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B cells signaling in response to antigen is proportional to antigen affinity,a process known as affinity discrimination. Recent research suggests that Bcells can acquire antigen in membrane-bound form on the surface ofantigen-presenting cells (APCs), with signaling being initiated within a fewseconds of B cell/APC contact. During the earliest stages of B cell/APCcontact, B cell receptors (BCRs) on protrusions of the B cell surface bind toantigen on the APC surface and form micro-clusters of 10-100 BCR/Antigencomplexes. In this study, we use computational modeling to show that B cellaffinity discrimination at the level of BCR-antigen micro-clusters requires athreshold antigen binding time, in a manner similar to kinetic proofreading. Wefind that if BCR molecules become signaling-capable immediately upon bindingantigen, there is a loss in serial engagement due to the increase in bondlifetime as koff decreases. This results in decreasing signaling strength asaffinity increases. A threshold time for antigen to stay bound to BCR beforethe latter becomes signaling-capable favors high affinity BCR-antigen bonds, asthese long-lived bonds can better fulfill the threshold time requirement thanlow-affinity bonds. A threshold antigen binding time of ~10 seconds results inmonotonically increasing signaling with affinity, replicating the affinitydiscrimination pattern observed in B cell activation experiments. This timematches well (within order of magnitude) with the experimentally observed time(~ 20 seconds) required for the BCR signaling domains to undergo antigen andlipid raft-mediated conformational changes that lead to association with Syk.

Affinity Discrimination in B cells in Response to Membrane Antigen Requires Kinetic Proofreading