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The who, how and where of antigen presentation to B cells

Nature Reviews Immunology volume 9, pages 15–27 (2009)Cite this article

Key Points

  • Recognition of specific antigen through the B-cell receptor (BCR) stimulates the activation of B cells, which ultimately results in the production of high-affinity antibodies and the provision of long-lasting memory responses to secondary encounters with the same antigen. Although B cells can recognize and respond to antigen in various forms, the current view is that membrane-bound antigens are the predominant forms that initiate B-cell activation in vivo.

  • Secondary lymphoid organs (SLOs), such as the lymph nodes and spleen, are specialized to maximize the probability of lymphocytes encountering their specific cognate antigen, which is provided by the lymphatic fluid and blood, respectively.

  • Recent high-resolution imaging studies have provided new insights into the spatio-temporal dynamics of B cells in lymph nodes in vivo, particularly in identifying numerous sites and mechanisms for the presentation of antigen to B cells.

  • In SLOs, small soluble antigens (such as low-molecular-mass toxins) can diffuse through small pores in the subcapsular sinus and activate follicular B cells. However, as the subcapsular sinus and conduit network limit the free diffusion of larger antigens (such as immune complexes, particulates, bacteria or viruses), their access to follicular B cells is restricted.

  • Larger antigens, including antigen in immune complexes, can be presented to B cells on the surface of cells, such as dendritic cells, macrophages and follicular dendritic cells (FDCs). These presenting cells might use a combination of lectin receptors, complement receptors and/or Fc receptors, and might potentially internalize antigen into neutral non-degradative endosomes prior to their recycling to the cell surface.

  • In addition to their role in the recognition of specific antigen through the BCR, B cells can transport antigen to FDCs, as illustrated by splenic marginal-zone B cells. These cells shuttle from the marginal zone to the follicle and can therefore transport antigen independently of the BCR, through its binding to complement receptors.

Abstract

A functional immune system depends on the appropriate activation of lymphocytes following antigen encounter. In this Review, we summarize studies that have used high-resolution imaging approaches to visualize antigen presentation to B cells in secondary lymphoid organs. These studies illustrate that encounters of B cells with antigen in these organs can be facilitated by diffusion of the antigen or by the presentation of antigen by macrophages, dendritic cells and follicular dendritic cells. We describe cell-surface molecules that might be important in mediating antigen presentation to B cells and also highlight the key role of B cells themselves in antigen transport. Data obtained from the studies discussed here highlight the predominance, importance and variety of the cell-mediated processes that are involved in presenting antigen to B cells in vivo.

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Figure 1: The organization of secondary lymphoid organs.
Figure 2: B-cell encounters with specific antigen in the lymph node.
Figure 3: B cells mediate antigen transport to follicular dendritic cells using complement receptors.

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Acknowledgements

We thank members of the Lymphocyte Interaction Laboratory for critical reading of the manuscript, particularly P. Barral for providing multiphoton microscopy images.

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  1. Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Facundo D. Batista & Naomi E. Harwood

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  1. Facundo D. Batista
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Correspondence to Facundo D. Batista.

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Glossary

Total internal reflection fluorescence microscopy

A microscopy method that allows for the identification of fluorescence within 100–200 nm of the interface between cells and their substrate (for example, lipid bilayers or glass coverslips), thereby providing a high lateral and axial resolution at the cell–substrate interface and the ability to observe nanoscale movement of signalling molecules during cellular activation.

Intravital multiphoton microscopy

A microscopy method that combines the advanced optical techniques of laser-scanning confocal microscopy with long-wavelength multiphoton fluorescence excitation to capture high-resolution, three-dimensional images of living cells and/or tissues that have been labelled with fluorophores. It provides a greater tissue imaging depth (up to 350 μm depending on the tissue) and less photobleaching and phototoxicity than conventional imaging methods.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B-cell follicles during an immune response. It is the main site of B-cell maturation, during which memory B cells and plasma cells that produce high-affinity antibody are generated.

Plasma cell

A non-dividing, terminally differentiated, antibody-secreting cell of the B-cell lineage.

Memory B cell

An antigen-experienced B cell that expresses high-affinity antibodies and quickly differentiates into a plasma cell during antigen-recall responses.

Alymphoplastic (aly/aly) mice

Mice that are characterized by the absence of lymph nodes and Peyer's patches. Alymphoplasia is caused by a spontaneous mutation in the gene that encodes nuclear-factor-κB-inducing kinase.

T-cell-dependent antigen

A protein antigen that needs to be recognized by T helper cells (in the context of MHC molecules) and requires cooperation between these antigen-specific T cells and B cells for a specific antibody response to be generated.

Affinity maturation

A process whereby the mutation of antibody variable-region genes followed by selection for higher-affinity variants in the germinal centre leads to an increase in average antibody affinity for an antigen as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with free antibody to capture decreasing amounts of antigen.

μmt−/− mice

A strain of mutant mice that carry a stop codon in the first membrane exon of the μ-chain constant region. They lack IgM+ B cells, and B-cell development is arrested before the differentiation stage at which IgD can be expressed.

T-cell-independent antigen

An antigen that directly activates B cells.

Metallophilic macrophage

A macrophage that is located at the border of the white pulp and the marginal zone of the spleen. These macrophages express high levels of CD169 but lack expression of the mannose receptor.

Clodronate-loaded liposome

A liposome that contains the drug dichloromethylene diphosphonate. These liposomes are ingested by macrophages, resulting in cell death.

Endosome

A vacuolar compartment where large molecules are transported after being engulfed by endocytosis. The endosome can then mature and fuse with lysosomes, which contain degrading enzymes. Endosomal and phagosomal pathways are interconnected.

B-1 cell

An IgMhiIgDlowMAC1+B220lowCD23− cell that is dominant in the peritoneal and pleural cavities. B-1-precursor cells develop in the fetal liver and omentum, and in adult mice the size of the B-1-cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.

Somatic hypermutation

(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, SHM leads to affinity maturation of B cells in germinal centres.

Cobra venom factor

The complement-activating glycoprotein component of cobra venom, which is functionally analogous to the mammalian complement factor C3b.

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Batista, F., Harwood, N. The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9, 15–27 (2009). https://doi.org/10.1038/nri2454

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