Antigen footprint governs activation of the B cell receptor

Alexey Ferapontov, Marjan Omer, Isabelle Baudrexel, Jesper Sejrup Nielsen, Daniel Miotto Dupont, Kristian Juul-Madsen, Philipp Steen, Alexandra S. Eklund, Steffen Thiel, Thomas Vorup-Jensen, Ralf Jungmann, Jørgen Kjems and Søren Egedal Degn ()
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Alexey Ferapontov: Aarhus University
Marjan Omer: Aarhus University
Isabelle Baudrexel: Aarhus University
Jesper Sejrup Nielsen: Aarhus University
Daniel Miotto Dupont: Aarhus University
Kristian Juul-Madsen: Aarhus University
Philipp Steen: Max Planck Institute of Biochemistry
Alexandra S. Eklund: Aarhus University
Steffen Thiel: Aarhus University
Thomas Vorup-Jensen: Aarhus University
Ralf Jungmann: Aarhus University
Jørgen Kjems: Aarhus University
Søren Egedal Degn: Aarhus University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Antigen binding by B cell receptors (BCR) on cognate B cells elicits a response that eventually leads to production of antibodies. However, it is unclear what the distribution of BCRs is on the naïve B cell and how antigen binding triggers the first step in BCR signaling. Using DNA-PAINT super-resolution microscopy, we find that most BCRs are present as monomers, dimers, or loosely associated clusters on resting B cells, with a nearest-neighbor inter-Fab distance of 20–30 nm. We leverage a Holliday junction nanoscaffold to engineer monodisperse model antigens with precision-controlled affinity and valency, and find that the antigen exerts agonistic effects on the BCR as a function of increasing affinity and avidity. Monovalent macromolecular antigens can activate the BCR at high concentrations, whereas micromolecular antigens cannot, demonstrating that antigen binding does not directly drive activation. Based on this, we propose a BCR activation model determined by the antigen footprint.

Date: 2023
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DOI: 10.1038/s41467-023-36672-0

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