B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events

Abstract

Engagement of the B cell antigen receptor initiates two concurrent processes, signaling and receptor internalization. While both are required for normal humoral immune responses, the relationship between these two processes is unknown. Herein, we demonstrate that following receptor ligation, a small subpopulation of B cell antigen receptors are inductively phosphorylated and selectively retained at the cell surface where they can serve as scaffolds for the assembly of signaling molecules. In contrast, the larger population of non-phosphorylated receptors is rapidly endocytosed. Each receptor can undergo only one of two mutually exclusive fates because the tyrosine-based motifs that mediate signaling when phosphorylated mediate internalization when not phosphorylated. Mathematical modeling indicates that the observed competition between receptor phosphorylation and internalization enhances signaling responses to low avidity ligands.

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

“…In the case of the BCR, we and others have demonstrated receptor internalization is dependent upon conserved tyrosine-based signaling motifs within the cytosolic tail of Ig␣/Ig␤ (34,35). Different motifs for endocytosis and trafficking are consistent with the known biological functions of the BCR.…”

“…Different motifs for endocytosis and trafficking are consistent with the known biological functions of the BCR. Successful signaling induces the phosphorylation of the tyrosine-based Ig␣/Ig␤ internalization motifs preventing internalization (35). Selective retention of phosphorylated BCRs on the cell surface is predicted to prolong signaling responses and enhance cellular responses to low-avidity ligands.…”

Capture of plasma membrane fragments from target cells by trogocytosis requires signaling in T cells but not in B cells

“…Our observation that the capture of membrane fragments from APCs by B cells is not affected by several different enzyme inhibitors was quite unexpected, yet, a careful review of the literature identifies BCR signaling and antigen internalization as mutually exclusive, 30 a notion supported by the dissociation we observed between trogocytosis and activation in B cells. In addition, the literature provides several examples of signalingindependent events of B-cell biology including BCR endocytosis with antigen (see Caballero et al 31 and references therein), BCR recruitment into lipid rafts, 32 antigen capture by B cells, 33 and, in one study, 33 but not in another one, 26 the formation of immunologic synapses between APCs and B cells.…”

Pregnancy and Malaria Exposure Are Associated with Changes in the B Cell Pool and in Plasma Eotaxin Levels

“…Consistent with this lineage, in which surface Ig expression is downregulated in favor of transition to secretory Ig (53), we did observe a lower amount of surface IgG (MFI levels) in active atypical MBC compared with the mean IgG levels in B cells in the NP, ENP, and EP groups. Nevertheless, decreased IgG levels may also result from Ig (BCR) internalization after B cell activation (46,47). Thus, active atypical MBC may recognize and internalize Ags at a higher rate than other B cells, at least in conditions of persistent B cell priming.…”

“…4D). To investigate whether the lower surface IgG levels found in active atypical MBC were a consequence of IgG internalization after BCR engagement (46,47), in another set of samples we studied the surface expression of transferring receptor (CD71), which is known to recycle constitutively between early endosomes and the cell surface (48). Conversely, higher CD71 expression was found in active atypical MBC compared with the average B cell levels (Fig.…”