Elsevier

Seminars in Immunology

Volume 14, Issue 4, August 2002, Pages 259-266
Seminars in Immunology

Follicular dendritic cell-signaling molecules required for proliferation and differentiation of GC-B cells

https://doi.org/10.1016/S1044-5323(02)00058-1Get rights and content

Abstract

To study the functional role of follicular dendritic cells (FDC) in germinal center (GC)-B cell differentiation, we have established an in vitro experimental model that mimics GC-reactions in vivo. Using this culture system, we have characterized the distinct function of FDC from activated T cells. The primary function of FDC is to prevent apoptosis and support proliferation of GC-B cells, whereas activated T cells induce the differentiation of GC-B cells by providing CD40L and cytokines. Furthermore, we have identified two FDC-signaling molecules that mediate proliferation of GC-B cells in vitro and in vivo.

Introduction

The peripheral lymphoid organs where immune responses occur are well-organized microanatomic compartments that are composed mainly of T and B cell zones.1., 2. T cell zones are located in the paracortex of lymph nodes, the periarteriolar lymphoid sheath of spleens, and extra-follicular zone of tonsils. B cell areas are in the form of either resting primary follicles or activated secondary follicles. A primary B cell follicle is composed of IgM+IgD+ naive recirculating B cells and follicular dendritic cells (FDC). A secondary B cell follicle is composed of a follicular mantle in tonsil or marginal zone in spleen containing IgM+IgDlo B cells and germinal center (GC) containing IgD− centroblasts, centrocytes, and FDC.

The primary immune response occurs in 2–3 days following Ag-stimulation. During this response, IgM producing B cells differentiate in the primary follicles.3 In 5–10 days following Ag-stimulation, selected T and B cells migrate from the primary follicles to the secondary follicles to form GC. In GC, lymphocytes accumulate within the extensive processes of FDC that form a scattered network in the B cell zone. The immigrant B cells rapidly proliferate, filling the FDC reticulum, and acquiring novel phenotypes (e.g. IgD−CD38+CD44−CD77+CD10+PNA+ in human).4., 5.

Shortly after the initial period of expansion, GC polarizes to form a dark zone (proximal to the T cell zone) containing IgD−CD38+CD44−CD77+ centroblasts and a distal light zone containing IgD−CD38+CD44−CD77− centrocytes. The cell tracking studies suggest that centrocytes are derived from centroblasts.6 In addition to the surface phenotypic change, there is a dramatic change in the Ig molecules. Most of the centroblasts contain Ig with a high degree of hypermutation of IgVH regions. The hypermutation of IgVH is accompanied by the rapid proliferation of centroblasts.7 Isotype switching takes place in the transition stage from centroblasts to centrocytes.8., 9. Such VDJ rearrangement has been confirmed by the recent discovery that RAG expression was enhanced in GC.10., 11. It is unclear what drives centroblast proliferation in GC dark zone where T cells are rare.12

This review article concerns human FDC because, compared to the murine model, human FDC and B cell subpopulations have well-characterized markers and can be isolated in relatively homogeneous populations.

Section snippets

Follicular dendritic cells

The FDC has been known for many years since it was recognized as a cell that traps and retains Ag for a long time.13 However, the origin of FDC is controversial.14., 15., 16. In mouse, FDC may be related to stromal cells whereas they may be related to fibroblasts in human. Recent experiments with the lymphotoxin α (LTα) and TNF-R knock out mice suggest that FDC may not originate from bone marrow.17 When the GC-reaction occurs following Ag-stimulation, FDC proliferates in the presence of T and B

The role of chemokines

GC-reactions are initiated by the rapid proliferation of Ag-activated B cells in association with FDC. In vitro, GC-B cells undergo apoptosis in the absence of FDC since disruption of FDC-B cell clusters results in apoptosis of B cells indicating the existence of survival signals derived from FDC.27., 28. The in vitro observation was recently supported by the in vivo finding in the LTα knock out mice and SCID mice that the initial interaction between FDC and B cells is essential for

In vitro experimental model that mimics GC-reaction in vivo

The minimal cellular requirements for GC-formation are T cells, B cells, and FDC, following Ag-stimulation. The role of Ag-activated T cells has been well characterized in mice deficient for CD40,36 CD40 ligand (CD40L),37 LTα/β,38 TNF, and TNFR.39., 40. These gene-targeted mice, lack the ability to form GC and their secondary immune responses are abrogated. Although the in vivo experimental model generated by the gene-targeting method has revealed the essential requirement of these individual T

Distinct functional roles of FDC and T cells for B cell differentiation in GC

GC-B cells undergo complex interactions with FDC and T cells in the course of differentiation into memory B and plasma cells. To delineate the individual roles of FDC and T cells at each stage of GC-B cell differentiation at the clonal level and to analyze the signals involved, we adopted a unique experimental model using HK cells and a lymphoma cell line, L3055, that resembles centroblasts.54 A detailed phenotypic analysis revealed that L3055 cells represented a clonal population originating

FDC-signaling molecules (FDC-SMs)

Although FDC have been recognized for more than 40 years, the signaling molecules that mediate the FDC function have not been identified. In 1990, it was reported that the very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1) interaction is involved in the adhesion of human B cells to FDC in vitro.56 Such interaction rescued GC-B cells from apoptosis.57., 58., 59. VCAM-1 is constitutively expressed in FDC.56., 60. mAb specific to intercellular adhesion molecule-1 (ICAM-1),

The role of FDC in lymphomagenesis

GC is a specialized microenvironment where B cells undergo somatic mutation, isotype switching, and differentiation into plasma cells and memory B cells. The FDC is a stromal cell unique to primary and secondary lymphoid follicles. Somatic mutation of Ig raises the possible genetic instability for malignant transformation,65 since clonal expansion of follicular lymphoma apparently occurs subsequent to Ag selection.66., 67. The generation and blast transformation of follicular lymphoma occurs in

Concluding remarks

Based upon the experimental evidence presented earlier, we can make a reasonable hypothesis as follows. In the early stage of GC-reaction, B cell–FDC aggregates are formed at the site of inflammation triggered by foreign Ag. For this aggregation to occur, Ag-activated B cells producing LT attract FDC from the stromal cells in the adjacent tissues. The interaction between FDC chemokine CXCL13 and its ligand, CXCR5 on B cells is also required. For the survival of Ag-activated B cells, FDC provide

Acknowledgements

The authors appreciate the collaboration with Clive Wood (Genetics Institute) for cloning the genes, Johannes Gerdes (Forschungszentrum Borstel) for confocal microscopy, and generous gift of CD40L from Richard Armitage (Immunex). The former and current fellows, H.S. Kim, J.S. Choe, X. Zhang, and J. Jung have contributed to this work. The secretarial skill of Ms. V. Dellinger was invaluable in preparing this article.

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