Edited by: Christopher G. Mueller, Centre National de la Recherche Scientifique, France
Reviewed by: Kang Liu, Columbia University, USA; Marie Kosco-Vilbois, NovImmune SA, Switzerland
*Correspondence: Mohey Eldin M. El Shikh, Centre for Experimental Medicine and Rheumatology, 2nd floor, John Vane Science Centre, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. e-mail:
This article was submitted to Frontiers in Antigen Presenting Cell Biology, a specialty of Frontiers in Immunology.
This is an open-access article distributed under the terms of the
Follicular dendritic cells (FDCs) are unique immune cells that contribute to the regulation of humoral immune responses. These cells are located in the B-cell follicles of secondary lymphoid tissues where they trap and retain antigens (Ags) in the form of highly immunogenic immune complexes (ICs) consisting of Ag plus specific antibody (Ab) and/or complement proteins. FDCs multimerize Ags and present them polyvalently to B-cells in periodically arranged arrays that extensively crosslink the B-cell receptors for Ag (BCRs). FDC-FcγRIIB mediates IC periodicity, and FDC-Ag presentation combined with other soluble and membrane bound signals contributed by FDCs, like FDC-BAFF, -IL-6, and -C4bBP, are essential for the induction of the germinal center (GC) reaction, the maintenance of serological memory, and the remarkable ability of FDC-Ags to induce specific Ab responses in the absence of cognate T-cell help. On the other hand, FDCs play a negative role in several disease conditions including chronic inflammatory diseases, autoimmune diseases, HIV/AIDS, prion diseases, and follicular lymphomas. Compared to other accessory immune cells, FDCs have received little attention, and their functions have not been fully elucidated. This review gives an overview of FDC structure, and recapitulates our current knowledge on the immunoregulatory functions of FDCs in health and disease. A better understanding of FDCs should permit better regulation of Ab responses to suit the therapeutic manipulation of regulated and dysregulated immune responses.
In 1968, Andras K. Szakal and Michael G. Hanna, Jr. (Szakal and Hanna, Jr.,
The characteristics that distinguish FDCs from other cells of the immune system are their ability to retain antigen (Ag)-antibody (Ab)-complement complexes (i.e., immune complexes, ICs) long-term on their surfaces and their follicular localization. Unlike other immune accessory cells, FDCs lack phagocytic activity, lysosomes, lysozyme, and Birbeck granules. FDCs localized to the follicles of secondary lymphoid tissues form interactive networks or reticula of non-mobile Ag-bearing cells. Immobile FDCs in these FDC-reticula engage the mobile B and T-cells and other mobile cells trafficking through the follicles (Szakal et al.,
FDCs in germinal center (GC) light zones of B-cell follicles (Figures
FDCs multimerize intact monomeric proteins and present Ags in ICs to B-cells with regular periodicity
Engagement of BCRs by free Ag can induce B-cell activation; however, an immunogen is converted into ICs as soon as Ab is produced in a primary response, and instantaneously in recall responses by Ab persisting from previous immunizations. IgG-ICs coligate BCR with FcγRIIB and inhibit B-cell activation via the tyrosine-based inhibitory motif (ITIM). In contrast, IgG-ICs trapped by FDC-FcγRIIB do not engage B-cell-FcγRIIB and consequently ITIM-mediated signaling is minimized (Tew et al.,
Not only FDCs provide the necessary Ag for B-cell stimulation but they orchestrate the removal of self-Ags released from apoptotic cells in the GC environment. FDCs secrete the bridging factor Mfge8, which crosslinks apoptotic cells in the GCs and the phagocytic “tingible body macrophages” (TBMs). This promotes selective debris removal and engulfment of dead cells. Mice lacking LT or LT receptors, which are devoid of FDCs, or lacking the bridging protein Mfge8 itself, are significantly susceptible to autoimmunity suggesting the role of FDCs in protection against autoimmunity by expediting the removal of potentially self-reactive debris from the GCs (Kranich et al.,
Beyond their immunoregulatory functions, FDCs are critically involved in the pathogenesis of several diseases. FDCs are important HIV reservoir where FDC-trapped HIV persists for long periods and can reignite infection and perpetuate the disease (Smith et al.,
In addition, several lines of evidences support the critical role of FDCs in the pathogenesis of autoimmune diseases. Chronic inflammatory autoimmune disorders frequently display follicles with IC-bearing FDCs, autoreactive GCs, and ongoing affinity maturation (Aloisi and Pujol-Borrell,
In this review we address the current knowledge about the structure and function of FDCs and their role in immune regulation in health and disease.
Light and electron microscopy studies of FDCs have revealed structural details that help clarify FDC functions. FDCs are slightly larger than lymphocytes and possess many fine dendritic processes. These dendrites extend and intimately interact with neighboring cells, creating a unique microenvironment. This intimate interaction with surrounding lymphocytes appears to be important for FDCs to provide potent signals that promote humoral immune responses. Scanning electron microscopy (SEM) has identified two morphological types of FDCs: one having filiform or finger-like processes, and one with “beaded” dendrites. The transition from one form of FDC into another appears to be related to the formation of a specialized Ag delivery system. The resulting “beads” are called “iccosomes” to denote that they consist of immune complex-coated bodies (Schnizlein et al.,
FDCs possess a scanty cytoplasm with few mitochondria, rough endoplasmic reticulum, a Golgi apparatus, and vesicles. They have irregular, sometimes bilobed, euchromatic nuclei containing distinct nucleoli. The dendritic processes of FDCs appear in two general forms: some are attenuated, with folds and intermittent thickenings that form a variety of differently shaped cytoplasmic extensions, while others form more uniform, highly convoluted, labyrinthine configurations. These dendritic processes interdigitate with one another and form a vast network or reticulum on which ICs are trapped (Schnizlein et al.,
The cellular origin of FDCs is still controversial and various cell types have been proposed as a possible origin of FDCs. FDCs, at least in their mature form, are stationary, however, the possibility of an inflow of earlier progenitors of FDCs from other sites could not be fully excluded (Kasajima-Akatsuka and Maeda,
At present there are data supporting a haematopoietic origin and more data supporting a stromal cell origin. FDCs are radiation resistant making it difficult to study development using adoptive transfer models. Information available on FDCs is based primarily on studies using humans and rodents. However, FDCs are present and functional in birds and if FDCs are defined broadly as cells with the ability to trap ICs, they appear to exist in all jawed vertebrates, including amphibians, reptiles, and fish (El Shikh et al.,
Using mice homozygous for the SCID mutation, which lack T, B lymphocytes, and FDCs, demonstrated that after reconstitution with bone marrow from donor mice, the FDCs of the reconstituted mice expressed the donor phenotype. These authors concluded that FDC precursors came from bone marrow (Kapasi et al.,
On the other hand, stromal cells expressing FDC markers have been described in several independent studies, and seem to be present in the splenic white pulp before the development of functionally and ultrastructurally recognizable FDC. Using an
Recent transcriptome analysis showed that FDCs express many mesenchyme-associated genes suggesting that FDCs are specialized mesenchymal cell population within the GCs of lymphoid tissues (Mabbott et al.,
Another recent study has suggested a mechanism of FDC development that involves both resident and migratory cells. Specifically, it was proposed that a FDC is generated by a cell fusion event between a stromal cell and a migratory CD35+B220+ precursor cell, which is consistent with several observations of binucleate FDCs (Murakami et al.,
TNF and the related molecule LT are essential for FDC development, and mice deficient in these cytokines, their receptors, or associated downstream signaling molecules fail to properly develop FDCs and GCs in secondary lymphoid organs. Through irradiation chimera and adoptive transfer experiments, it was established that TNF and LT were required on lymphocytes, specifically B-cells for normal FDC development. The differential role of soluble and membrane bound TNF in FDC development has been also investigated with more significant role of soluble TNF in FDC development in primary follicles and the membrane-bound TNF form in FDCs of the GCs (Allen and Cyster,
FDCs help maintain primary follicles as a B-cell exclusive niche and they act to retain and promote the survival of GC B-cells within GCs. Within two days of FDC ablation, primary B-cell follicles lose their homogeneity and become disorganized bands of cells around T zones. Ablation of FDCs during the GC response causes rapid GC B-cell dispersal, death, and disappearance of the GCs (Wang et al.,
The cardinal feature of FDCs is the surface retention of native Ags for extended periods of time and presentation of these Ags together with costimulatory signals to B-cells during normal and abnormal immune responses. This unique property of Ag retention and presentation by FDCs: (1) occurs in different sites of secondary lymphoid tissues, including the spleen, LNs, and mucosa-associated lymphoid tissues (MALT); (2) can be induced in tertiary lymphoid tissues in different organs as a consequence of chronic inflammatory and autoimmune reactions; (3) depends on Ag retention on FDCs, which is directly associated with different Ag transport mechanisms in secondary and tertiary lymphoid tissues; (4) can be induced in cells of haematopoietic and stromal origin under physiological and pathological conditions
A notable feature of the FDC network is that it is located centrally in the follicle and typically does not extend to the subcapsular sinus (SCS), interfollicular regions or T-cell zone. The logic for this separation of FDCs from the sites of earliest Ag capture has not been defined but it prompted studies on the mechanisms of Ag transport to the FDC reticulum dating back to the early 1980s.
Perhaps being centred in the follicle and not in substantial contact with macrophages, DCs, or circulatory fluids provide a protected environment in which opsonized Ags can be displayed for long periods without being proteolysed or removed by phagocytic cells. However, the physical isolation of FDCs in follicles necessitates mechanisms for Ag to travel from the first point of capture to the FDC (Cyster,
In the early 1980s, elegant light and electron microscopic studies indicated that as early as 1 min after Ag injection in passively immune mice, localization of Ag occurs at distinct sites in the SCS and subjacent areas of the cortex on the afferent side. At these sites, between 1 min and 24 h, the Ag forms light microscopically identifiable trails which reaches progressively deeper into the cortex with time toward individual follicular regions. By 24 h this apparent migration of Ag is complete, and the Ag is localized in follicles. Electron microscopy indicated that the apparent migration of ICs was mediated by a group of cells observed in the migration path that had ICs sequestered on their surface or in plasma membrane infoldings. These Ag transporting cells (ATC) were relatively large non-phagocytic cells, with lobated or irregular euchromatic nuclei and cell processes of various complexities. ATCs observed in or near the SCS appeared to be less differentiated, whereas those located deeper in the cortex, appeared more differentiated, interdigitated with Ag-retaining dendritic cells, and shared morphologic characteristics with FDC (Szakal et al.,
More recently, it was reported that large MW proteins (>60 kDa) injected into passively immune mice form ICs that activate complement, resulting in covalent attachment of C3 (C3-IC). SCS macrophages (SCSM) have a low rate of Ag internalization and degradation (Cyster,
It has been also reported that SCSM themselves transport ICs directly to FDCs after immunization with Ag in adjuvant (Cyster,
Both marginal zone (MZ) B and B-1-cells help reorganization of FDC networks (Ferguson et al.,
Major challenges delayed the systematic analysis of FDC functions in health and disease. Retrieval and characterization of FDC-retained Ags, isolation of the Ag-retaining FDCs, detection of picogram quantities of Ags in GCs, and the lack of
FDCs are fragile cells and are tightly associated with B-cells which hamper the process of FDC isolation. Several FDC lines were established to overcome these problems, however, as these cells are maintained over several weeks in culture, their phenotype no longer reflects the
Artificial engineering of lymphoid tissue equivalents is an emerging field that aims to provide models for therapeutic applications of vaccines, and drugs used in the treatment of chronic inflammation, autoimmunity, and cancer. Being the hotspot of Ab production, more work on developing
FDCs critically regulate Ag presentation to B-cells in the GCR. In the following section we will introduce the types of Ags and the GCR before we discuss the specific immunoregulatory functions of the FDCs.
Long before T and B lymphocytes were discovered, it was known that certain Ags of bacterial origin were fundamentally different from protein Ags. Lipopolysaccharide (LPS), for example, was found to be immunogenic at very low concentrations and even 1000 molecules could induce a detectable immune response dominated by 19S Abs (IgM) (Moller,
With regard to their capacity for Ab-induction, Ags are classified as T-cell dependent (TD) or T-cell independent (TI). In the immune responses to TD Ags, provision of cognate T-cell help to B lymphocytes is essential for B-cell proliferation, immunoglobulin (Ig) secretion, class switch recombination (CSR), affinity maturation, and memory B-cell generation. On the contrary, TI Ags induce B-cell activation and Ab production without T-cell help. TI Ags are further divided into TI type 1 Ags (TI-1), which are polyclonal B lymphocyte activators, and TI type 2 (TI-2) Ags which are classically polysaccharides fit for extensive crosslinking of multiple BCRs.
Protein Ags without repetitive epitopes require cognate T-cell help to induce high affinity B-cell immunity. These TD Ags are processed and presented by Ag presenting cells (APCs) which activate Ag-specific helper T (Th) cells in the T-cell zones of secondary lymphoid tissue. Activated Th cells expand and differentiate into effector Th cells that regulate the development of Ag primed B-cells. Under Th cell control, these primed B-cells can switch Ig isotype, terminally commit to the plasma cell pathway or enter the GCR to experience cycles of SHM, affinity maturation, selection of high affinity B-cells, and memory B-cell generation. Ag-specific Th cells contribute to the GCRs where they critically regulate the affinity-based selection of memory B-cells. A long-lived memory Th cell compartment is established in the immune responses to TD Ags, where Ag rechallenge induces exaggerated cellular expansion in the memory B and T-cell compartments (Parker,
A complex mixture of TD Ags (peptides and proteins) and TI Ags (glycolipids and complex polysaccharides) are present in microorganisms (Leyva-Cobian et al.,
TI-2 Ags are classically large MW polysaccharides displaying repeating immunogenic epitopes with poor biodegradability, and complement fixation ability. These Ags can crosslink BCRs and stimulate Ab production by mature B-cell in athymic nude mice lacking MHC class II restricted T-cell help [detailed in (Dintzis et al.,
In spite of their chemical diversity, structural analysis of classic TI-2 Ags has shown that all share a minimal MW of 100 kDa and repetitive epitopes that are expressed on a stable backbone with a two-dimensional epitope spacing of 95–675 Å. An extended length of the backbone of 460 nm, carrying 48 epitopes engaging 10–50 mIg receptors forming a small number of highly crosslinked clusters of mIg molecules with 14-fold reduction in the diffusion coefficient of the bound mIg receptors is critical for delivering the BCR-mediated signal in TI-2 responses (Vos et al.,
In view of recent studies, the operational characteristics of TI-2 Ags have been extended beyond classic polysaccharides. Reports on the requirements for generation of Ab responses to repetitive determinants on polymers and higher order structures such as viral capsid proteins indicated that high MW arrays of Ag are efficient in eliciting Ab responses independent of T-cell help, whereas their less ordered counterparts are less immunogenic and require T-cell help (Dintzis et al.,
A clinically important group among the TI-2 Ags are the bacterial capsular polysaccharides. Capsular polysaccharides of
TI B-cell activation is further discussed in the immunoregulatory functions of FDCs.
GCs are highly structured tissue microdomains in activated B-cell follicles wherein B lymphocytes undergo clonal expansion, CSR, Ab gene diversification, and affinity maturation.
GCs were first observed in 1884 by Flemming and his associates who concluded that GCs were one of the major sources of lymphocytes throughout the body. Though the name given to the sites of intense proliferation in the follicles is still used, we now know that the conclusion that the cells originate/germinate within the GC is not true. The term “reaction” in GCR is used to stress the reactive nature of the GC response, i.e., the development (and decline) of a GC as a result of antigenic stimulation (Nieuwenhuis and Opstelten,
GCRs differ slightly from organ to organ and from species to species. GCs also form in atypical sites (referred to as tertiary lymphoid tissues) such as in the stomach during
GCs arise in primary lymphoid follicles of secondary lym-phoid tissues. The sites that become involved are those receiving the antigenic stimulus via drainage of lymph, blood, or specialized cells in the epithelium called “M” cells. The GCR is a complex process involving numerous cellular and cell surface components together with multiple signaling pathways (Nieuwenhuis and Opstelten,
The primary B-cell follicle contains a mixture of recirculating naïve and memory B-cells. Upon B-cell activation in the T-cell zone, a few committed Ag specific B-cells migrate into the follicle and expand clonally. Several studies indicated that low numbers of Ag-specific B-cells can be seen within the follicles in the primary response as early as 36 h post-immunization. Three to four Ag-specific B-cells colonize a follicle and go through repeated rapid cell cycles increasing some 4000-fold in around three days. In doing this, they fill the spaces between the network of FDCs. Within 72–84 h of exponential growth the cells differentiate to form a mature GC chracterized by the presence of a light zone and a dark zone. The proliferating cells move to one pole of the GC and become centroblasts. Centroblasts produce non-proliferating centrocytes that are thought to migrate to the light zone of the GC, which is rich in Ag-trapping FDCs and T follicular helper (Tfh) cells. Small, non-cycling follicular B-cells are then moved closer together, forming the follicular mantle. The light zone contains a rich network of FDCs that have the capacity to take up Ag and hold it on their surface for periods of more than a year. The Ag is held as an IC in a native unprocessed form; but the Ag may be taken up from FDC by B-cells, which can process and present it to T-cells. The open structure of GCs allows high-affinity Ag-specific B-cells to be recruited to an ongoing GCR. This enhances competition for the FDC-bound Ags and ensures that rare high-affinity B-cells can participate in Ab responses (MacLennan,
One of the hallmarks of the GCR is the introduction of somatic mutations into IgV genes of GC centroblasts, mainly single base pair mutations, followed by an efficient selection procedure that ensures selection of Abs with higher affinity (Song et al.,
Upon exiting the GCR, selected B-cells can differentiate into two long-lived compartments; memory B-cells, and bone marrow-resident plasma cells. Both cell populations participate in sustaining high-titred Ab levels. Memory B-cells recirculate in the periphery, where they can survive for decades in humans. Upon re-encounter with the Ag for which they are specific, memory B-cells can rapidly proliferate and differentiate into plasma cells secreting high affinity Abs. on the other hand, bone marrow-resident long-lived plasma cells secrete Abs for long periods of time (MacLennan et al.,
GCs persist for about 3 weeks following immunization (MacLennan,
The contribution of T-cells to the GCR has been studied extensively as T-cell help to B-cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Tfh cells differentiate in response to immunization or infection and provide help to GC B-cells. Tfh cells, initially described in 2000–2001, are CD4+ T-cells that mature in a Bcl-6-dependent manner and are capable of providing IL-21-dependent help to B-cells for GC formation and switched Ag-specific Ab responses (Vinuesa and Cyster,
The original description of GCs entailed definite T-cell dependency (Nieuwenhuis and Opstelten,
Several models have been proposed for the cellular dynamics during the GCR (McHeyzer-Williams et al.,
Autoreactive and malignant GC B-cells induce a unique class of disorders because they originate from cells of the immune system that divert from the normal maturation programmes, via genetic rearrangements or somatic mutations. As SHM and gene rearrangements are the physiological landmarks of Ag-driven GC responses, the risk for genetic lesions (and hence autoimmunity and malignant transformation) is exponentially enhanced (Hollowood and Goodlad,
Although the enzyme activation-induced deaminase (AID) is essential for creating Ab diversification by causing mutations during the GCR, it also greatly enhances the chance of B-cell lymphoma development. AID increases the mutation rate to one per thousand bases, six orders of magnitude more than spontaneous mutagenesis, and can ultimately lead to mutations of proto-oncogenes and chromosomal translocations resulting in a wide variety of B-cell lymphomas that are thought to derive from GC B-cells based on their carrying somatically mutated V region genes (Peperzak et al.,
In tertiary lymphoid tissues, infiltrating B- and T-lymphocytes organize themselves into ectopic follicles and GCs. This has been observed in several autoimmune, chronic inflammatory, and neoplastic diseases. Ectopic GCs are architecturally similar to GCs in conventional secondary lymphoid organs, and comprise proliferating B-cells and networks of FDCs. T-cells are also a regular component of ectopic GCs where they provide cognate T-cell help required for the progression of the GC B-cell response (Aloisi and Pujol-Borrell,
Although some elements of the cellular interactions between cell types within GCs have now been visualized, it is yet to attain the ability to image over extended time periods in order to have clearer image of the GC kinetics.
Studies of TD Ags including ovalbumin, horseradish peroxidase, and human serum albumin indicated that these immunogens are almost instantaneously converted into ICs by Abs persisting from prior immunization(s). Moreover, in primary responses, ICs form as soon as Ab is produced and these ICs are trapped in the FDC reticula. Ag trapping and retention is exquisitely localized to draining lymphoid tissues. Ag injection into a single limb of an immune mouse will be localized to the draining LNs and to a lesser extent in the spleen (Mandel et al.,
FDCs trap ICs via Fc and C receptors (Tew et al.,
FDCs multimerize native Ags in a periodic manner as initially discovered using SEM with Ags trapped
Using two-photon microscopy, it was recently shown that the B-cell encounter with FDC-associated Ag could be detected for >1 week after immunization. B-cell-FDC contact times were often brief but occasionally persisted for >30 min and B-cells sometimes acquired Ag together with FDC surface proteins. These observations establish that FDCs serve as sites of B-cell Ag capture, with their prolonged display time ensuring that even rare B-cells have the chance of Ag encounter (Suzuki et al.,
Persisting Ags on FDCs are critical for SHM which is important for affinity maturation. SHM is a late GC event beginning 9–11 days after primary challenge, and a late specific Ag signal (a week after priming) is delivered by Ags persisting on FDCs to promote SHM and affinity maturation (Wu et al.,
Strikingly, FDCs display Ags even in the presence of high levels of specific Ab which might be expected to mask epitopes and thus block successful Ag presentation. However, B-cells cluster with FDCs forming a synapse at the point of FDC-B-cell contact and Ag-specific B-cells recognize FDC-Ag via their BCRs in the synapse even in the presence of high levels of Abs during the GC reaction (El Shikh et al.,
Not only do FDCs provide C3 (CD21L) as a complement derived cosignal, but FDC-C4bBP has been recently reported to engage B-cell CD40 and serve as a cosignal in FDC-dependent TI responses to polysaccharides. TI polysaccharide Ags fix the alternative complement pathway directly and the classical pathway indirectly by making ICs with specific IgM produced early in the response. In addition to accessory signals delivered by the complement derived CD21L, activated forms of both C3 (C3b) and C4 (C4b) bind C4 binding protein (C4BP), which in humans and likely in rodents, colocalizes with ICs on FDCs. C4bBP in ICs trapped on FDCs has been shown to signal B-cells via intact CD40 in short-lived Ag-specific TI GCs independent of T-cell derived CD40L (CD154). More specifically, in mice with normal FDCs, injection of a blocking mAb, FDC-M2, which recognizes an epitope on C4 bound within ICs, also inhibited TI GC development. C3- and C4-deficient mice showed impaired TI Ab responses consistent with the hypothesis that ICs on FDCs can provide Ag-specific, complement-derived, and CD40-mediated signals to B-cells initiating B-cell proliferation in TI GCs (Gaspal et al.,
Recent studies indicated a critical role for IL-6, whose primary source in GCs is FDCs (Kopf et al.,
TI type 2 Ags trapped on FDCs can induce GCs in animals lacking cognate T and B-cell interactions. When mice with mutations that inactivate the
Typically ~48 h is needed before primed T-cells are able to provide cognate help and it is unlikely that cognate T helper cells are involved in 48 h TI responses. It is important to appreciate that IC activated FDCs produce BAFF and IL-6 and that these cytokines can in turn rapidly induce cytokine production by T-cells (Huard et al.,
The ability of FDCs to convert TD Ags into TI Ags was recently reported. TD Ags in ICs on FDCs are spaced 200–500 Å apart on the flexible backbone of FDC membranes which is geometrically fit for extensive BCR crosslinking. Moreover, FDCs provide BAFF and C4bBP, which are known to support TI B-cell activation. Nude or athymic mice challenged with ICs produce specific IgM in 48 hr while challenge with free Ag in adjuvant failed to induce IgM even after many weeks. Moreover, the draining lymph nodes of IC-challenged nude mice exhibit well-developed GCs associated with FDC Ag retaining reticula and plasmablasts within 48 h. IgM is the first class of Abs produced during primary Ab responses, and the ability to induce FDC-dependent, TI IgM responses may be critical in host defence in the initial phases of infections before T-cell help is provided or in disease conditions where T-cell insufficiency prevails (El Shikh et al.,
Table
BAFF | FDC-BAFF supports TI B-cell activation (El Shikh et al., |
CD21/35 (CR1/2) | CRs are crucial for IC retention especially in the spleen (Tew et al., |
CD21L (iC3b, C3d or C3dg) | Engagement of CD21 in the B-cell co-receptor complex by complement derived FDC-CD21L delivers a critical co-signal. Coligation of BCR and CD21 facilitates association of the two receptors and the cytoplasmic tail of CD19 is phosphorylated by a tyrosine kinase associated with the BCR complex. This co-signal augments stimulation delivered by Ag and blockade of FDC-CD21L reduces B-cell proliferation, activation induced cytidine deaminase, and Ab production 10–1000 fold (Croix et al., |
CD23 (Fcε RII) | FDC-Fcε RII mediates IC retention, and the regulation of the GC reaction and IgE levels (El Shikh et al., |
CD29, CD44 | FDCs express CD44 and CD29 and FDC binding to collagen type I |
CD32 (FcγRIIB) | FDC-FcγRIIB is critically involved in conversion of poorly immunogenic ICs into a highly immunogenic form, FDC activation, IC periodicity, long-term IC retention, and regulation of serum IgG levels (El Shikh et al., |
CD320 (8D6) | The 8D6 molecule inhibits apoptosis and influences both proliferation and Ab secretion by GC B-cells. Moreover, GC B-cells that are induced to differentiate into pre-plasma cells are the most sensitive to the neutralizing effects of anti-8D6 (Zhang et al., |
CD40 | FDCs express CD40 and when incubated with either CD40L trimer or agonistic anti-CD40 Ab, the expression of FDC-CD23 is increased both at the mRNA and protein levels. FDC-CD23 helps regulate IgE levels (Payet-Jamroz et al., |
CD54 (ICAM-1), CD106 (VCAM-1), MadCAM-1 | Abs reactive with murine ICAM-1 and/or leukocyte functional Ag-I (LFA-I) interfere with FDC-B-cell clustering resulting in reduced B-cell proliferation. In addition, VLA-4 and VCAM-1 have been observed in GCs and likely also play a role in FDC-B-cell interactions. These adhesion molecules are thought to stabilize the FDC-B-cell synapse and promote interaction of FDC-Ag and FDC-costimulatory molecules with B-cells (Kosco et al., |
CXCL13 | CXCL13 is secreted by FDCs and acts as chemoattractant for B-cells via the CXCR5 chemokine receptor. FDC development and expression of this chemokine depend on LTα β, and TNF-α. The maintenance of lymphoid follicle structure is mediated by a positive feedback loop: CXCL13 stimulates B-cells to express high levels of LTα β, and TNF-α which stimulates FDCs to produce CXCL13 (Ansel et al., |
Fcα /μ R | In humans, FDCs are the predominant cell type expressing Fcα /μ R which are involved in IC retention (El Shikh et al., |
FDC-M1 (Mfge8) | Fat globule epidermal growth factor 8 (Mfge8) “licenses” tingible body macrophages (TBMs) to engulf apoptotic bodies in GCs and helps minimize autoimmunity (Kranich et al., |
FDC-M2 (C4b eptiope) | C4b binding protein (C4bBP) binds C4b and co-localizes with ICs on FDCs. FDC-C4BP has been shown to signal B-cells via CD40, independent of T-cell CD40L (CD154). Injection of mice with FDC-M2 inhibits C4BP development and TI-GC development (Taylor et al., |
Hedgehog (HH) ligand | Sonic Hedgehog (SHH) ligand is produced by FDCs within the GCs of lymphoid follicles, and SHH ligand protects GCer B-cells from apoptosis. GC B-cells express the HH receptors, and their survival is altered after inhibition of the HH signaling pathway (Sacedon et al., |
IL-15 | IL-15 is produced by FDCs and is captured by IL-15R on the surface of FDCs. Surface IL-15 is active and promotes GC-B-cell proliferation (Park et al., |
IL-6 | FDCs are the source of IL-6 in GCs. Engaging FDC-Fcγ RIIB by ICs activates FDCs and enhances FDC-IL-6 production. FDC-IL-6 promotes GC development, IgG production, and SHM and terminal B-cell differentiation (Wu et al., |
IL-7 | IL-7 has been found in isolated tonsilar FDCs using RT-PCR and cell staining. IL-7 signaling coupled with crosslinking of surface immunoglobulin receptors results in B-cell proliferation (Kroncke et al., |
Notch ligands | Notch ligands, Delta-like1 and Jagged 1, are expressed by FDCs and support GC-B-cell growth and survival (Yoon et al., |
Prostaglandins (PGs) | The role of PGs in regulation of the GC reaction has been suggested in the late 90s. TBM were found to be rich in PGs via which they can downregulate the GC reaction (Smith et al., |
TNFα-R and LT-R | FDC development and maturation (Allen and Cyster, |
TNF-α | FDCs produced soluble TNF-α that promotos GC T-cell activation (Thacker et al., |
Toll-like receptors (TLRs) | Dramatic upregulation of FDC-ICAM-1, VCAM-1, and FcγRIIB is observed after injecting LPS into animals expressing WT TLR4 but not in animals with mutated TLR4. Incubation of FDCs with LPS in vitro upregulates FcγRIIB, ICAM-1, and VCAM-1. FDCs express mRNA for TLR2, 3, 4 and 9 and injection of poly I:C brings up FDC-Fcγ RIIB to levels comparable with LPS (El Shikh et al., |
Wnt5a | FDCs secrete Wnt5a and its production is upregulated by polyI:C. FDC-Wnt5a is a GC B-cell survival factor and might be a potential target for the regulation of B-cell immunity (Kim et al., |
Expression of FDC surface and secreted molecules is subject to regulation, and engagement with ICs, TLR ligands, or collagen type 1 induces FDC activation and upregulation of these molecules. In the GCs, FDCs bear high levels of Fcγ RIIB, ICAM-1, and VCAM-1, and these molecules are involved in converting poorly immunogenic ICs into a highly immunogenic form and facilitate FDC-B-cell interactions. FDC-trapped ICs (El Shikh et al.,
Activated FDCs provide Ags to B-cells in a highly immunogenic form by: (1) multimerizing the Ags thus extensively crosslink multiple BCRs (El Shikh et al.,
A major consequence of activation is a marked increase in accessory activity. Both specific Ab responses and SHM are dramatically enhanced when FDCs are activated by TLR ligands suggesting that adjuvant activity likely involves FDC-activation and not just DC activation for T-cell co-stimulation (El Shikh et al.,
In addition to their contributions in regulated immunity, FDCs also play important roles in pathological states, including HIV/AIDS, prion diseases, autoimmunity and B-cell lymphomas.
Autoimmune disorders frequently display follicles with IC-bearing FDCs, autoreactive GCs, and ongoing affinity maturation (Aloisi and Pujol-Borrell,
Data in various models and human studies suggests the requirement for auto-Ag to sustain the autoimmune response and that auto-Ag withdrawal inhibits it (Bach et al.,
In contrast to self-Ags of low valency such as small soluble proteins, multivalent Ags crosslink BCRs, maintain downstream signaling, and induce B-cell activation. In addition, tolerized B-cells exhibit enhanced rates of BCR-mediated Ag uptake. However, when the Ag is repetitive, stable, and resistant to BCR-mediated endocytosis, like multimerized FDC-bound Ags, BCRs aggregate and signaling is maintained. This results in clonal expansion and Ab production that is dependent on the multitude of BCR signalosomes activated by extensive crosslinking of BCRs (Hinton et al.,
Not only FDCs present Ags in a periodic multivalent ICs, but also they provide complement-mediated B-cell co-stimulation (Qin et al.,
Previous
The initial Ab needed to trap Ag on FDCs may be induced by molecular mimics or by polyclonal B-cell activation, which may occur as a consequence of infections that herald many autoimmune diseases (Granholm and Cavallo,
Polyvalent presentation of self-proteins in repetitive arrays breaches B-cell tolerance in immune-tolerant animal models (Sauerborn et al.,
The contributions of FDCs to HIV pathogenesis include the storage of a large and diverse reservoir of infectious virus, including drug resistant variants, in an activated microenvironment where CD4 T-cells targets are attracted but impaired in their ability to leave thereby increasing the likelihood of their infection. Just as Ags, intact HIV particles are found trapped on FDC dendritic presented in the form of ICs containing Ab and/or complement proteins. FDCs retain virus particles for long periods of time and, in fact, as long as FDCs are present in infected individuals, HIV can be found associated with them (Heath et al.,
FDCs provide a microenvironment that is highly conducive to HIV transmission. HIV ICs remain infectious for months, and HIV on FDCs is “presented” to T-cells resulting in propagation of infection. FDC-secreted TNF-α increases the rate of HIV transcription by about three-fold in infected T-cells resulting in a significant increase in virus production (Thacker et al.,
FDCs appear to play an important role in prion diseases as evidenced by the finding that in experimental models where FDCs are not present, prion diseases do not typically appear. Prion diseases occur in both animals and humans and are caused by misfolded proteins encoded by the Prnp gene and consist of a normal form (PrPc) and its aberrant counterpart (PrPSc). Without the normal PrPc protein, whose function is still unknown, the diseases are not manifest (Nuvolone et al.,
Upon exposure to prions, the agents are transported into secondary lymphoid tissues where the proteins accumulate and replicate on FDCs. FDCs is a major source of PrPc and complement proteins play critical role in its retention. PrPc-expressing FDCs are sufficient to sustain prion replication in the spleen (McCulloch et al.,
After prion replication in the secondary lymphoid tissues, the PrPc-PRPSc complexes are transported to the central nervous system where neurodegeneration occurs. The exact mechanism of prion transport from FDCs to peripheral nerves is unknown. Prions could be (1) transported by various cell types leaving GCs toward nerve terminals; (2) incorporated by budding retroviruses; (3) released in FDC-derived iccosomes, or (4) passively diffuse from the site of replication to the site of peripheral innervation (Nuvolone et al.,
Follicular lymphomas morphologically resemble conventional GCs having B-cells, T-cells, macrophages, and FDCs. Recent studies suggest that the microenvironment in which the malignant cells reside is critical for disease pathogenesis and progression. The malignant cells appear to require the contributions of T-cells, macrophages, and FDCs as evidenced by the observation that in the absence of these cells, the malignant cells are difficult to survive. In addition to providing signals important to tumor cell growth, FDCs also can provide signals that spare malignant B-cells from undergoing apoptosis or programmed cell death. Moreover, FDCs establish a protective sanctuary for malignant cells from otherwise effective chemotherapeutic agents (Asadullah et al.,
FDCs represent a unique accessory immune cell that provides both Ag-driven and co-signals to B-cells. FDC-derived signals contribute to the ability of B-cells to survive, proliferate, differentiate, and produce optimal levels of specific high affinity Abs during the GC reaction. Apart from their immunoregulatory functions, FDCs also contribute to several disease conditions including autoimmune diorders, AIDS, prion diseases, and follicular lymphomas. Further understanding of FDC biology is essential for better control of humoral immunity and paves the way for therapeutic management of FDC-mediated immune disorders.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by William Harvey Research Limited grant number EMRG1C9R for M. El Shikh.