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

TL;DR

This paper demonstrates through computational modeling that B cell affinity discrimination relies on kinetic proofreading dominating over serial triggering, requiring a threshold antigen binding time to match experimental observations and ensure effective immune response.

Contribution

It reveals that a threshold binding time, akin to kinetic proofreading, is essential for B cells to discriminate antigen affinity, a novel insight into BCR signaling mechanisms.

Findings

Kinetic proofreading must predominate over serial engagement for proper affinity discrimination.

A threshold binding time of several seconds is necessary to match experimental B cell signaling.

Affinity-dependent binding times influence BCR conformational changes and signaling.

Abstract

B cells receptor (BCR) 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 BCR molecules become signaling-capable immediately upon binding antigen, the loss in serial engagement as affinity increases results in weaker signaling with increasing affinity. A threshold time for antigen to stay bound to BCR 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 BCR 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 BCR 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.