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  • Review Article
  • Published:

Follicular dendritic cells: dynamic antigen libraries

Nature Reviews Immunology volume 14, pages 495–504 (2014)Cite this article

Subjects

Key Points

  • Follicular dendritic cells (FDCs) are non-haematopoietic cells that are of stromal origin. They are integrated into the continuous stromal network within lymphoid organs.

  • FDCs can acquire antigen through multiple pathways; small antigens flow through conduits directly to the FDCs, whereas larger antigens are transported to FDCs by B cells in a complement-dependent manner.

  • Acquired antigens are retained in their native form by FDCs for long periods of time. The antigens are protected from damage by storage in non-degradative endosomal vesicles that periodically cycle to the cell surface.

  • Retention and concentration of antigen by FDCs is important for an efficient germinal centre reaction, especially under conditions of limited antigen availability.

  • Toll-like receptor signalling in FDCs may affect their functions, such as their retention and cycling of antigen.

  • HIV might hijack the cycling mechanism of FDCs in order to evade the immune system, which makes FDCs unique as a non-infected cell that is also an infectious reservoir of the virus.

Abstract

Follicular dendritic cells (FDCs) are essential for high-affinity antibody production and for the development of B cell memory. Historically, FDCs have been characterized as 'accessory' cells that passively support germinal centre (GC) responses. However, recent observations suggest that FDCs actively shape humoral immunity. In this Review, we discuss recent findings concerning the antigen acquisition and retention functions of FDCs, and relevant implications for protective immunity. Furthermore, we describe the roles of FDCs within GCs in secondary lymphoid organs and discuss FDC development within this dynamic environment. Finally, we discuss how a better understanding of FDCs could facilitate the design of next-generation vaccines.

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Figure 1: Basic overview of lymph node architecture and FDC morphology.
Figure 2: Timeline of major discoveries in the FDC field*
Figure 3: The germinal centre reaction.
Figure 4: Antigen acquisition by FDCs.
Figure 5: FDCs function as HIV reservoirs.

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Acknowledgements

The authors thank all members of the M.C.C. laboratory for suggestions and valuable insights. They acknowledge S. F. Gonzalez for the use of his electron microscopy image and T. Vorup-Jensen for valuable insights into the CR3–C3d–CR2 complex. M.C.C. is supported by the US National Institutes of Health (RO1 AI039246 and R37 AI054636).

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Authors and Affiliations

  1. Children's Hospital Boston and Department of Pediatrics, The Program in Cellular and Molecular Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Balthasar A. Heesters, Riley C. Myers & Michael C. Carroll

  2. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Balthasar A. Heesters

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  1. Balthasar A. Heesters
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Correspondence to Michael C. Carroll.

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Glossary

Germinal centre

(GC). A structure that develops in the B cell follicles of a lymph node after exposure to, or immunization with, a T cell-dependent antigen. GCs facilitate the development of long-lived plasma cells — that produce high-affinity antibodies — and memory B cells, and they can be divided into a dark zone and a follicular dendritic cell (FDC)-rich light zone.

Somatic hypermutation

(SHM). B cells diversify their B cell receptor by mutating the variable regions of immunoglobulin genes, thus creating a more specific repertoire. This occurs within the germinal centre and requires follicular dendritic cell-mediated help.

Affinity maturation

The process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response. Follicular dendritic cells repeatedly present the same antigens to B cells and this leads to the production of antibodies with successively greater affinities.

Immune complexes

Structures that are formed by the binding of an antibody to a soluble antigen and subsequent complement deposition.

Mural cells

These include vascular smooth muscle cells and pericytes, which are contractile cells that wrap around the endothelial cells of venules and capillaries. Such cells are responsive to vascular endothelial growth factor (VEGF).

Lymphoid tissue organizer cells

These include mesenchymal or endothelial stromal cells that are required for the formation of lymphoid tissues and are seeded throughout the body. Only when induced by retinoid acid do they secrete CXC-chemokine ligand 13 (CXCL13), which initiates cell clustering.

Lymphoid tissue inducer cells

(LTi cells). These cells are required for the development of conventional lymph nodes and isolated lymphoid follicles but not the spleen. They are attracted by CXC-chemokine ligand 13, mature and then interact with stromal cells through lymphotoxin α1β2, which leads to further lymph node growth.

Conduit

A filamentous collagen bundle that allows for the transport of low molecular weight (70 kDa, ∼5.5 nm) particles from the subcapsular sinus into the B cell follicle and the medulla.

SCS macrophages

Macrophages that line the subcapsular sinus (SCS) of the lymph node and sample antigens. They are capable of transporting antigens from their apical to their basolateral surface, which allows for antigen transport into the B cell follicle.

Non-degradative endosomal compartments

Vesicular bodies that do not proceed to the late endosomal compartment but are instead cycled back to the surface without a drop in pH. The most well-known function of these compartments is in the recycling of the transferrin receptor.

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Heesters, B., Myers, R. & Carroll, M. Follicular dendritic cells: dynamic antigen libraries. Nat Rev Immunol 14, 495–504 (2014). https://doi.org/10.1038/nri3689

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