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

Cellular & Molecular Immunology volume 9, pages 62–74 (2012)Cite this article

Abstract

B-cell 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 antigen binding, which results in decreasing serial engagement as affinity increases, then increasing affinity can lead to weaker signaling. Rather, antigen must stay bound to B-cell receptors for a threshold time of several seconds before becoming signaling-capable, a process similar to kinetic proofreading. This process overcomes the loss in serial engagement due to increasing antigen affinity, and replicates the monotonic increase in B-cell signaling with increasing affinity that has been observed in B-cell activation experiments. This finding matches well with the experimentally observed time (∼20 s) 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 for a threshold time of antigen binding might lie in the formation timescale of B-cell receptor dimers. The time required for dimer formation decreases with increasing antigen affinity, thereby 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 have important implications in applications such as vaccine design.

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Acknowledgements

The authors thank Dr Emanual Maverakis, Dr Aaron Dinner and Dr Stephen Kaattari for proofreading the manuscript and offering valuable advice. PT and SR are supported by NIH grant AI074022.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of California, Davis, CA, USA

    Philippos K Tsourkas, Somkanya C Das & Subhadip Raychaudhuri

  2. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    Wanli Liu & Susan K Pierce

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  1. Philippos K Tsourkas
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  2. Wanli Liu
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Correspondence to Subhadip Raychaudhuri.

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Tsourkas, P., Liu, W., Das, S. et al. Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement. Cell Mol Immunol 9, 62–74 (2012). https://doi.org/10.1038/cmi.2011.29

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