A spatio-temporal model reveals self-limiting FcɛRI cross-linking by multivalent antigens

Abstract

Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (FcɛRI) in the plasma membrane of mast cells. However, understanding of the mechanisms of FcɛRI aggregation remains incomplete. Experimental reports indicate that FcɛRI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse FcɛRI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.