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Intrinsic differences in the initiation of B cell receptor signaling favor responses of human IgG(+) memory B cells over IgM(+) naive B cells.

Abstract

The acquisition of long-lived memory B cells (MBCs) is critical for the defense against many infectious diseases. Despite their importance, little is known about how Ags trigger human MBCs, even though our understanding of the molecular basis of Ag activation of B cells in model systems has advanced considerably. In this study, we use quantitative, high-resolution, live-cell imaging at the single-cell and single-molecule levels to describe the earliest Ag-driven events in human isotype-switched, IgG-expressing MBCs and compare them with those in IgM-expressing naive B cells. We show that human MBCs are more robust than naive B cells at each step in the initiation of BCR signaling, including interrogation of Ag-containing membranes, formation of submicroscopic BCR oligomers, and recruitment and activation of signaling-associated kinases. Despite their robust response to Ag, MBCs remain highly sensitive to FcγRIIB-mediated inhibition. We also demonstrate that in the absence of Ag, a portion of MBC receptors spontaneously oligomerized, and phosphorylated kinases accumulated at the membrane and speculate that heightened constitutive signaling may play a role in maintaining MBC longevity. Using high-resolution imaging, we have provided a description of the earliest events in the Ag activation of MBCs and evidence for acquired cell-intrinsic differences in the initiation of BCR signaling in human naive and MBCs.

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    • Authors

    Davey AM, Pierce SK

    Institution

    Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.

    Source

    Journal of immunology (Baltimore, Md. : 1950) 188:7 2012 Apr 1 pg 3332-41

    MeSH

    Antibodies, Anti-Idiotypic
    Antigens, CD27
    B-Lymphocyte Subsets
    Biotinylation
    Fluorescent Dyes
    Humans
    Immunoglobulin Fab Fragments
    Immunoglobulin G
    Immunoglobulin M
    Immunoglobulin kappa-Chains
    Immunologic Memory
    Intracellular Signaling Peptides and Proteins
    Lipid Bilayers
    Lymphocyte Activation
    Microscopy, Fluorescence
    Microscopy, Video
    Phosphorylation
    Protein Kinases
    Protein Processing, Post-Translational
    Protein-Tyrosine Kinases
    Receptors, Antigen, B-Cell
    Receptors, IgG
    Single-Cell Analysis
    Time-Lapse Imaging

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Intramural

    Language

    eng

    PubMed ID

    22379037