Follicular Dendritic Cells (B Lymphocyte Stimulating)


Follicular dendritic cells (FDCs) are found in all secondary lymphoid tissues, where they function as a repository of antigens to maintain long‐term IgG and IgE responses. Antigens are trapped and retained on FDCs in the form of immune complexes; and while most immune complexes require large quantities to induce an immune response, FDC‐trapped antigens are remarkably immunogenic and only a few picogram can induce microgram concentrations of a specific antibody. In addition to providing antigens, FDCs provide a number of additional signals (e.g. BAFF, IL‐6) that further contribute to antibody production. In addition to their contributions to immunity in health, FDCs are involved in some pathological situations including HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome), sarcoma/lymphoma, prion‐mediated transmissible spongiform encephalopathies (e.g. Creutzfeldt–Jakob) and Castleman disease. A further understanding of FDCs and their functions in both health and disease may aid our ability to better regulate immunity and ameliorate some disease states.

Key Concepts

  • FDCs trap antigens as immune complexes that consist of antigen in the presence of either specific antibodies or complement proteins, or both. FDCs trap immune complexes using CD32 and/or CD21.
  • FDC‐trapped antigens or iccosomes are highly immunogenic and minute amounts (picogram) can induce significant quantities (microgram) of a specific antibody.
  • FDC‐trapped antigens remain on the surface of FDCs and are not internalised. These antigens are not degraded but maintain their native configuration and immunoreactivity for many months.
  • In addition to trapping conventional antigens, FDCs also trap HIV (and potentially other viruses) and maintain the infectious nature for many months. FDC‐trapped HIV can transmit infection to adjacent target cells (e.g. CD4+ T lymphocytes).
  • FDCs provide both antigen and other signals that are central to the induction and maintenance of specific antibody responses.
  • FDCs can play roles in both health and disease (e.g. HIV/AIDS, prion diseases and follicular lymphomas).

Keywords: follicular dendritic cells; secondary lymphoid tissues; germinal centres; anamnestic antibody responses; complement proteins and receptors; Fc receptors; antigen presentation to B‐lymphocytes; HIV reservoir; prions; follicular lymphoma and sarcoma

Figure 1. Light and electron micrographs of isolated FDCs. (a) Light micrograph of an FDC in suspension. Note the long dendritic processes emanating from the cell body. These processes allow intimate interactions with surrounding lymphocytes. The arrows indicate an FDC. (b) Scanning electron micrograph of an isolated FDC cultured on collagen type 1 illustrating the extensive dendritic networks generated in vitro. Reproduced from Dr. Andras K Szaka Creative Commons Compatible License.
Figure 2. FDCs trapping fluorescently labelled ICs in vivo and in vitro. (a) Photomicrograph of FDCs in vivo demonstrating trapping of ovalbumin ICs (ovalbumin + antiovalbumin). The ICs on FDCs are detected using goat antibody directed against the antiovalbumin present in the immune complexes (i.e. goat‐anti‐IgG (blue)). The arrows designate two FDC networks containing trapped fluorescent ICs. (b) FDC‐trapping of fluorescent antigen in vitro. Ovalbumin ICs were incubated with highly enriched FDCs in culture. Detection of the FDC‐trapped antigen is performed using goat antibody specific for the IgG in the ovalbumin–anti‐ovalbumin complexes (red) and the FDCs are labelled using FDC‐M1 (blue). (c) Higher magnification of an isolated FDC with ICs labelled as in panel b. Contributed by Dr. John G. Tew.
Figure 3. Important FDC‐membrane‐associated signalling molecules. In experimental animals with specific Abs, ICs form instantaneously upon Ag challenge and are trapped by FDC‐Fcγ RIIB and CR1/2. The engagement of FDC‐FcγRIIB with ICs provides signals to FDCs that result in the production of BAFF and IL‐6. These same ICs also activate complement and generate C3 and C4 fragments that are covalently bound to FDC‐ICs and can also be seen ‘decorating’ the FDC membranes. C3 fragments (CD21 ligand) engage FDC‐CR1/2, whereas C4BP binds C4b and localises on the FDC‐ICs. The periodically arranged FDC‐ICs engage BCRs, and extensive BCR cross‐linking delivers an Ag‐specific stimulatory signal. FDC‐CD21‐ligand binds B‐cell CD21, FDC‐C4BP ligates B‐cell CD40, FDC‐BAFF engages B‐cell BAFF‐R, and FDC IL‐6 binds B‐cell IL‐6R, delivering additional co‐stimulatory signals that promote B‐cell activation, proliferation and differentiation. Contributed by Dr. John G. Tew.
Figure 4. FDC contributions in health and disease. FDCs serve as a repository of retained antigens important in maintaining IgG and IgE memory responses. In addition, FDCs provide signs that promote the germinal centre (GC) reaction and license macrophages (MO) to destroy and remove apoptotic cells from the GC. In disease, FDCs also play important roles, serving as a reservoir of infectious HIV, and a source of PrPC, the normal form of the prion protein. Furthermore, these cells appear to play roles in some malignancies and in Castleman disease.


Allen CD, Okada T, Tang HL, et al. (2007) Imaging of germinal center selection events during affinity maturation. Science 315: 528–531.

Aydar Y, Balogh P, Tew JG, et al. (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. Journal of Immunology 171: 5975–5987.

Aydar Y, Balogh P, Tew JG, et al. (2004) Follicular dendritic cells in aging, a "bottle‐neck" in the humoral immune response. Ageing Research Reviews 3: 15–29.

Balogh P, Aydar Y, Tew JG, et al. (2002) Appearance and phenotype of murine follicular dendritic cells expressing VCAM‐1. Anatatomical Record 268: 160–168.

Biberfeld P, Porwit A, Biberfield G, et al. (1988) Lymphadenopathy in HIV (HTLV‐III LAV) infected subjects: the role of virus and follicular dendritic cells. Cancer Detection and Prevention 12: 217–224.

Brown KL, Stewart K, Ritchie DL, et al. (1999) Scrapie replication in lymphoid tissues depends on prion protein‐expressing follicular dendritic cells. Nature Medicine 5: 1308–1312.

Burton GF, Conrad DH, Szakal AK, et al. (1993) Follicular dendritic cells (FDC) and B cell co‐stimulation. Journal of Immunology 150: 31–38.

Carrasco YR and Batista FD (2007) B cells acquire particulate antigen in a macrophage‐rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27: 160–171.

Chan AC, Chan KW, Chan JK, et al. (2001) Development of follicular dendritic cell sarcoma in hyaline‐vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies. Histopathology 38: 510–518.

Dintzis RZ, Middleton MH and Dintzis HM (1983) Studies on the immunogenicity and tolerogenicity of T‐independent antigens. Journal of Immunology 131: 2196–2203.

Donaldson SL, Kosco MH, Szakal AK, et al. (1986) Localization of antibody‐forming cells in draining lymphoid organs during long‐term maintenance of the antibody response. Journal of Leukocyte Biology 40: 147–157.

El Shikh ME, El Sayed R, Szakal AK, et al. (2006) Follicular dendritic cell (FDC)‐Fc gamma RIIB engagement via immune complexes induces the activated FDC phenotype associated with secondary follicle development. European Journal of Immunology 36: 2715–2724.

El Shikh ME, El Sayed RM, Wu Y, et al. (2007) TLR4 on follicular dendritic cells: an activation pathway that promotes accessory activity. Journal of Immunology 179: 4444–4450.

El Shikh ME, El Sayed RM, Szakal AK, et al. (2009) T‐independent antibody responses to T‐dependent antigens: a novel follicular dendritic cell‐dependent activity. Journal of Immunology 182: 3482–3491.

El Shikh ME, El Sayed RM, Sukumar S, et al. (2010) Activation of B cells by antigens on follicular dendritic cells. Trends in Immunology 31: 205–211.

El‐Osta HE and Kurzrock R (2011) Castleman's disease: from basic mechanisms to molecular therapeutics. The Oncologist 16: 497–511.

Estes JD, Keele BF, Tenner‐Racz K, et al. (2002) Follicular dendritic cell‐mediated up‐regulation of CXCR4 expression on CD4 T Cells and HIV pathogenesis. Journal of Immunology 169: 2313–2322.

Estes JD, Thacker TC, Hampton DL, et al. (2004) Follicular dendritic cell regulation of CXCR4‐mediated germinal center CD4 T cell migration. Journal of Immunology 173: 6169–6178.

Ferguson AR, Youd ME and Corley RB (2004) Marginal zone B cells transport and deposit IgM‐containing immune complexes onto follicular dendritic cells. International Immunology 16: 1411–1422.

Fletcher CV, Staskus K, Wietgrefe SW, et al. (2014) Persistent HIV‐1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proceedings of the National Academy of Science U S A 111: 2307–2312.

Haase AT (1999) Population biology of HIV‐1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annual Reviews of Immunology 17: 625–656.

Heath SL, Tew JG, Szakal AK, et al. (1995) Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 377: 740–744.

Humphrey JH, Grennan D and Sundaram V (1984) The origin of follicular dendritic cells in the mouse and the mechanism of trapping of immune complexes on them. European Journal of Immunology 14: 859–864.

Kairouz S, Hashash J, Kabbara W, et al. (2007) Dendritic cell neoplasms: an overview. American Journal of Hematology 82: 924–928.

Keele BF, Tazi L, Gartner S, et al. (2008) Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1. Journal of Virology 82: 5548–5561.

Krautler NJ, Kana V, Kranich J, et al. (2012) Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell 150: 194–206.

Kuppers R (2004) Prognosis in follicular lymphoma – it's in the microenvironment. New England Journal of Medicine 351: 2152–2153.

Mabbott NA, Mackay F, Minns F, et al. (2000) Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie [letter]. Nature Medicine 6: 719–720.

Mabbott NA, Young J, McConnell I, et al. (2003) Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. Journal of Virology 77: 6845–6854.

Mandel TE, Phipps RP, Abbot A, et al. (1980) The follicular dendritic cell: long term antigen retention during immunity. Immunological Reviews 53: 29–59.

Montrasio F, Frigg R, Glatzel M, et al. (2000) Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288: 1257–1259.

Palmer S, Maldarelli F, Wiegand A, et al. (2008) Low‐level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proceedings of the National Academy of Science U S A 105: 3879–3884.

Pantaleo G, Graziosi C, Demarest JF, et al. (1993) HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362: 355–358.

Phipps RP, Mandel TE and Tew JG (1981) Effect of immunosuppressive agents on antigen retained in lymphoid follicles and collagenous tissue of immune mice. Cellular Immunology 57: 505–516.

Racz P, Tenner‐Racz K and Schmidt H (1989) Follicular dendritic cells in HIV‐induced lymphadenopathy and AIDS. Acta pathologica, microbiologica, et immunologica Scandinavica. Supplementum 8: 16–23.

Schwickert TA, Lindquist RL, Shakhar G, et al. (2007) In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446: 83–87.

Smith BA, Gartner S, Liu Y, et al. (2001) Persistence of infectious HIV on follicular dendritic cells. Journal of Immunology 166: 690–696.

Sukumar S, El Shikh ME, Tew JG, et al. (2008) Ultrastructural study of highly enriched follicular dendritic cells reveals their morphology and the periodicity of immune complex binding. Cell and Tissue Research 332: 89–99.

Sun X, Chang KC, Abruzzo LV, et al. (2003) Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman's disease. Human Pathology 34: 835–840.

Szakal AK, Holmes KL and Tew JG (1983) Transport of immune complexes from the subcapsular sinus to lymph node follicles on the surface of nonphagocytic cells, including cells with dendritic morphology. Journal of Immunology 131: 1714–1727.

Szakal AK, Kosco MH and Tew JG (1988) A novel in vivo follicular dendritic cell‐dependent iccosome‐mediated mechanism for delivery of antigen to antigen‐processing cells. Journal of Immunology 140: 341–353.

Szakal AK, Kosco MH and Tew JG (1989) Microanatomy of lymphoid tissue during humoral immune responses: structure function relationships. Annual Reviews of Immunology 7: 91–109.

Szakal AK, Taylor JK, Smith JP, et al. (1990) Kinetics of germinal center development in lymph nodes of young and aging immune mice. Anatomical Record 227: 475–485.

Szakal AK, Kapasi ZF, Masuda A, et al. (1992) Follicular dendritic cells in the alternative antigen transport pathway: microenvironment, cellular events, age and retrovirus related alterations. Seminars in Immunology 4: 257–265.

Tenner‐Racz K, Racz P, Schmidt H, et al. (1991) Virus trapping by follicular dendritic cells in retrovirus infections inducing follicular hyperplasia of lymph nodes. In: Racz P, Dijkstra CD and Gluckman JC (eds) Accessory Cells in HIV and Other Retroviral Infections, pp. 83–97 Basel: Karger.

Tew JG, Kosco MH and Szakal AK (1989) The alternative antigen pathway. Immunology Today 10: 229–232.

Tew JG, Mandel TE and Miller GA (1979) Immune retention: immunological requirements for maintaining an easily degradable antigen in vivo. Australian Journal of Experimental and Biological Medical Science 57: 401–414.

Thacker TC, Zhou X, Estes JD, et al. (2009) Follicular dendritic cells and human immunodeficiency virus type 1 transcription in CD4+ T cells. Journal of Virology 83: 150–158.

Wopfner F, Weidenhofer G, Schneider R, et al. (1999) Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein. Journal of Molecular Biology 289: 1163–1178.

Yagi K, Yamamoto K, Umeda S, et al. (2013) Expression of multidrug resistance 1 gene in B‐cell lymphomas: association with follicular dendritic cells. Histopathology 62: 414–420.

Zhang J and Perelson AS (2013) Contribution of follicular dendritic cells to persistent HIV viremia. Journal of Virology 87: 7893–7901.

Further Reading

Allen CD and Cyster JG (2008) Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Seminars in Immunology 20: 14–25.

Fu YX and Chaplin DD (1999) Development and maturation of secondary lymphoid tissues. Annual Reviews of Immunology 17: 399–433.

Kosco‐Vilbois MH (2003) Are follicular dendritic cells really good for nothing? Nature Reviews of Immunology 3: 764–769.

Kuppers R (2004) Prognosis in follicular lymphomas – it's in the microenvironment. New England Journal of Medicine 351: 2152–2153.

Petrasch S, Brittinger G, Wacker HH, Schmitz J and Kosco‐Vilbois M (1994) Follicular dendritic cells in non‐Hodgkin's lymphomas. Leukemia and Lymphoma 15: 33–43.

Tew JG, Wu J, Fakher M, Szakal AK and Qin D (2001) Beyond the necessity of T cell help. Trends in Immunology 22: 361–367.

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Wang, Changna, Ollerton, Matthew T, and Burton, Gregory F(Feb 2016) Follicular Dendritic Cells (B Lymphocyte Stimulating). In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001129.pub3]