Mechanical Forces in B cell Activation

Abstract

The generation of protective antibodies depends on the selective expansion of B cells with the strongest binding of their B cell receptors (BCRs) to foreign antigens. This process starts by formation of B cell immune synapses with antigen-presenting cells. BCR signaling in immune synapses triggers extraction of the antigens, leading to B cell antigen processing and presentation to helper T cells - a step that ultimately controls the relative expansion of B cell clones. To internalize antigen from immune synapses, B cells generate tensile forces by activating the non-muscle myosin IIa. Myosin contractility invaginates synaptic antigen clusters and promotes antigen internalization by clathrin-mediated endocytosis. Forces generated by myosin IIa in B cell synapses rupture low avidity interactions between the BCR and antigens and provide thus a negative feedback to BCR antigen binding and signaling, which promotes B cell affinity discrimination. These results suggest that B cells use mechanical forces to test the strength of antigen binding to the BCR. The location, intensity and timing of the forces are distinctly regulated in B cell subsets. In naive B cells, antigen clusters form and grow in lamellipodia, move centripetally and are collected in the center of the synapse. Tensile forces are applied at the base of lamellipodia, creating a delay that allows cluster growth, increase in cluster avidity and greater sensitivity of endocytosis. In contrast, germinal centre B cells, which undergo affinity selection, apply strong forces on small antigen clusters in the periphery of the synapse. This synaptic architecture of germinal center B cells is associated with higher stringency of affinity discrimination. Thus, B cell selection is regulated by the architecture of immune synapses through the coordination of signaling, contractility and endocytosis.