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  • Review Article
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Dynamics of B cells in germinal centres

Nature Reviews Immunology volume 15, pages 137–148 (2015)Cite this article

Subjects

Key Points

  • The germinal centre (GC) of lymphoid organs is the microenvironment in which antigen-activated B cells diversify their immunoglobulin genes by somatic hypermutation (SHM) to generate high-affinity antibodies. A subset of the cells also undergoes class-switch recombination to generate antibodies with specialized effector functions.

  • Early in an immune response, antigen-stimulated B cells form long-lived interactions with antigen-specific T cells at the border between the B cell zone and the T cell zone or the interfollicular region to become fully activated. Antigen-activated B cells and T cells are committed to differentiate into GC B cells and T follicular helper cells (TFH cells), respectively, outside of the follicle. Migration into the follicle is facilitated by B cell lymphoma 6 (BCL-6), which is the master transcriptional regulator of GC B cells.

  • One day after TFH cells have moved into the follicle, GC precursor B cells migrate from the border between the B cell zone and the T cell zone or the interfollicular region into the centre of the follicle to form an early GC. The B cells differentiate into blasts and, over the next several days, rapidly divide and begin to fill the centre of the follicle until they have formed a mature GC that is polarized into two microenvironments known as the dark and light zones.

  • Dark zone B cells, which are GC B cells that undergo active SHM, are programmed to proliferate extremely rapidly and thereby to generate a large number of immunoglobulin mutations in a short time. Dark zone B cells differentiate into light zone B cells, at which stage mutants expressing high-affinity antibodies are selected and instructed to either recirculate to the dark zone to undergo further rounds of SHM or to differentiate into memory B cells or plasma cells.

  • Light zone B cells capture antigen via the B cell receptor (BCR) and present the processed antigen on MHC complexes to TFH cells. Higher BCR affinity is directly associated with greater antigen capture and leads to a higher density of peptide–MHC complex presentation on the surface of the B cell. This results in the greatest share of T cell help, which in turn drives selection.

  • Evidence suggests that the transcription factors MYC and the nuclear factor-κB subunit REL are essential for the maintenance of the GC reaction as they 'license' antigen-selected light zone B cells to recirculate to the dark zone. Inhibition of the terminal differentiation of GC B cells is controlled by multiple mechanisms that include both transcriptional and non-transcriptional regulation.

Abstract

Humoral immunity depends on the germinal centre (GC) reaction during which somatically mutated high-affinity memory B cells and plasma cells are generated. Recent studies have uncovered crucial cues that are required for the formation and the maintenance of GCs and for the selection of high-affinity antibody mutants. In addition, it is now clear that these events are promoted by the dynamic movements of cells within and between GCs. These findings have resolved the complexities of the GC reaction in greater detail than ever before. This Review focuses on these recent advances and discusses their implications for the establishment of humoral immunity.

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Figure 1: Initiation of the GC reaction and the formation of the mature GC in the lymph node.
Figure 2: Expression pattern and/or functional requirement of molecules during the initiation and formation of the mature GC.
Figure 3: Dynamics of the GC reaction and selection of high-affinity antibody mutants.
Figure 4: Molecular control of GC maintenance.

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Acknowledgements

The authors thank the members of the Klein laboratory and in particular N. Heise for discussions. This work was supported by National Cancer Institute (NCI) and US National Institutes of Health (NIH) grant R01-CA157660 to U.K. and a Cancer Biology Training Program fellowship (NCI and NIH grant 5T32-CA009503-26) to N.S.D..

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  1. Herbert Irving Comprehensive Cancer Center and Departments of Pathology and Cell Biology, and Microbiology and Immunology, Columbia University, 1130 St Nicholas Avenue, New York, 10032, New York, USA

    Nilushi S. De Silva & Ulf Klein

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  1. Nilushi S. De Silva
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  2. Ulf Klein
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Correspondence to Ulf Klein.

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PowerPoint slides

Glossary

Plasma cells

Non-dividing, terminally differentiated antibody-secreting cells of the B cell lineage.

Memory B cells

Antigen-experienced B cells that express high-affinity antibodies and that quickly differentiate into plasma cells in antigen-recall responses.

Somatic hypermutation

(SHM). The process by which point mutations are introduced in the heavy or light chain variable region gene segments, resulting in a change in the expressed protein, which may alter affinity or specificity for antigen.

Affinity maturation

The somatic mutation process by which B cells are selected for survival and proliferation on the basis of their increased affinity for antigen.

Follicular dendritic cells

(FDCs). Specialized non-haematopoietic stromal cells that reside in lymphoid follicles and germinal centres. These cells have long dendrites and carry intact antigens on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies.

Plasmablasts

The B cell lineage precursors of non-dividing plasma cells, which have the capacity to divide and have migratory potential.

Two-photon intravital microscopy

Laser-scanning microscopy that uses pulsed infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. The main advantage is deep tissue penetration of the infrared light owing to the low level of light scattering within the tissue.

T follicular helper cells

(TFH cells). A specialized subset of T cells that guide the selection of high-affinity germinal centre (GC) B cells within the light zone of the GC.

B cell lymphoma 6

(BCL-6). A transcriptional repressor and the master regulator of the germinal centre B cell reaction. Together with cofactors, BCL-6 represses genes involved in B cell activation, negative cell cycle regulation, the response to genotoxic stress, and differentiation into memory B cells and plasma cells.

Early GC

(Early germinal centre). The earliest GC structure that arises from the coalescence of antigen-activated B cell blasts within the network of follicular dendritic cells in the centre of the B cell follicle.

Dark zone B cells

Proliferating germinal centre B cells localized in the dark zone with rearranged variable region immunoglobulin genes that are undergoing somatic hypermutation.

Interferon-regulatory factor 4

(IRF4). A member of the interferon-regulatory factor family of transcription factors. IRF4 exerts its function through heteromerization with cofactors and can either activate or repress gene expression. IRF4 is required for germinal centre formation and for plasma cell differentiation.

Light zone B cells

The progeny of dark zone B cells. These cells need to be selected on the basis of their affinity for antigen, following interaction with immune complexes that are associated with follicular dendritic cells and their ability to elicit help from T follicular helper cells. A subset of light zone B cells undergoes class-switch recombination or differentiates into memory B cells or plasma cells.

Nuclear factor-κB

(NF-κB). Activation of the NF-κB signalling pathway via stimulation of cell-surface receptors can occur via two different routes, the canonical and the alternative pathways, and it induces the transcription of genes that are involved in cellular activation, cell growth and proliferation.

Class-switch recombination

(CSR). The process by which B cells change their immunoglobulin isotype to generate antibodies with different effector functions.

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De Silva, N., Klein, U. Dynamics of B cells in germinal centres. Nat Rev Immunol 15, 137–148 (2015). https://doi.org/10.1038/nri3804

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