The Effect of Lipid Mediated Attraction and Antigen Affinity on B-Cell Receptor Microcluster Formation

Abstract

We present findings from our energy-based Monte Carlo simulation involving antigen (Ag) bound, B-cell receptor (BCR) interaction with crucial cellular components, namely the lipid membrane, src family tyrosine kinase and Syk kinase activity. After encountering antigen presenting cells and binding Ags, one of the earliest events of signalsome assembly is the formation of BCR microclusters. BCR recognition of antigen results in a monotonically increasing graded signaling response with increasing BCR-Ag affinity. Recent experiments indicate an important role of very early (within seconds) signaling events in this affinity discrimination process. Our current studies improve upon our most recent biophysical models for BCR-Ag microcluster and macrocluster formation by incorporating lipid-mediated BCR attraction factors. We examine the effect of varying attractive forces and interactions between lipids, BCR bound state and kinase activity. Our model can show that strong coupling between BCR/BCR and BCR/lipid (sphingolipids) molecules generates affinity-dependent microclustering similar to what has been observed in experiments. Our results indicate that microcluster size and number increase with increasing affinity while the formation times of such early BCR-Ag clusters decrease. These features can have important implications for the B cell affinity discrimination problem.