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B cells receptor (BCR) signaling in response to membrane-bound antigenincreases with antigen affinity, a process known as affinity discrimination. Weuse computational modeling to show that B cell affinity discrimination requiresthat kinetic proofreading predominate over serial engagement. We find that ifBCR molecules become signaling-capable immediately upon binding antigen, theloss in serial engagement as affinity increases results in weaker signalingwith increasing affinity. A threshold time for antigen to stay bound to BCR forseveral seconds before the latter becomes signaling-capable, similar to kineticproofreading, is needed to overcome the loss in serial engagement due toincreasing antigen affinity, and replicate the monotonic increase in B cellsignaling with affinity observed in B cell activation experiments. This findingmatches well with the experimentally observed time (~ 20 seconds) required forthe BCR signaling domains to undergo antigen and lipid raft-mediatedconformational changes that lead to Src-family kinase recruitment. Wehypothesize that the physical basis of the threshold time of antigen bindingmay lie in the formation timescale of BCR dimers. The latter decreases withincreasing affinity, resulting in shorter threshold antigen binding times asaffinity increases. Such an affinity-dependent kinetic proofreading requirementresults in affinity discrimination very similar to that observed in biologicalexperiments. B cell affinity discrimination is critical to the process ofaffinity maturation and the production of high affinity antibodies, and thusour results here have important implications in applications such as vaccinedesign.

Discrimination of Membrane Antigen Affinity by B cells Requires Dominance of Kinetic Proofreading over Serial Triggering