitional Immature B Cells Due to Levels of Membrane Cholesterol

“…For example, transitional immature B cells are relatively impaired in their ability to activate protein kinase C (PKC) (9) and exhibit an associated inability to sustain signaling through the PKC␤/NF-B/c-myc pathway (23). Furthermore, although mature B cells readily translocate their BCR to the lipid raft compartment following stimulation as determined by both biochemical means and immunofluorescent microscopy, transitional immature B cells do not (1,23). We have previously reported that the plasma membrane of both early transitional immature B cells (T1) and the more mature T2 subset contain less unesterified free cholesterol than do mature B cells (23).…”

“…A ntigen-or anti-BCR-mediated aggregation of the BCR on mature B cells leads to its organization into cholesterol-enriched membrane microdomains termed lipid rafts, actin-dependent polarization of the engaged BCRs into concentrated "caps", and dynamic changes in plasma membrane morphology termed "ruffling" (1)(2)(3)(4). Each of these processes occurs coincident with generation of sustained signals necessary for B cell activation.…”