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; Søren Egedal Degn

doi:10.1038/s41467-023-36672-0

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, Søren Egedal Degn^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

6 Citations (Scopus)

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.

Original language	English
Article number	976
Journal	Nature Communications
Volume	14
Issue	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-36672-0
Publication status	Published - Dec 2023

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title = "Antigen footprint governs activation of the B cell receptor",

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 na{\"i}ve 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.",

author = "Alexey Ferapontov and Marjan Omer and Isabelle Baudrexel and Nielsen, {Jesper Sejrup} and Dupont, {Daniel Miotto} and Kristian Juul-Madsen and Philipp Steen and Eklund, {Alexandra S.} and Steffen Thiel and Thomas Vorup-Jensen and Ralf Jungmann and J{\o}rgen Kjems and Degn, {S{\o}ren Egedal}",

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year = "2023",

month = dec,

doi = "10.1038/s41467-023-36672-0",

language = "English",

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AU - Ferapontov, Alexey

AU - Omer, Marjan

AU - Baudrexel, Isabelle

AU - Nielsen, Jesper Sejrup

AU - Dupont, Daniel Miotto

AU - Juul-Madsen, Kristian

AU - Steen, Philipp

AU - Eklund, Alexandra S.

AU - Thiel, Steffen

AU - Vorup-Jensen, Thomas

AU - Jungmann, Ralf

AU - Kjems, Jørgen

AU - Degn, Søren Egedal

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

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Antigen footprint governs activation of the B cell receptor

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