(600e) Antigen Discrimination at B Cell Surfaces: Probing the Role of Mechanical Forces

Understanding the influence of mechanical forces at membranes is critical for understanding how B cells distinguish between self and foreign ligands. Although B cells can be activated by soluble antigens, B cells in vivo are activated predominantly by antigens attached to membrane surfaces. Fascinating 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 surface. However, a framework to understand collective effects at the B cell surface and to probe underlying mechanisms is missing.

In this work, we develop hybrid computational models that 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 use these models to investigate how mechanical forces modulate the interactions of B cells with surface-presented antigens. The activation of B cells is controlled largely by the B cell antigen receptor (BCR). We study dynamics of BCRs at an intermembrane junction and show that the number of BCRs engaged by antigens increases sharply (in an ultrasensitive manner) as a function of the binding affinity. In contrast, equilibrium binding without mechanical forces produces a broad response. Both membrane and cytoskeletal mechanics contribute to the sharp discrimination. We further show that the stiffness of the antigen-presenting membrane influences the affinity threshold at which substantial BCR engagement occurs. Above the threshold, antigens are internalized through a mechanism involving BCR clustering. The physical picture that emerges is that B cells use forces to test receptor-ligand binding strength; nucleation and growth of a cluster of BCR-antigen complexes then allows the complexes to share the load of significantly deforming the antigen-presenting surface.

Taken together, our results highlight the importance of forces at B cell interfaces and suggest that both membrane deformations and intracellular forces enhance affinity discrimination. We conclude by discussing our results in the context of antigen discrimination by T cells and B cells.