The B-cell receptor (BCR) is a multiprotein structure that provides important signalling cues for the development, and activation or inactivation, of B cells. The binding of the BCR to antigen can stimulate two processes: the initiation of signalling events and the internalization of the occupied BCRs. Surprisingly, little was known about the relationship between signalling and internalization — until now. Reporting in PLoS Biology, Hou et al. show that BCR signalling and internalization events are mutually exclusive, and that, on binding antigen, the BCR is either phosphorylated and retained at the cell surface, or internalized.

Binding of antigen by the BCR induces the phosphorylation of tyrosines that are within conserved motifs in the cytosolic tails of the two signalling chains of the BCR. The authors determined that the unphosphorylated tyrosines in the cytosolic tail of the main BCR signalling chain, immunoglobulin-α, are required for BCR internalization (also known as endocytosis).

Knowing that the phosphorylation of tyrosine-based motifs in other receptors inhibits internalization, the authors next predicted that, when the BCR is phosphorylated (and therefore can actively signal), it is preferentially retained at the cell surface. They confirmed their prediction using several methods, which included a direct visualization assay in which phosphorylated complexes of BCRs could be seen only on the surface of the cells and not in the cytosol. Interestingly, Hou et al. also determined that only a small fraction of surface BCR complexes were actually phosphorylated (and therefore available to initiate signalling) following binding of antigen.

Last, the authors developed a mathematical model that allowed them to compare both a scenario in which receptor internalization and phosphorylation are mutually exclusive events, and a more conventional scenario in which these two processes are competing events. Using this model, Hou et al. gained insights into some of the seemingly contradictory observations on the relationships between the internalization and phosphorylation of the BCR. They also showed that when internalization and phosphorylation are mutually exclusive (as was observed experimentally), responses to low-avidity antigens are enhanced — this could have physiological implications for the initial detection of antigens.

The authors suggest that their model might be helpful in explaining some of the disparate observations in the literature regarding BCR spatial regulation, and say that further studies to identify how receptors are selected for internalization are required. The experimental results presented in this paper have certainly provided a useful platform from which we will hopefully be able to decipher the complex dynamics of BCR signalling and internalization.