Force Generation in B-Cell Synapses: Mechanisms Coupling B-Cell Receptor Binding to Antigen Internalization and Affinity Discrimination

摘要

The B-cell receptor (BCR) controls B-cell activation by biochemical signaling and by physical acquisition of antigens from immune synapses with antigen-presenting cells. B cells grab and gather antigens by engaging conserved biomechanical modules for cell spreading, receptor clustering, receptor transport, and generation of pulling forces, which culminate in antigen extraction and endocytosis. The mechanical activity in B-cell synapses follows a pattern of positive and negative feedbacks that regulate the amount of extracted antigen by directly manipulating the dynamics of BCR-antigen bonds. In particular, spreading and clustering increase the association of BCR with antigen, providing amplification and sensitivity, while pulling forces dissociate the BCR from the antigen, testing the quality of antigen binding. The emergent effect of mechanical forces in B-cell synapses is ligand discrimination that can be scaled across a range of BCR affinities, provided that the magnitude and timing of the mechanical forces are precisely coordinated with biochemical readouts from the BCR. Such coordination predicts not only novel connections between BCR signaling, endocytosis, and the actomyosin cytoskeleton but also mechanosensitivity of these pathways. The mechanical control of bond formation and separation may be generally beneficial in signaling networks with variable thresholds.