Force-Induced Ultrasensitivity at Cell-Cell Interfaces

Recent experiments have revealed that B cells use mechanical forces transmitted by the actin cytoskeleton to discriminate between antigens of similar binding affinity and to internalize portions of the antigen-presenting membrane. However, there is no unifying theoretical framework to probe the role of forces in antigen discrimination at cell-cell interfaces. In this work, we develop a hybrid computational approach to account for key biophysical properties of immune cell interfaces, including stochastic receptor-ligand binding kinetics, membrane mechanics, and actin-mediated forces on the membrane. We show that the number of B cell receptors (BCRs) bound to antigens increases in an ultrasensitive manner as a function of the binding affinity, and that the stiffness of the antigen-presenting membrane influences the threshold of the response. Above the threshold, antigens are internalized through a mechanism involving BCR clustering. Taken together, our results highlight the importance of forces at B cell interfaces and suggest that affinity discrimination is enhanced by membrane deformations, intracellular forces, and the dynamic spatial organization of surface receptors.