Follicular dendritic cells and B cell chemotaxis

B cells isolated from germinal centers (GC) of immune mice 2–5 days after antigen (Ag) challenge migrate in response to chemotactic signals, whereas GC B cells isolated at other times and resting B cells do not. Since B cells are in direct contact with follicular dendritic cells (FDC) in GC we reasoned that FDC might play a role in enabling B cells to become chemotactically active. Resting B cells were co-cultured with FDC either with or without anti-μ-dextran (anti-μ-dex) as an Ag surrogate and/or recombinant interleukin (rIL)-4 as a T cell surrogate. After 3 days, the B cells were isolated and their migration to chemotactic factors contained in zymosan-activated serum assessed in microchemotaxis chambers. B cells incubated alone or with anti-μ-dex or rIL-4 showed minimal migration, which could be increased if both anti-μ-dex and rIL-4 were present. However, maximal migration was obtained when B cells were cultured with FDC, and this was not increased by addition of anti-μ-dex and/or rIL-4, indicating that the FDC signal was a primary signal and did not require pre-activation of the B cells. Checkerboard analysis using variation in concentration and location of the chemoattractant in chemotaxis chambers indicated that both chemotaxis and chemokinesis occurred. B cell migration began within 6 h of culture, peaked by 48 h and decreased thereafter. Removal of FDC or interference with FDC-B cell contact ablated or significantly decreased induction of B cell migration. Furthermore, induction did not require functional T cells. These data indicate that FDC can induce resting B cells to become responsive to chemotactic signals.     

Follicular dendritic cells in Hodgkin's disease

The distribution of follicular dendritic cells (FDCs) was studied in 66 lymph nodes affected by Hodgkin's disease (HD) from as many patients with the use of the monoclonal antibody Ki-FDC1P, which stains FDCs in paraffin sections. Two distinct FDC patterns were distinguishable in the neoplastic areas: pattern A, showing FDC networks occupied by nongerminal center cells, often expanded and disrupted; and pattern B, with FDCs rare or lacking. Pattern A, with follicle-occupying cells represented by epithelioid and lymphocytic and histiocytic (L and H) cells, was found in about 90% of the cases of nodular lymphocyte predominance type and in about half of the cases of nodular sclerosis type, with the follicle-occupying cells being lacunar cells. In the group of mixed cellularity type, approximately one-fifth of the cases exhibited pattern A and in these cases the follicle-occupying cells were Sternberg-Reed, Hodgkin's, and epithelioid cells. The presence of follicular structures, although abnormal, is a more common occurrence in HD than is appreciable with the use of conventional histologic methods.     

Follicular dendritic cells in TSE pathogenesis

The pathogenesis of transmissible spongiform encephalopathies (TSEs) often includes a replication phase in lymphoid tissues before infection spreads to the central nervous system. Recent studies show that the follicular dendritic cells of the germinal centres are critical for this replication. These cells are therefore potential targets for therapy or prophylaxis in natural TSEs, such as variant Creutzfeldt-Jakob disease.     

Follicular dendritic cells and the maintenance of IgE responses

Antigen (Ag) is retained for long periods of time in secondary lymphoid tissues in the form of immune complexes on follicular dendritic cells (FDC). Ag retained on FDC is thought to play a role in maintaining antibody (Ab) responses in vivo. A model for study of Ab production induced by retained Ag in vitro is the spontaneous Ab response. In this response, specific Ab production is induced spontaneously (no exogenous Ag needed) in cultures derived from secondary lymphoid tissues containing persisting Ag. Specific IgG is spontaneously induced and we reasoned that FDC may also play a role in the maintenance of specific IgE responses. To test this hypothesis, we monitored spontaneous antiovalbmin (OVA) IgE production in cultures of lymph node (LN) fragments from OVA-immunized mice. In addition, highly enriched preparations of OVA bearing FDC were added to OVA-specific memory cells in an attempt to stimulate OVA-specific IgE production. Months after secondary immunization, anti-OVA IgE responses were spontaneously induced when fragments from draining LN were placed into culture. Furthermore, FDC bearing OVA from draining LN induced anti-OVA IgE production when incubated with spleen cells from OVA-immune mice whereas identical cultures with FDC bearing environmental Ag from non-draining LN of the OVA immune animals did not. The anti-OVA IgE responses were elicited only in cultures containing OVA-immune memory cells indicating that specific memory cells were critical for these anti-OVA IgE responses. Removal of FDC from cultures with an FDC-specific mAb dramatically decreased anti-OVA IgE production. These studies demonstrate that FDC can induce specific memory T and B cells to produce IgE and help support the concept that FDC-associated antigen may be involved in the long-term maintenance of specific IgE responses.     

The Ig-alpha ITAM is required for efficient differentiation but not proliferation of pre-B cells

Signals from the pre-B cell receptor (pre-BCR) mediated by the cytoplasmic tails of Ig-alpha/Ig-beta are essential for developing B cells. To analyze the role of Ig-alpha ITAM and non-ITAM tyrosines in pre-BCR signaling, we reconstituted individual tyrosine mutants of Ig-alpha in src homology 2 domain-containing leukocyte protein of 65 kDa (SLP-65)/Ig-alpha double-deficient pre-B cells. We show that the Ig-alpha mutants led to comparable pre-BCR expression on the cell surface, while the pre-BCR-induced tyrosine phosphorylation was different. We further show that the reconstitution of Ig-alpha and the resulting pre-BCR expression led to enrichment of the pre-BCR-expressing cells in vitro irrespective of the introduced Ig-alpha mutation. We show that, even though the enrichment rate increased by lowering the IL-7 concentration, residual amounts of IL-7 were required for optimal enrichment. Our results indicate that surface IL-7 receptor expression is modulated by the pre-BCR, thereby increasing the IL-7 sensitivity of the respective cells. In contrast to the comparable pre-B cell proliferation, however, the Ig-alpha mutants differed in their capacity to induce calcium flux and activate efficient pre-B cell differentiation. Together, our data suggest that ITAM tyrosines and Y204 are required for efficient pre-B cell differentiation but not proliferation.     

Origin and differentiation of dendritic cells

Despite extensive, recent research on the development of dendritic cells (DCs), their origin is a controversial issue in immunology, with important implications regarding their use in cancer immunotherapy. Although, under defined experimental conditions, DCs can be generated from myeloid or lymphoid precursors, the differentiation pathways that generate DCs in vivo remain unknown largely. Indeed, experimental results suggest that the in vivo differentiation of a particular DC subpopulation could be unrelated to its possible experimental generation. Nevertheless, the analysis of DC differentiation by in vivo and in vitro experimental systems could provide important insights into the control of the physiological development of DCs and constitutes the basis of a model of common DC differentiation that we propose.     

Follicular dendritic cells as targets for intervention in transmissible spongiform encephalopathies

Transmissible spongiform encephalopathies (TSEs) are often acquired peripherally, for example by ingestion or iatrogenic exposure. After entry, TSE agents, as identified by disease-specific protein accumulation, usually accumulate on follicular dendritic cells (FDCs) in lymphoid tissues long before infection spreads to the brain. Neuroinvasion of TSE agents is significantly impaired in the absence of mature FDCs. Treatments that interfere with the integrity or function of FDCs extend survival time by blocking replication in lymphoid tissues and spread to the brain. The identification of FDCs as critical for TSE pathogenesis provides a cellular target to which therapies can be specifically directed.     

Follicular dendritic cells and presentation of antigen and costimulatory signals to B cells

Summary: This review focuses on how immunogens trapped by FDC In the form of Ag-Ab complexes productively signal B cells. In vitro, Ag-Ab complexes are poorly immunogenic but m vivo immune complexes elk ii potent recall responses. FDC trap Ag-Ab complexes and make immune complex mated bodies or "iccosomes". B cells endocytose iccosomes, the Ag is processed, and T-cell help is elicited. In vitro, addition of FDC bearing appropriate Ag-Ab complex to memory T and B cells provoke potent recall responses (IgG and IgE). FDC also provide nonspecific costimulatory signals which augment B-cell proliferation and Ab production. B cell-FDC contact is important and interference with ICAM-1-LFA-1 interactions reduces FDC-mediated costimulation. Preliminary data suggest that a costimulatory signal may be delivered via CRZL on FDC binding CR2 on B cells. FDC can also stimulate B cells to become chemotactically active and can protect lymphocytes from apoptosis. FDC also appear to be rich in that groups and may replace reducing compounds such as 2 mercaptoethanol in cultures. In short, FDC-Ag specifically signals B cells through BCR, and FDC provide B cells with iccosomal-Ag necessary for processing to elicit T i ell help. In addition, FDC provide nonspecific signals that are important to promote B-cell proliferation, maintain viability, and induce chemotactic responsiveness.     

Follicular dendritic cells and their role in HIV infection.

Recently, much attention has focussed on the role of follicular dendritic cells as a reservoir of infectious particles in retroviral, particularly HIV, infection. In this report from a recent meeting, Johannes Gerdes and Hans-Dieter Flad describe these studies in the context of a growing awareness of the morphological, phenotypic and functional heterogeneity of the cells.     

Follicular dendritic cells share a membrane-bound protein with fibroblasts

The expression of a fibroblast antigen (AS02) on a proportion of CD21+ follicular dendritic cells (FDCs) provides evidence in support of their fibroblastic reticular origin. This antigen is expressed on the membrane of tissue fibroblasts but is absent from lymphocytes, macrophages or granulocytes. The distribution of AS02 in conjunction with other FDC markers (DRC-1, RFD3, CD23, IgM, and vitronectin) showed six types of FDCs. AS02 is present in the outer layers of primary and secondary follicles, but gradually decreases and disappears in the centre of germinal centres. In contrast, there is a progressive up-regulation of the other FDC markers. AS02 is re-expressed in involuting FDCs. Intermediate forms from fibroblastic to dendritic appearance are also apparent and occasionally FDC processes contain collagen type I and IV fibres, a characteristic feature of fibroblasts. In pathological follicles the normal differentiation pattern is disrupted, with persistence of the fibroblast marker, possibly due to altered interactions between FDCs and disrupted lymphocytic patterns. These findings provide new evidence for a local differentiation pathway of fibroblasts to mature FDCs.     

T cell priming by dendritic cells: thresholds for proliferation,differentiation and death and intraclonal functional diversification

The variables that influence priming of human naive CD4+ T cells by dendritic cells (DC) were dissected in vitro by analyzing the response to the bacterial superantigen toxicshock syndrome toxin or to alloantigens. We show that under conditions that force DC-T cell interactions a single DC can prime up to 20 naive T cells. Moreover, the strength of antigenic stimulation, as determined by DC numbers, antigen dose, TCR avidity and duration of DC-T cell interactions, drives the progressive differentiation of proliferating T cells from a non-effector CCR7+ stage, to an effector CCR7- stage and, eventually, to cell death. We also show that the proliferating CCR7+ and CCR7- populations share clonotypic sequences, demonstrating that the two cell fates can be generated within a single clone. Taken together these results indicate that the strength of antigenic stimulation regulates T cell progression through thresholds of proliferation, differentiation and death. However, the random nature of DC-T cell encounters introduces a critical stochastic element in T cell stimulation, which leads to the generation of cells endowed with distinct homing potentials and effector functions within a given T cell clone.     

Follicular dendritic cells in extranodal non-Hodgkin lymphomas of MALT and non-MALT type

Extranodal lymphomas of the thyroid (n=19), kidney (n=15) and testis (n=30) were investigated histologically and immunohistochemically for follicular dendritic cell pattern using the monoclonal antibody Ki-FDC1P. This recognizes follicular dendritic cells in paraffin sections. Follicular dendritic cells were most predominant in lymphomas of the thyroid. These thyroid lymphomas showed the morphological features of mucosa-associated lymphoid tissue (MALT) type lymphomas in 18 of 19 cases and were classified as high-grade malignant lymphoma of MALT type with evidence of a low-grade malignant component (n=18). Ten of these cases contained destroyed reactive follicles of follicular dendritic cells. In 6 of these 10 cases follicular dendritic cells occurred in a pattern of tumour-associated abortive follicle type. The remaining lymphoma of the thyroid was an immunoblastic lymphoma of B-cell type showing no detectable follicular dendritic cells. In extranodal lymphomas of non-MALT type follicular dendritic cells occurred in only two cases where immunocytoma involved the kidney. Malignant lymphomas of the kidney (chronic lymphocytic leukaemia,n=2; immunocytoma,n=4; centroblastic lymphoma,n=9) and of the testis (immunocytoma,n=2; centroblastic lymphoma,n=27; immunoblastic lymphoma of B-cell type,n=1) revealed no characteristics of MALT type lymphoma, cytologically or with respect to follicular dendritic cells. Classical lymphoepithelial lesions formed by centrocyte-like cells, a hallmark of MALT, occurred exclusively in thyroid lymphomas of MALT type. Although occurrence of classical lymphoepithelial lesions formed by centrocyte-like cells was limited to thyroid lymphomas of MALT type, a growth pattern of lymphoid blasts, with formation of lesions mimicking lymphoepithelial lesions superficially, was found in 6 of 27 testicular centroblastic lymphomas. Follicular dendritic cells in non-Hodgkin's lymphomas of MALT type show distinct follicular patterns not found in other extranodal lymphomas such as those found in the kidney and testis.     

Follicular dendritic cells: beyond the necessity of T-cell help.

Follicular dendritic cells (FDCs) are potent accessory cells for B cells, but the molecular basis of their activity is not understood. Several important molecules involved in FDC-B-cell interactions are indicated by blocking the ligands and receptors on FDCs and/or B cells. The engagement of CD21 in the B-cell coreceptor complex by complement-derived CD21 ligand on FDCs delivers a crucial signal that dramatically augments the stimulation delivered by the binding of antigen to the B-cell receptor (BCR). The engagement of Fc gamma receptor IIB (FcgammaRIIB) by the Ig crystallizable fragment (Fc) in antigen-antibody complexes held on FDCs decreases the activation of immunoreceptor tyrosine-based inhibition motifs (ITIMs), mediated by the crosslinking of BCR and FcgammaRIIB. Thus, FDCs minimize a negative B-cell signal. In short, these ligand-receptor interactions help to signal to B cells and meet a requirement for B-cell stimulation that goes beyond the necessity of T-cell help.