Antigen affinity discrimination is an intrinsic function of the B cell receptor

Antibody affinity maturation, a hallmark of adaptive immune responses, results from the selection of B cells expressing somatically hypermutated B cell receptors (BCRs) with increased affinity for antigens. Despite the central role of affinity maturation in antibody responses, the molecular mechanisms by which the increased affinity of a B cell for antigen is translated into a selective advantage for that B cell in immune responses is incompletely understood. We use high resolution live-cell imaging to provide evidence that the earliest BCR-intrinsic events that follow within seconds of BCR–antigen binding are highly sensitive to the affinity of the BCR for antigen. High affinity BCRs readily form oligomers and the resulting microclusters grow rapidly, resulting in enhanced recruitment of Syk kinase and calcium fluxes. Thus, B cells are able to read the affinity of antigen by BCR-intrinsic mechanisms during the earliest phases of BCR clustering, leading to the initiation of B cell responses.

• Publication year

  2010

• Venue

  Journal of Experimental Medicine

• Publication date

  2010-05-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20092123PMID 20404102PMCID 2867278
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2009influential reference
• The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens.

  2009influential reference
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  2009cited by this paper
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  2008cited by this paper
• Membrane heterogeneities in the formation of B cell receptor–Lyn kinase microclusters and the immune synapse

  2008influential reference
• Single-molecule imaging of fluorescent proteins.

  2008cited by this paper
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  2008cited by this paper
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  2008cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2006cited by this paper
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  2006cited by this paper
• Fluorescence resonance energy transfer in living cells reveals dynamic membrane changes in the initiation of B cell signaling.

  2006influential reference
• Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation

  2006cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005influential reference
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  2002influential reference
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  2002influential reference
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  2001influential reference
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  1999cited by this paper
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• Evidence for a preformed transducer complex organized by the B cell antigen receptor.

  1996influential reference
• Methods of Digital Video Microscopy for Colloidal Studies

  1996cited by this paper
• Affinity maturation of antibodies.

  1991cited by this paper
• Kinetic maturation of an immune response

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• Antibody engineering for the analysis of affinity maturation of an anti‐hapten response.

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• Molecular events during maturation of the immune response to oxazolone

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