Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement

Abstract

B cells receptor signaling in response to membrane-bound antigen increases with antigen affinity, a process known as affinity discrimination. We use computational modeling to show that B cell affinity discrimination requires that kinetic proofreading predominate over serial engagement. We find that if B cell receptors become signaling-capable immediately upon binding antigen, decreasing serial engagement as affinity increases results in weaker signaling with increasing affinity. A threshold time for antigen to stay bound to B cell receptors for several seconds before the latter becomes signaling-capable, similar to kinetic proofreading, is needed to overcome the loss in serial engagement due to increasing antigen affinity, and replicate the monotonic increase in B cell signaling with affinity observed in B cell activation experiments. This finding matches well with the experimentally observed time (~ 20 seconds) required for the B cell receptor signaling domains to undergo antigen and lipid raft-mediated conformational changes that lead to Src-family kinase recruitment. We hypothesize that the physical basis of the threshold time of antigen binding may lie in the formation timescale of B cell receptor dimers. The latter decreases with increasing affinity, resulting in shorter threshold antigen binding times as affinity increases. Such an affinity-dependent kinetic proofreading requirement results in affinity discrimination very similar to that observed in biological experiments. B cell affinity discrimination is critical to the process of affinity maturation and the production of high affinity antibodies, and thus our results here have important implications in applications such as vaccine design.

Network-of-queues approach to B-cell-receptor affinity discrimination

“…Our method avoids deterministic time thresholds nevertheless delivering results in agreement with both in silico observations and experimental results reported in Ref. [11]. The method exploits ideas outlined for T-cell receptors (TCRs) [13], where each compartment of the kinetic proofreading scheme is described as a queue.…”

“…The unbinding rates k Syk off and k Lyn off are reported to be within two orders of magnitude [11,26]. The fastest unbinding rates (10s −1 ) did not lead to a good discrimination accuracy.…”

“…The parameters used in the simulations are reported in Table II and have been extracted from [11,28], and references therein. The main issue is to identify suitable values for the ratio k on /k off .…”

“…Recent studies [6,10] provide novel, yet contrasting, interpretations on this phenomenon. To our knowledge, the mechanism of BCR affinity discrimination has been addressed using a time threshold for a kinetic proofreading scheme involving BCR-antigen binding and activated Lyn and Syk kinases [11]. Kinetic proofreading models have been applied in immunology after the seminal work of McKeithan [12].…”

“…The model accounts for activation and deactivation rates of a series of biochemical reactions occurring at receptor tails under the assumption that upon antigen unbinding the receptor jumps back to the native state regardless of its biochemical modifications. In [11] well-defined transition rates tuned for the discrete stochastic model have been proposed, with binding or unbinding events implicitly modeled as geometric random variables. This model has two major limitations.…”