  B cells signaling in response to antigen is proportional to antigen affinity,
a process known as affinity discrimination. Recent research suggests that 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 B cell/APC contact. During the earliest stages of B cell/APC
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. In this study, we use computational modeling to show that B cell
affinity discrimination at the level of BCR-antigen micro-clusters requires a
threshold antigen binding time, in a manner similar to kinetic proofreading. We
find that if BCR molecules become signaling-capable immediately upon binding
antigen, there is a loss in serial engagement due to the increase in bond
lifetime as koff decreases. This results in decreasing signaling strength as
affinity increases. A threshold time for antigen to stay bound to BCR before
the latter becomes signaling-capable 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, replicating the affinity
discrimination pattern observed in B cell activation experiments. This time
matches well (within order of magnitude) with the experimentally observed time
(~ 20 seconds) required for the BCR signaling domains to undergo antigen and
lipid raft-mediated conformational changes that lead to association with Syk.
