J. Pathol. 189: 147–149 (1999)

EDITORIAL

FOLLICULAR DENDRITIC CELLS AND T CELLS:NURSES AND EXECUTIONERS IN THE GERMINAL

CENTRE REACTION

*

Research Center Borstel, Division of Molecular Immunology, Parkallee 22, D-23845 Borstel, Germany

SUMMARY

The humoral immune response constitutes an efficient system to protect the organism against diseases caused by invading pathogens.To guarantee a highly efficient defence, the humoral immune system has to be tightly regulated. Two cell subsets in particular, T cellsand follicular dendritic cells (FDCs), contribute to the success of these regulation processes. Whereas the particular role of T cells is theelimination of autoreactive clones, the main role of FDCs is to present unprocessed antigen and check B-cell clones for higher affinity.B-cell clones unsuited for improved humoral immune response will be specifically killed. Involvement of Fas-mediated apoptosis mightbe an additional tool not only in T-cell-mediated regulation, but also in FDC–B cell interaction in the germinal centre. Copyright ? 1999John Wiley & Sons, Ltd.

KEY WORDS—germinal centre reaction; selection; follicular dendritic cells; Fas-mediated apoptosis

The humoral immune response ensures the efficientdefence against invading pathogens. All dysregulationsendanger the integrity of the organism, so that cautiousregulation of all factors involved in the humoral immuneresponse is a prerequisite. Dysregulations concerning theeffector cells could lead to malignant tumours such asHodgkin’s and non-Hodgkin’s lymphoma precedinglethally disarranged B-cell development.1,2 Dysregula-tions with regard to the effector molecules expressed byB cells, the antibodies, could lead to immunodeficiencies,as seen in acquired immunodeficiency syndrome (AIDS)or hyper-IgM syndrome. Patients suffering fromhyper-IgM syndrome or AIDS completely lack affinitymatured antibody responses, leading to an increasedsusceptibility for infections with the known lethalconsequences.3,4

Specific and high affinity antibodies (immunoglobu-lins), directed at the invading pathogen, are obligatoryfor a successful humoral immune response. Pathogenswill be tagged by soluble immunoglobulins, whichleads to activation of the complement system induc-ing complement-mediated lysis of the pathogen andactivates phagocytes to eliminate pathogens directlyby endocytosis. Binding antigens by surface-boundimmunoglobulin (sIg) will activate the B cells and inducea complex maturation process resulting in an increasedefficiency of the humoral defence.

What happens during B-cell maturation? B cellsmigrate into the secondary lymphoid organs, where theyfind their specific antigen. The bound antigen will be

CCC 0022–3417/99/110147–03$17.50Copyright ? 1999 John Wiley & Sons, Ltd.

degraded and presented together with MHC on the cellsurface. While the activated B cells pass the T-cell area,these presented antigens will be recognized specificallyby T lymphocytes and T-cell help is contributed bystimulating CD40 and secretion of interleukin-4 (IL-4).Reaching the B-cell area, the activated B cells colonizeprimary follicles, consisting of resting B cells and follicu-lar dendritic cells (FDCs). Immigration of activated Bcells into the primary follicle causes the generation of agerminal centre, with an organized network of FDCsand separation of dark and light zones constituting sitesof different stages of B-cell development. In the germinalcentre the B cells undergo proliferation, somatic hyper-mutation, and selection, aiming at the generation ofhigh-affinity B-cell clones producing specific immuno-globulins with improved affinity. This so-called germinalcentre reaction results in the generation of high affinitymatured plasma and memory cells.5,6

To exclude the expansion of autoreactive and lowaffinity clones, the activated B cell has to pass a two-stepselection process. During the initial selection process, theprocessed peptide presented by the activated B cellhas to be recognized by antigen-specific T cells. Thisso-called linked recognition ensures the selection ofB-cell clones recognizing foreign but not self-antigens.In addition, this interaction activates the T cell to pro-vide supplementary signals required for further B-celldevelopment.7

Processing of antigens is obligatory to gain T-cellsupport, but for efficient elimination of pathogens,immunoglobulins have to recognize unprocessed struc-tures directly. To select for high-affinity antigen bind-ing, including specific recognition of conformationalepitopes, the matured B cells have to be scrutinized for

*Correspondence to: Professor Dr Johannes Gerdes, ResearchCenter Borstel, Division of Molecular Immunology, Parkallee 22,D-23845 Borstel, Germany.

Received 16 February 1999Revised 23 February 1999

Accepted 27 May 1999

148 EDITORIAL

binding native antigen. FDCs trap immunocomplexedantigens on their surface and the matured sIg has tocompete with the antibodies present in these immuno-complexes for antigen binding. During this second selec-tion process, rescue and induction of differentiation ofthe matured B cell depend on successful stimulation oftheir matured sIg. To sustain this stimulation, FDCsexpress CD23, which acts as a cofactor in sIg triggeringby binding to CR2 and/or CD19 on the activated B celland promotes the differentiation into plasma cells.8 Inaddition, FDCs secrete IL-7, which has been shown topromote B-cell survival in vitro.9,10

Because of the complex objective, the course of thegerminal centre reaction has to be tightly regulated.Explicit support of B-cell clones expressing antigenreceptors with improved affinity is concurrent withelimination of B-cell clones with autoreactive or low-affinity antigen receptors. T cells and FDCs are involvedin elimination, but also promote survival and differen-tiation of B-cell clones. An expression of this conflictingrole is the interplay between induction of and rescuefrom apoptosis. Activated B cells are shown to expressseveral factors involved in the induction and course ofapoptosis, such as Fas, c-fos, c-myc, p53, and bax,11,12

so that apoptotic cell death would be the natural fate ofall activated B cells. The only possibility of survivingand overcoming the induction of apoptosis is by ex-pression of opposing survival factors. In a nurse-likefashion, FDCs and T cells support the survival ofpositively selected B cells. Interaction of T and B cellsduring the linked recognition process and FDC–B cellinteraction in the germinal centre induce the expressionof members of the bcl-2 family, which on their sideinhibit apoptosis.13,14

Besides their role as nurses, FDCs and T cells alsoappear to act as executioners, eliminating negativelyselected B-cell clones by induction of apoptosis. A majorsystem inducing cell death is Fas/FasL-mediated apop-tosis.15 Fas is expressed constitutively on germinalcentre B cells. The expression of Fas is up-regulatedafter stimulation of CD4016 and down-regulated afterstimulation of surface antigen receptors in the germinalcentre.17 Fas ligation in vitro induces apoptosis in CD40-activated tonsillar B cells, indicating the involvementof Fas-mediated apoptosis in both selection processesduring B-cell maturation.16 The missing link to verify apossible role of Fas/FasL interaction in the germinalcentre reaction was the inability to localize FasL ongerminal centre cells.

In the article presented by Verbeke et al.18 in thisissue, the authors investigated the expression of FasL inhuman peripheral lymphoid organs. By western blotanalysis, FasL proteins of different molecular weightswere detected, probably representing the membrane-bound as well as the soluble isoform of FasL. Anadditional result of this work was that by immunohisto-chemistry, the authors succeeded in locating FasLexpression in the light zone of the germinal centres.Because of the distinct appearance in a meshwork-likepattern and a possible co-localization with CNA.42 andCD23, the authors speculate about an association ofFasL with FDCs.

Copyright ? 1999 John Wiley & Sons, Ltd.

The expression of FasL on FDCs sustains the hypoth-esis of Fas/FasL as an additional mechanism for specificregulation of affinity maturation in the germinal centre.The likelihood of Fas as a tool in regulation of thegerminal centre reaction is further supported by the factthat besides Fas, other members of the TNF superfamilyand their ligands have also been shown to be involvedin regulatory processes leading to germinal centre for-mation and high-affinity humoral immune response.Experimentally induced genetic deficiencies in TNFsuperfamily-related genes in the mouse have been shownto lead to shortcomings in FDC organization andGC formation. LTalpha, LTbeta, TNF or CD40L,TNFRI, and LTbetaR deficiencies result in theabsence of GCs with altered affinity maturation, indicat-ing an involvement of these proteins in regulatoryprocesses.19–25

The regulation of FDC organization and GC for-mation with affinity matured immune responses appearsto be strongly influenced by members of the TNFsuperfamily and their ligands. Restoration experimentsdemonstrate the necessity of the expression of TNFsuperfamily-related genes, both in bone marrow-derivedB lymphocytes and in non-bone marrow-derivedgerminal centre cells such as FDCs, for successful GCformation and B-cell maturation.26–28

The interplay between induced cell death and sup-ported differentiation during the germinal centre reac-tion seems to be strongly influenced by membersof the TNF superfamily and their ligands, supportingFDCs and T cells in their biased roles as nurses andexecutioners.

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J. Pathol. 189: 147–149 (1999)