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Towards a unifying model for B-cell receptor triggering

Nature Reviews Immunology (2024)Cite this article

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Abstract

Antibodies are exceptionally versatile molecules with remarkable flexibility in their binding properties. Their natural targets range from small-molecule toxins, across viruses of different sizes, to bacteria and large multicellular parasites. The molecular determinants bound by antibodies include proteins, peptides, carbohydrates, nucleic acids, lipids and even synthetic molecules that have never existed in nature. Membrane-anchored antibodies also serve as receptors on the surface of the B cells that produce them. Despite recent structural insights, there is still no unifying molecular mechanism to explain how antibody targets (antigens) trigger the activation of these B-cell receptors (BCRs). After cognate antigen encounter, somatic hypermutation and class-switch recombination allow BCR affinity maturation and immunoglobulin class-specific responses, respectively. This raises the fundamental question of how one receptor activation mechanism can accommodate a plethora of variant receptors and ligands, and how it can ensure that individual B cells remain responsive to antigen after somatic hypermutation and class switching. There is still no definite answer. Here we give a brief historical account of the different models proposed to explain BCR triggering and discuss their merit in the context of the current knowledge of the structure of BCRs, their dynamic membrane distribution, and recent biochemical and cell biological insights.

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Fig. 1: The four main models of B-cell receptor (BCR) triggering.
Fig. 2: Overview of some B-cell transmembrane receptors.
Fig. 3: Nature and diversity of antigens.

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Acknowledgements

S.E.D. is supported by the Danish National Research Foundation Centre of Excellence, CellPAT, the Center for Cellular Signal Patterns (DNRF135), the Lundbeck Foundation (R238-2016-2954), the LEO Foundation (LF-OC-22-000977), and the Independent Research Fund Denmark through a Sapere Aude Research Leader grant (9060-00038), as well as a Carlsberg Foundation Distinguished Fellowship (CF18-0446). P.T. is supported by the Wellcome Trust (grant 223196/Z/21/Z) and the UK Medical Research Council (grant MR/X009254/1).

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Authors and Affiliations

  1. Laboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Søren E. Degn

  2. Centre for Cellular Signal Patterns (CellPAT), Aarhus University, Aarhus, Denmark

    Søren E. Degn

  3. Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK

    Pavel Tolar

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S.E.D. and P.T. co-wrote the first draft, revised and finalized the manuscript.

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Glossary

Allostery

Derived from the Greek ‘allos’ meaning ‘other’ and ‘stereos’ meaning ‘solid, three-dimensional’. It describes the phenomenon whereby binding at one site causes effects transmitted through the protein to a distal site.

Antigen

Originally defined as a substance able to elicit an antibody response, but since expanded to encompass targets that elicit a T-cell response. This definition does not include haptens, which in monovalent form and in the absence of a carrier would not elicit an antibody response. However, here in the context of BCR triggering, we loosely refer to antigens as substances that may trigger antigen-specific BCR activation, whether or not this would lead to a productive downstream antibody response.

B-cell activation

The threshold activation of a B cell, driven by BCR signalling and/or auxiliary signalling pathways, such as those downstream of CD19/CD21/CD81, CD40 and cytokine receptors, and modified by inhibitory signalling from (for example) FcγRIIb, CD22, CD72 and LILRB.

BCR engagement

Binding of antigen to the BCR. This may, or may not, trigger (activate) the BCR.

BCR signalling

Describes the whole pathway triggered by antigen engagement of the BCR, and hence encompasses both BCR activation or triggering and signalling downstream of the BCR.

BCR triggering

The event(s) that translate(s) antigen binding in the Fab region(s) to a signal on the intracellular side of the membrane.

Epitope

The molecular determinant recognized by a given antibody/BCR (or T-cell receptor for peptide–MHC), often a smaller component of a given antigen.

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Degn, S.E., Tolar, P. Towards a unifying model for B-cell receptor triggering. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01073-x

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