Computational modeling of B cell signaling shows B cell affinity discrimination requires kinetic proofreading (84.2)

Abstract

Abstract B cells signaling in response to antigen is proportional to antigen affinity, a process known as affinity discrimination. B cells can acquire antigen in membrane-bound form on the surface of antigen-presenting cells (APCs), with signaling being initiated within a few seconds of contact. During the early stages of contact, B cell receptors (BCRs) on protrusions of the B cell surface bind to antigen on the APC surface and form micro-clusters of 10-100 BCR-antigen complexes. We use a Monte Carlo computational model to show that B cell affinity discrimination at the level of micro-clusters requires a threshold antigen binding time, similar to kinetic proofreading. We find that if BCR molecules become signaling-capable immediately upon binding antigen, there is a loss in serial engagement as BCR-antigen affinity increases, due to the increased bond lifetime of high-affinity bonds. This results in an unnatural decrease in signaling strength with increasing affinity. A threshold antigen binding time favors high affinity BCR-antigen bonds, as these long-lived bonds can better fulfill the threshold time requirement than low-affinity bonds. A threshold antigen binding time of ~10 seconds results in monotonically increasing signaling with affinity, as seen in B cell activation experiments. This time matches well with the experimentally observed time (~20 seconds) of lipid raft-mediated conformational changes in BCR signaling domains that lead to association with Syk.