spatial model from A spatio-temporal model reveals self-limiting Fc<i>ɛ</i>RI crosslinking by multivalent antigens

Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signaling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (Fc<i>ɛ</i>RI) in the plasma membrane of mast cells. However, understanding of the mechanisms of Fc<i>ɛ</i>RI aggregation remains incomplete. Experimental reports indicate that Fc<i>ɛ</i>RI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor crosslinking 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 Fc<i>ɛ</i>RI 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 crosslinking 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.多价抗原诱导细胞表面受体蛋白聚集，乃是免疫细胞信号传导的核心早期环节。过往已有多项实验与建模研究，针对肥大细胞膜上免疫球蛋白E受体（FcɛRI）的多价配体诱导聚集现象展开了探究。然而，目前学界对FcɛRI聚集的具体机制仍未完全阐明。已有实验研究表明，当受到多价配体刺激时，FcɛRI会形成尺寸相对有限的小型簇集结构。与之形成对比的是，建模研究显示，三价配体介导的受体交联，可能会形成大型受体超聚集体，进而诱发过度活跃的细胞应答。本研究构建了一种基于布朗动力学（Brownian dynamics）的时空模型，用于分析三价抗原诱导的FcɛRI聚集过程。与过往采用非空间模拟方法的现有模型不同，本模型显式考虑了多价物种（分子与复合物）的粗粒度位点特异性特征。该模型涵盖了任意结构的时变物种的膜扩散、空间位阻碰撞以及亚纳米级位点特异性相互作用。借助该模型，本研究探究了物种的时间演化过程及其扩散特性。与近期一项实验研究结果一致，本模型预测：当多价抗原介导受体交联时，细胞膜上的物种迁移率会出现急剧下降。研究表明，正是由于物种迁移率的这种下降，刺激后的受体聚集过程可能会出现自我限制效应。本研究的分析结果揭示了一种潜在的调控机制，可抑制免疫细胞在多价抗原刺激下发生过度活化。