Encyclopedia of Gerontology and Population Aging

Living Edition
| Editors: Danan Gu, Matthew E. Dupre

Follicular Dendritic Cells

  • Péter BaloghEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-69892-2_65-1



Follicular dendritic cells (FDCs) are non-hematopoietic cells of the follicles (B-cell rich zones) of the secondary lymphoid tissues in mammalians (including humans) that form the scaffolding of follicles and promote the follicular colonization, expansion, and survival of B cells during immune responses associated with antibody production upon antigenic stimulation.


Identification, Functions, and Cellular Characteristics of FDCs

The ability of the mammalian immune system to mount effective humoral immune responses with high-affinity antibody production coupled with the establishment of immunological memory (the capacity to elicit prompt reaction upon secondary antigenic encounter) critically depends on the organized microstructure of peripheral lymphoid tissues. These include the spleen, a unique singular lymphoid organ to combat blood-borne pathogens; lymph nodes, forming an extensive network of encapsulated organs arranged in a chain-like fashion filtering interstitial fluid throughout the body; and various forms of lymphoid aggregates in the gastrointestinal and genitourinary mucosa and in the airways.

After their production in the bone marrow, B cells expressing cell surface immunoglobulin recirculate between various peripheral lymphoid tissues where they accumulate within the follicles, separately from the bulk of T cells. Although they constitute the vast majority of cells dwelling in these regions, other hematopoietic cells, including some T cells, macrophages, and dendritic cells that can take up or recognize antigens, can also be found here. Pivotal studies in the 1960s using radioisotope-labeled antigens performed on rodents demonstrated that, following their entry, antigens accumulate within the follicles (Miller and Nossal 1964) in a clumped arrangement (Nossal et al. 1968; Szakal and Hanna 1968). According to ultrastructural studies, this deposition of antigens represents their retention mediated by non-phagocytic (i.e., macrophage) cells. These cells possess extensive filiform membrane extensions (henceforth named as follicular dendritic cells; Chen et al. 1978) or dendrites with bead-like microsphere structures (Schnizlein et al. 1985; Szakal et al. 1985), which can be transferred to B cells as immune complex containing the antigens together with antibody and complement fragments (Szakal et al. 1988). The general structure of lymph node follicles is illustrated schematically in Fig. 1a.
Fig. 1

(a) Schematic diagram of a segment of a lymph node. A: Subcapsular area, containing macrophages (Mc) and marginal reticular cells (MRC; putative FDC precursors), which area serves as antigen entry route via the afferent lymphatics (indicated as brown dashed line). B: Follicle (black encircled), arranged around FDC meshwork retaining the antigen in immune complex form (depicted as small grey dots), surrounded mostly by B cells (resting/rest or activated/act or memory/mem) as well as follicular T helper cells (Tfh). C: Extrafollicular (paracortical) region comprising mainly of T cells, majority belonging to the CD4 subsets. Their stromal scaffolding as well as possible other stromal elements at the T/B boundary are not depicted. The blood-borne lymphocytes enter through the high endothelial venules (HEV). (b) Splenic follicular dendritic cells (green fluorescence staining of CR 1/2 antigen) with arborized extensions are located in B-cell rich regions (red fluorescence staining of B220 antigen) adjacent to T-cell zone (blue fluorescence staining of Thy-1.2) forming the periarteriolar lymphoid sheath (PALS) around the central arteriole (arrow). 40 × magnification

The FDCs are rather uniformly distributed within the primary follicles, whereas following antigenic stimulation they are typically confined to the light zone of secondary follicles containing germinal centers (Szakal et al. 1989; MacLennan 1994).

Given the difficulties of selectively locating FDCs within the follicles overwhelmed by B lymphocytes using traditional staining, the identification of FDCs by immunohistological labeling represented an important advance for their subsequent analyses. In mice, they were found to express FcγRIII/FcγRIIB (CD16/32; Schnizlein et al. 1985; Kosco et al. 1986), followed by the demonstration of complement receptor 1/2 (CD21/35) display (Yoshida et al. 1993), similarly to humans (Reynes et al. 1985; Johnson et al. 1986). Although these markers are not specific for FDCs, their increased production compared to that of B cells has further strengthened the hypothesis of their involvement in converting and presenting immune complexes into a highly immunogenic form by FDCs as a critical element for supporting recall immune responses (Qin et al. 1998; Qin et al. 2000). Figure 1b shows a typical FDC cluster in a primary follicle using multicolor immunofluorescence with specific antibodies against T cells, B cells, and FDCs.

To strengthen antigen-specific interactions with antigen-stimulated B cells during immune responses, FDCs also demonstrate enhanced adhesion with B cells by increased expression of several adhesion molecules (including VCAM-1, ICAM-1 and MAdCAM-1), which further increase during immune responses, demonstrating the inducible capacities of FDCs (Koopman et al. 1991; Kosco et al. 1992; Szabo et al. 1997; Balogh et al. 2002).

Development of FDCs and their Pre-immune Role in the Formation of Follicles

The origin of FDCs remained a contested issue for decades. Their restricted presence in the follicles of secondary lymphoid tissues suggested hematopoietic origin, in a close dependence with the presence of B cells, as the elimination of B cells resulted in the loss of FDCs (Cerny et al. 1988), although unlike the hematopoietic cells, FDCs are radioresistant (Humphrey et al. 1984). Subsequently, congenitally severe immunodeficient (SCID) mice lacking B-and-T-cells were found to lack FDCs, but capable of generating FDCs upon transfer of mature B cells with increased expression of FcγR and complement receptors involved in long-term immune complex retention (Kapasi et al. 1993; Yoshida et al. 1994). Thus, the absence of FDCs in SCID mice offered a feasible in vivo experimental system to study the emergence of FDCs. In this approach, the origin of FDCs was defined either as local host-derived (Yoshida et al. 1994) or could also at least partly be supplied by the bone marrow (Kapasi et al. 1998). Using several advanced cell-lineage tracing in vivo experimental systems, the tissue origin of FDCs is now generally accepted as local mesenchymal derivatives from undifferentiated perivascular precursors (Krautler et al. 2012) also present at the periphery of lymph nodes as marginal reticular cells (Jarjour et al. 2014), also serving as expansion pools for FDCs in immune responses. However, possible peripheral lymphoid tissue-specific features distinguishing between the spleen and different types of peripheral lymph nodes may exist (Wang et al. 2011; Castagnaro et al. 2013).

The discovery of the role of lymphotoxin α (LTα) represented a seminal finding, opening the road to define critical molecular elements of lymphoid organogenesis generally, and the development of FDCs particularly (De Togni et al. 1994). LTα-deficient mice lack lymph nodes and Peyer’s patches, and their spleen demonstrated impaired T/B distribution, coupled with the lack of FDCs, also resulting in defective germinal center formation upon immunization (Matsumoto et al. 1996). Analyzing similar roles for other members of the expanding tumor necrosis-lymphotoxin (TNF-LT), it turned out that, in addition to LTα that can be generated as a soluble LTα3homotrimer, the appearance of FDCs also requires the related member LTβ, complexed in an LTαβ2 heterotrimeric form that binds to a separate receptor LTβR (Androlewicz et al. 1992; Crowe et al. 1994). Several subsequent studies have established that splenic FDC development requires LTβR engagement via its heterotrimeric LTαβ2 ligand (Koni et al. 1997; Fütterer et al. 1998), whereas their follicular maturation is dependent on TNF, both supplied by B cells (Pasparakis et al. 1996; Endres et al. 1999; Pasparakis et al. 2000). Importantly, even fully developed FDC network can be dissolved by disrupting LTβR-mediated signaling using a soluble decoy receptor analogue (Mackay and Browning 1998), indicating the continued need for LTαβ2 ligands also for the maintenance of FDCs.

The general feature of lymphoid cell segregation within the peripheral tissues into T- and B-cell zones raised the issue of the mechanism of this separation. This segregation is sensitive to pertussis toxin blocking G-protein-coupled receptor-mediated (GPCR) signalization (Lyons and Parish 1995; Cyster and Goodnow 1995). Subsequent discovery of the GPCR member chemokine receptor CXCR5 (originally denoted as BLR1) on B cells as a key molecule for their follicular recruitment represented a major progress in defining the mechanism of follicular build-up (Förster et al. 1996). As its ligand, CXCL13 (originally named B-lymphocyte chemoattractant/BLC) produced by FDCs, was identified (Gunn et al. 1998). After its discovery, CXCL13 was demonstrated to be able to induce the upregulation of LTαβ2 heterotrimer on B cells, thus suggesting the existence of a positive feedback relationship between the FDCs (or their precursors) expressing LTβR and producing CXCL13, and the B cells generating the pair of complementary ligand and receptor LTαβ2 and CXCR5, respectively (Ansel et al. 2000). The process of CXCL13-driven follicular movement of B cells leading to the follicular segregation is linked to the follicular conduit as a physical platform, a nonvascular drainage system, formed by follicular stromal cells, possibly FDCs (Nolte et al. 2003).

An important aspect for follicular organization and B-cell responsiveness is the B-cell survival within follicles, promoted by another member of TNF family BAFF (B-cell activating factor; Schneider et al. 1999) and its analogues TACI and BCMA (Gross et al. 2000). This function is probably performed by a subset of non-hematopoietic cells (possibly related to T-zone fibroblastic cells/FRCs) producing BAFF within the follicles distinct from the FDCs, and these two cell types jointly control follicular B-cell recruitment (via FDC-derived CXCL13) and survival (via follicular FRC-derived BAFF; Cremasco et al. 2014).

Age-Associated Deviations of FDC Functions in Supporting Humoral Immune Reactions and Memory Responses

Aging has been characterized by declining immune responsiveness, and enhanced frequency of autoimmunity and malignancies “Human Immune System in Aging”. As long-term preservation of FDC-associated antigen is necessary for the maintenance of memory, the aging-related decline of FDCs to sustain germinal center reactions has been known to impair humoral immune responsiveness, including reduced preservation of immunological memory and the capacity to mount recall responses (Szakal et al. 2002; McElhaney and Effros 2009; Ciabattini et al. 2018) “Cytomegalovirus and Human Immune Aystem Aging” and “Influenza Vaccination in Older Adults”. Unlike the studies performed on isolated aged T and B cell subsets, however, similar analyses addressing the impact of aging on purified FDCs are notoriously difficult to perform in mice, owing to the technical difficulties in their isolation. Moreover, such cells are beyond availability in humans unless some invasive procedure (in most cases lymph node biopsy or tonsillectomy) is employed. Nevertheless, histological analyses and in vivo cell murine experiments via transfer of young lymphocytes into aged recipients have been informative in revealing significant functional impairment of FDCs in old animals.

Initial observations indicated substantially reduced germinal center formation in aged mice (Hanna et al. 1967; Kosco et al. 1989). Subsequent immunohistochemical analyses demonstrated that, although the size of FDC reticulum was not significantly different between aged and young mice, the time-course for upregulating FcγR (inhibitory type FcγRIIB) by FDCs was substantially reduced, associated with the FDCs’ reduced capacity to retain antigen. Using in vitro experimental approaches to combine young or old B cells and young and old FDCs, a significant reduction in the co-stimulatory capacity of old FDCs was noted, and explored in details (reviewed by Aydar et al. 2004). According to the hypothesis based on these findings, FDCs in young mice efficiently upregulate and dominantly grab immune complexes via inhibitory-type FcγRIIB receptors, precluding their suppressive effect prevailing on antigen-stimulated B cells which, in turn, will preferentially utilize complement receptors (CR1/2), thus delivering potent co-stimulatory signals. In contrast, in aged FDCs such upregulation of FcγRIIB is defective, thereby antigen-stimulated B cells will not be rescued from having their FcγRIIB engaged by immune complexes (Szakal et al. 2002; Aydar et al. 2002; Aydar et al. 2003). Using immune complexes for immunization resulted in an enhanced in vivo responsiveness, increased antibody formation coupled with long-lived plasma cell differentiation, and accumulation in the bone marrow (Zheng et al. 2007).

In the spleen, the acquisition of immune complexes requires the shuttling of marginal zone (MZ) B cells into the follicles, delivering the antigen in immune complex form on the surface of FDCs (Cinamon et al. 2008). It was found that this shuttling of MZ B cells is impaired, probably resulting in a reduced amount of available immune complex to be deposited onto FDCs (Turner and Mabbott 2017). In aged mice, the splenic distribution of CXCL13 chemokine production was also notably different from that of the young mice, which may be implicated in the reduced mobility of MZ B cells transporting antigens into the follicles (Wols et al. 2010).

Of the key morphogenic members of the TNF/LT family for FDC differentiation, up to date no significant alteration associated with aging has been reported either in mice or humans. On the other hand, various autoimmune diseases affecting synovium, kidney, and other target organs have been described to be associated with ectopic (tertiary) lymphoid neogenesis, including the local appearance of FDCs within the affected tissues (Aloisi and Pujol-Borrell 2006; Bombardieri et al. 2017). Thus while the fitness of differentiated FDCs within secondary lymphoid tissues may deteriorate locally, the organism’s general capacity to produce such cells is retained. This uncertainty (possible reduction in secondary lymphoid tissues, and increased appearance ectopically) may also hinder their laboratory analysis in patients through measuring soluble mediators (like BAFF or CXCL13) due to their undeterminable origin. Using recent advances in lineage-related cell tracing combined with multiparameter analysis of purified stromal cells, including FDCs (Rodda et al. 2018), the eventual changes of mRNA profile of purified FDCs from old mice can shed light on vital alterations associated with aging. Figure 2 illustrates the possible elements contributing to the decline of FDC functions in aging.
Fig. 2

Possibilities contributing to impaired humoral immune responses involving FDCs in old individuals (right) compared to young (left). FDC-associated immune complexes are depicted as grey dots. FDC precursors likely originate from local tissue precursors

While the overwhelming majority of findings point to a negative impact of aging on FDC functions involved in humoral immune responsiveness, the decline of FDCs appear to reduce the transmission and neurodegeneration induced by scrapie agents (Brown et al. 2009). FDCs are necessary for initial prion replication (Brown et al. 1999), and their inactivation through the blockade of LTβR by soluble decoy receptor treatment resulted in blocked prion propagation (Mabbott et al. 2000; Montrasio et al. 2000), before the translocation of prion agent(s) to the central nervous system via the vegetative innervation of peripheral lymphoid tissues (Glatzel et al. 2001). Although this blunted spreading may be perceived as a positive consequence of FDC impairment associated with aging, it also warrants caution for the possibility of more frequent occurrence of subclinical transmissible spongioform encephalopathy amongst aged individuals.

Key Research Findings

FDCs develop from local non-hematopoietic cells of the peripheral lymphoid tissues that create suitable microenvironment for B cells and promote their follicular clustering by chemotactic stimuli. To perform their functions throughout life, the FDCs’ persistence requires several members of TNF/LT family. In their interactions with B cells, FDCs utilize different types of receptors for antigen retention, which also determines the resulting signal preference (activating or inhibitory) of the partnering B cells, which alters during aging.

Future Directions of Research

As FDCs may derive from different precursors in various peripheral lymphoid tissues, the identification of tissue-specific factors affecting the formation of FDCs in different peripheral lymphoid tissues and at ectopic location may reveal possible means for their manipulation in a tissue-specific manner. Further studies should reveal whether aging-related impairment of FDCs can be reversed, by enhancing their encounter with B cells to promote the stimulatory effects or by overcoming inhibitory signals. As FDCs are usually inaccessible for in vitro analyses, monitoring their functionalities necessitates the development of novel laboratory diagnostic approaches.


FDCs are non-hematopoietic cells with significant role for, and dependence upon, B cells, in promoting high-affinity antibody responses and establishing a highly ordered lymphoid tissue architecture. Their development requires recognition of several members of TNF/LT family produced by B cells or other lymphoid cells. The FDC:B cell-clustering B cells involves the production of CXCL13 chemokine by FDCs. Upon antigenic encounter FDCs retain antigen for activated B cells as immune complexes in a favorable proportion of receptor binding to circumvent B-cell suppression. In contrast, in aged FDCs this preference is altered, so aged FDCs can no longer shield B cells from receiving inhibitory signals, thus leading to premature termination of B-cell expansion and antibody production. While aging causes a progressive loss of FDC support capacity, autoimmune disease often manifest in the ectopic appearance of FDCs, which may potentially perpetuate tissue damage of the affected organ.



  1. Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6(3):205–217Google Scholar
  2. Androlewicz MJ, Browning JL, Ware CF (1992) Lymphotoxin is expressed as a heteromeric complex with a distinct 33-kDa glycoprotein on the surface of an activated human T cell hybridoma. J Biol Chem 267(4):2542–2547Google Scholar
  3. Ansel KM, Ngo VN, Hyman PL, Luther SA, Förster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406(6793):309–314Google Scholar
  4. Aydar Y, Balogh P, Tew JG, Szakal AK (2002) Age-related depression of FDC accessory functions and CD21 ligand-mediated repair of co-stimulation. Eur J Immunol 32(10):2817–2826Google Scholar
  5. Aydar Y, Balogh P, Tew JG, Szakal AK (2003) Altered regulation of Fc gamma RII on aged follicular dendritic cells correlates with immunoreceptor tyrosine-based inhibition motif signaling in B cells and reduced germinal center formation. J Immunol 171(11):5975–5987Google Scholar
  6. Aydar Y, Balogh P, Tew JG, Szakal AK (2004) Follicular dendritic cells in aging, a “bottle-neck” in the humoral immune response. Ageing Res Rev 3(1):15–29Google Scholar
  7. Balogh P, Aydar Y, Tew JG, Szakal AK (2002) Appearance and phenotype of murine follicular dendritic cells expressing VCAM-1. Anat Rec 268(2):160–168Google Scholar
  8. Bombardieri M, Lewis M, Pitzalis C (2017) Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol 13(3):141–154Google Scholar
  9. Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H, Morrison WI, Bruce ME (1999) Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 5(11):1308–1312Google Scholar
  10. Brown KL, Wathne GJ, Sales J, Bruce ME, Mabbott NA (2009) The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice. J Immunol 183(8):5199–5207Google Scholar
  11. Castagnaro L, Lenti E, Maruzzelli S, Spinardi L, Migliori E, Farinello D, Sitia G, Harrelson Z, Evans SM, Guidotti LG, Harvey RP, Brendolan A (2013) Nkx2-5(+)islet1(+) mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity. Immunity 38(4):782–791Google Scholar
  12. Cerny A, Zinkernagel RM, Groscurth P (1988) Development of follicular dendritic cells in lymph nodes of B-cell-depleted mice. Cell Tissue Res 254(2):449–454Google Scholar
  13. Chen LL, Adams JC, Steinman RM (1978) Anatomy of germinal centers in mouse spleen, with special reference to “follicular dendritic cells”. J Cell Biol 77(1):148–164Google Scholar
  14. Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D (2018) Vaccination in the elderly: The challenge of immune changes with aging. Semin Immunol 40:83–94Google Scholar
  15. Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG (2008) Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol 9(1):54–62Google Scholar
  16. Cremasco V, Woodruff MC, Onder L, Cupovic J, Nieves-Bonilla JM, Schildberg FA, Chang J, Cremasco F, Harvey CJ, Wucherpfennig K, Ludewig B, Carroll MC, Turley SJ (2014) B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat Immunol 15(10):973–981Google Scholar
  17. Crowe PD, VanArsdale TL, Walter BN, Ware CF, Hession C, Ehrenfels B, Browning JL, Din WS, Goodwin RG, Smith CA (1994) A lymphotoxin-beta-specific receptor. Science 264(5159):707–710Google Scholar
  18. Cyster JG, Goodnow CC (1995) Pertussis toxin inhibits migration of B and T lymphocytes into splenic white pulp cords. J Exp Med 182(2):581–586Google Scholar
  19. De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J et al (1994) Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264(5159):703–707Google Scholar
  20. Endres R, Alimzhanov MB, Plitz T, Fütterer A, Kosco-Vilbois MH, Nedospasov SA, Rajewsky K, Pfeffer K (1999) Mature follicular dendritic cell networks depend on expression of lymphotoxin beta receptor by radioresistant stromal cells and of lymphotoxin beta and tumor necrosis factor by B cells. J Exp Med 189(1):159–168Google Scholar
  21. Förster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M (1996) A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87(6):1037–1047Google Scholar
  22. Fütterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K (1998) The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9(1):59–70Google Scholar
  23. Glatzel M, Heppner FL, Albers KM, Aguzzi A (2001) Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31(1):25–34Google Scholar
  24. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404(6781):995–999Google Scholar
  25. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT (1998) A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature 391(6669):799–803Google Scholar
  26. Hanna MG Jr, Nettesheim P, Ogden L, Makinodan T (1967) Reduced immune potential of aged mice: significance of morphologic changes in lymphatic tissue. Proc Soc Exp Biol Med 125(3):882–886Google Scholar
  27. Humphrey JH, Grennan D, Sundaram V (1984) The origin of follicular dendritic cells in the mouse and the mechanism of trapping of immune complexes on them. Eur J Immunol 14(9):859–864Google Scholar
  28. Jarjour M, Jorquera A, Mondor I, Wienert S, Narang P, Coles MC, Klauschen F, Bajénoff M (2014) Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells. J Exp Med 211(6):1109–1122Google Scholar
  29. Johnson GD, Hardie DL, Ling NR, Maclennan IC (1986) Human follicular dendritic cells (FDC): a study with monoclonal antibodies (MoAb). Clin Exp Immunol 64(1):205–213Google Scholar
  30. Kapasi ZF, Burton GF, Shultz LD, Tew JG, Szakal AK (1993) Induction of functional follicular dendritic cell development in severe combined immunodeficiency mice. Influence of B and T cells. J Immunol 150(7):2648–2658Google Scholar
  31. Kapasi ZF, Qin D, Kerr WG, Kosco-Vilbois MH, Shultz LD, Tew JG, Szakal AK (1998) Follicular dendritic cell (FDC) precursors in primary lymphoid tissues. J Immunol 160(3):1078–1084Google Scholar
  32. Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA (1997) Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 6(4):491–500Google Scholar
  33. Koopman G, Parmentier HK, Schuurman HJ, Newman W, Meijer CJ, Pals ST (1991) Adhesion of human B cells to follicular dendritic cells involves both the lymphocyte function-associated antigen 1/intercellular adhesion molecule 1 and very late antigen 4/vascular cell adhesion molecule 1 pathways. J Exp Med 173(6):1297–1304Google Scholar
  34. Kosco MH, Tew JG, Szakal AK (1986) Antigenic phenotyping of isolated and in situ rodent follicular dendritic cells (FDC) with emphasis on the ultrastructural demonstration of Ia antigens. Anat Rec 215(3):201–213, 219–225Google Scholar
  35. Kosco MH, Burton GF, Kapasi ZF, Szakal AK, Tew JG (1989) Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing. Immunology 68(3):312–318Google Scholar
  36. Kosco MH, Pflugfelder E, Gray D (1992) Follicular dendritic cell-dependent adhesion and proliferation of B cells in vitro. J Immunol 148(8):2331–2339Google Scholar
  37. Krautler NJ, Kana V, Kranich J, Tian Y, Perera D, Lemm D, Schwarz P, Armulik A, Browning JL, Tallquist M, Buch T, Oliveira-Martins JB, Zhu C, Hermann M, Wagner U, Brink R, Heikenwalder M, Aguzzi A (2012) Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell 150(1):194–206Google Scholar
  38. Lyons AB, Parish CR (1995) Are murine marginal-zone macrophages the splenic white pulp analog of high endothelial venules? Eur J Immunol 25(11):3165–3172Google Scholar
  39. Mabbott NA, Mackay F, Minns F, Bruce ME (2000) Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nat Med 6(7):719–20Google Scholar
  40. Mackay F, Browning JL (1998) Turning off follicular dendritic cells. Nature 395(6697):26–27Google Scholar
  41. MacLennan IC (1994) Germinal centers. Annu Rev Immunol 12:117–139Google Scholar
  42. Matsumoto M, Mariathasan S, Nahm MH, Baranyay F, Peschon JJ, Chaplin DD (1996) Role of lymphotoxin and the type I TNF receptor in the formation of germinal centers. Science 271(5253):1289–1291Google Scholar
  43. McElhaney JE, Effros RB (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 21(4):418–424Google Scholar
  44. Miller JJ, Nossal GJ (1964) Antigens in immunity. VI. The phagocytic reticulum of lymph node follicles. J Exp Med 120:1075–1086Google Scholar
  45. Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A, Weissmann C (2000) Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288(5469):1257–1259Google Scholar
  46. Nolte MA, Beliën JA, Schadee-Eestermans I, Jansen W, Unger WW, van Rooijen N, Kraal G, Mebius RE (2003) A conduit system distributes chemokines and small blood-borne molecules through the splenic white pulp. J Exp Med 198(3):505–512Google Scholar
  47. Nossal GJ, Abbot A, Mitchell J, Lummus Z (1968) Antigens in immunity. XV. Ultrastructural features of antigen capture in primary and secondary lymphoid follicles. J Exp Med 127(2):277–290Google Scholar
  48. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G (1996) Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184(4):1397–1411Google Scholar
  49. Pasparakis M, Kousteni S, Peschon J, Kollias G (2000) Tumor necrosis factor and the p55TNF receptor are required for optimal development of the marginal sinus and for migration of follicular dendritic cell precursors into splenic follicles. Cell Immunol 201(1):33–41Google Scholar
  50. Qin D, Wu J, Carroll MC, Burton GF, Szakal AK, Tew JG (1998) Evidence for an important interaction between a complement-derived CD21 ligand on follicular dendritic cells and CD21 on B cells in the initiation of IgG responses. J Immunol 161(9):4549–4554Google Scholar
  51. Qin D, Wu J, Vora KA, Ravetch JV, Szakal AK, Manser T, Tew JG (2000) Fc gamma receptor IIB on follicular dendritic cells regulates the B cell recall response. J Immunol 164(12):6268–6275Google Scholar
  52. Reynes M, Aubert JP, Cohen JH, Audouin J, Tricottet V, Diebold J, Kazatchkine MD (1985) Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens. J Immunol 135(4):2687–2694Google Scholar
  53. Rodda LB, Lu E, Bennett ML, Sokol CL, Wang X, Luther SA, Barres BA, Luster AD, Ye CJ, Cyster JG (2018) Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity. Immunity 48(5):1014–1028Google Scholar
  54. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189(11):1747–1756Google Scholar
  55. Schnizlein CT, Kosco MH, Szakal AK, Tew JG (1985) Follicular dendritic cells in suspension: identification, enrichment, and initial characterization indicating immune complex trapping and lack of adherence and phagocytic activity. J Immunol 134(3):1360–1368Google Scholar
  56. Szabo MC, Butcher EC, McEvoy LM (1997) Specialization of mucosal follicular dendritic cells revealed by mucosal addressin-cell adhesion molecule-1 display. J Immunol 158(12):5584–5588Google Scholar
  57. Szakal AK, Hanna MG Jr (1968) The ultrastructure of antigen localization and viruslike particles in mouse spleen germinal centers. Exp Mol Pathol 8(1):75–89Google Scholar
  58. Szakal AK, Gieringer RL, Kosco MH, Tew JG (1985) Isolated follicular dendritic cells: cytochemical antigen localization, Nomarski, SEM, and TEM morphology. J Immunol 134(3):1349–59Google Scholar
  59. Szakal AK, Kosco MH, Tew JG (1988) A novel in vivo follicular dendritic cell-dependent iccosome-mediated mechanism for delivery of antigen to antigen-processing cells. J Immunol 140(2):341–353Google Scholar
  60. Szakal AK, Kosco MH, Tew JG (1989) Microanatomy of lymphoid tissue during humoral immune responses: structure function relationships. Annu Rev Immunol 7:91–109Google Scholar
  61. Szakal AK, Aydar Y, Balogh P, Tew JG (2002) Molecular interactions of FDCs with B cells in aging. Semin Immunol 14(4):267–274Google Scholar
  62. Turner VM, Mabbott NA (2017) Ageing adversely affects the migration and function of marginal zone B cells. Immunology 151(3):349–362Google Scholar
  63. Wang X, Cho B, Suzuki K, Xu Y, Green JA, An J, Cyster JG (2011) Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J Exp Med 208(12):2497–2510Google Scholar
  64. Wols HA, Johnson KM, Ippolito JA, Birjandi SZ, Su Y, Le PT, Witte PL (2010) Migration of immature and mature B cells in the aged microenvironment. Immunology 129(2):278–290Google Scholar
  65. Yoshida K, van den Berg TK, Dijkstra CD (1993) Two functionally different follicular dendritic cells in secondary lymphoid follicles of mouse spleen, as revealed by CR1/2 and FcR gamma II-mediated immune-complex trapping. Immunology 80(1):34–39Google Scholar
  66. Yoshida K, van den Berg TK, Dijkstra CD (1994) The functional state of follicular dendritic cells in severe combined immunodeficient (SCID) mice: role of the lymphocytes. Eur J Immunol 24(2):464–468Google Scholar
  67. Zheng B, Switzer K, Marinova E, Wansley D, Han S (2007) Correction of age-associated deficiency in germinal center response by immunization with immune complexes. Clin Immunol 124(2):131–137Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Immunology and BiotechnologyUniversity of Pécs Clinical CenterPécsHungary

Section editors and affiliations

  • Graham Pawelec
    • 1
    • 2
  1. 1.Center for Medical ResearchUniversity of TübingenTübingenGermany
  2. 2.Health Sciences North Research InstituteSudburyCanada