Polyvalent Antigens Stabilize B Cell Antigen Receptor Surface Signaling Microdomains

Abstract

The B cell Ag receptor (BCR) can distinguish subtle differences in Ag structure and trigger differential responses. In this study, we analyzed the effects of Ag valency on the signaling and Ag-targeting functions of the BCR. Although both paucivalent and polyvalent Ags induced the redistribution of the surface BCR into polarized caps, polyvalent Ag-induced BCR caps persisted. Ganglioside GM1, a lipid raft marker, and tyrosine-phosphorylated proteins, but not CD45 and transferrin receptor, were concentrated in BCR caps, suggesting BCR caps as surface-signaling microdomains. Prolonged BCR caps were concomitant with an increase in the level and duration of protein tyrosine phosphorylation and a reduction in BCR internalization and movement to late endosomes/lysosomes. Thus, Ag valency influences B cell responses by modulating the stability of BCR-signaling microdomains and BCR trafficking.

Independent Trafficking of Ig-α/Ig-β and μ-Heavy Chain Is Facilitated by Dissociation of the B Cell Antigen Receptor Complex

“…This discrepancy may reflect the different ligands used to cross-link the BCR. Our study used bona fide Ag, whereas the previous study used polyvalent cross-linkers, such as F(abЈ) 2 of anti-, which have been reported to slow the rate of BCR endocytosis (37). Importantly, our data are consistent with studies showing that BCR mutants lacking the ability to transduce signals remain competent to internalize receptors (28,38,39).…”

Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

“…The results of previous studies using anti-IgM Abs of varying valencies (29,30) are consistent with our results using multivalent Ag. Extensive cross-linking of the BCR by multivalent Ags induces the association of the BCR with detergent-insoluble lipid rafts (31) that are associated with long-term stable activation of tyrosine phosphorylation (32). The ability of multivalent Ags to establish more stable signaling domains is likely to be responsible for the quantitative boost in up-regulation of markers associated with B cell activation upon stimulation with multivalent HEL on VLPs.…”

Cutting Edge: Guillain-Barré Syndrome-Associated IgG Responses to Gangliosides Are Generated Independently of CD1 Function in Mice

“…Thus, this study and the work described above (14) highlight distinct pathways of Ab production to polysaccharides and LOS. Polysaccharide Ags contain repetitive carbohydrate epitopes that allow physical cross-linking of specific BCRs in lipid rafts (24). Further, surface CD1d molecules expressed on B cells, especially on CD1d high marginal zone B cells, may comigrate in rafts and transmit an activation signal via their cytoplasmic tail tyrosinecontaining motif, as suggested for CD1d ϩ intestinal epithelial cells (25,26).…”

“…Further, surface CD1d molecules expressed on B cells, especially on CD1d high marginal zone B cells, may comigrate in rafts and transmit an activation signal via their cytoplasmic tail tyrosinecontaining motif, as suggested for CD1d ϩ intestinal epithelial cells (25,26). In contrast, LOS, which is devoid of repetitive carbohydrate epitopes, may not be efficient in stabilizing lipid rafts (24), but their lipid A structure can transmit supporting signals for IgG responses directed against the sugar chain epitopes of LOS.…”