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Ultrastructural study of highly enriched follicular dendritic cells reveals their morphology and the periodicity of immune complex binding

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Abstract

Follicular dendritic cells (FDCs) are immune accessory cells found in the follicles of secondary lymphoid organs where they promote B cell maturation in germinal centers (GCs) that develop following antigen exposure. Recently, we published a method for isolating functional murine FDCs in high purity. We reasoned that disruption of FDC reticula in vivo would alter FDC morphology. The present study was undertaken to determine the morphological features of isolated FDCs. FDC-M1 and immune complex (IC) labeling were used to identify FDCs in isolated preparations. Results at the light-microscopic level revealed that isolated FDCs trapped ICs, expressed FDC-M1 and cadherins, but generally appeared non-dendritic. However, at the ultrastructural level, the majority of FDCs exhibited dendrites and typical euchromatic nuclei that appeared as single, bilobed, or double nuclei. Based on morphology, four varieties of FDCs were distinguishable, possibly indicative of differences in maturity. Remarkably, ICs trapped by FDCs showed a distinctive periodic arrangement consistent with that known to induce immune responses by thymus independent-2 (TI-2) antigens that engage and cross-link multiple B cell receptors. The ability of FDCs to trap ICs and then display these T-cell-dependent antigens with repeating periodicity suggests that multiple B cell receptors are cross-linked by antigen on FDCs, thus promoting B cell stimulation and proliferation. Rapid proliferation is characteristic of the GC reaction, and the arrangement of T-dependent antigens in this periodic fashion may help to explain the profuse B cell proliferation in the GC microenvironment.

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References

  • Alexander JS, Elrod JW, Park JH (2001) Roles of leukocyte and immune cell junctional proteins. Microcirculation 8:169–179

    Article  PubMed  CAS  Google Scholar 

  • Aydar Y, Sukumar S, Szakal AK, Tew JG (2005) The influence of immune complex-bearing follicular dendritic cells on the IgM response, Ig class switching, and production of high affinity IgG. J Immunol 174:5358–5366

    PubMed  CAS  Google Scholar 

  • Berek C, Ziegner M (1993) The maturation of the immune response. Immunol Today 14:400–404

    Article  PubMed  CAS  Google Scholar 

  • Burton GF, Conrad DH, Szakal AK, Tew JG (1993) Follicular dendritic cells (FDC) and B cell co-stimulation. J Immunol 150:31–38

    PubMed  CAS  Google Scholar 

  • Burton GF, Masuda A, Heath SL, Smith BA, Tew JG, Szakal AK (1997) Follicular dendritic cells (FDC) in retroviral infection: host/pathogen perspectives. Immunol Rev 156:185–197

    Article  PubMed  CAS  Google Scholar 

  • Chen LL, Adams JC, Steinman RM (1978) Anatomy of germinal centers in mouse spleen, with special reference to “follicular dendritic cells”. J Cell Biol 77:148

    Article  PubMed  CAS  Google Scholar 

  • Dintzis RZ, Middleton MH, Dintzis HM (1983) Studies on the immunogenicity and tolerogenicity of T-independent antigens. J Immunol 131:2196–2203

    PubMed  CAS  Google Scholar 

  • El Shikh ME, El Sayed R, Szakal AK, Tew JG (2006) FDC-FcgRIIB engagement via immune complexes induces the activated FDC phenotype associated with secondary follicle development. Eur J Immunol 36:2715–2724

    Article  PubMed  CAS  Google Scholar 

  • El Shikh ME, El Sayed RM, Tew JG, Szakal AK (2007) Follicular dendritic cells stimulated by collagen type I develop dendrites and networks in vitro. Cell Tissue Res 329:81–89

    Article  PubMed  CAS  Google Scholar 

  • Ennas MG, Chilosi M, Scarpa A, Lantini MS, Cadeddu G, Fiore-Donati L (1989) Isolation of multicellular complexes of follicular dendritic cells and lymphocytes: immunophenotypical characterization, electron microscopy and culture studies. Cell Tissue Res 257:9–15

    Article  PubMed  CAS  Google Scholar 

  • Freedman AS, Munro JM, Rhynhart K, Schow P, Daley J, Lee N, Svahn J, Eliseo L, Nadler LM (1992) Follicular dendritic cells inhibit human B-lymphocyte proliferation. Blood 80:1284–1288

    PubMed  CAS  Google Scholar 

  • Hanna MG Jr, Szakal AK (1968) Localization of 125I-labeled antigen in germinal centers of mouse spleen: histologic and ultrastructural autoradiographic studies of the secondary immune reaction. J Immunol 101:949–962

    PubMed  Google Scholar 

  • Heinen E, Radoux D, Kinet-Denoel C, Simar LJ (1983) Colloidal gold, a useful marker for antigen localization on follicular dendritic cells. J Immunol Methods 59:361–368

    Article  PubMed  CAS  Google Scholar 

  • Heinen E, Lilet-Leclercq C, Mason DY, Stein H, Boniver J, Radoux D, Kinet-Denoel C, Simar LJ (1984) Isolation of follicular dendritic cells from human tonsils and adenoids. II. Immunocytochemical characterization. Eur J Immunol 14:267–273

    Article  PubMed  CAS  Google Scholar 

  • Huber C, Thielen C, Seeger H, Schwarz P, Montrasio F, Wilson MR, Heinen E, Fu YX, Miele G, Aguzzi A (2005) Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes. J Immunol 174:5526–5536

    PubMed  CAS  Google Scholar 

  • Imai Y, Sato T, Yamakawa M, Kasajima T, Suda A, Watanabe Y (1989) A morphological and immunohistochemical study of lymphoid germinal centers in synovial and lymph node tissues from rheumatoid arthritis patients with special reference to complement components and their receptors. Acta Pathol Jpn 39:127–134

    PubMed  CAS  Google Scholar 

  • Kinet-Denoel C, Heinen E, Radoux D, Simar LJ (1982) Follicular dendritic cells in lymph nodes after X-irradiation. Int J Radiat Biol Relat Stud Phys Chem Med 42:121–130

    Article  PubMed  CAS  Google Scholar 

  • Kosco MH, Pflugfelder E, Gray D (1992) Follicular dendritic cell-dependent adhesion and proliferation of B cells in vitro. J Immunol 148:2331–2339

    PubMed  CAS  Google Scholar 

  • Kraal G, Weissman IL, Butcher EC (1982) Germinal centre B cells: antigen specificity and changes in heavy chain class expression. Nature 298:377–379

    Article  PubMed  CAS  Google Scholar 

  • Liu YJ, Malisan F, Bouteiller O de, Guret C, Lebecque S, Banchereau J, Mills FC, Max EE, Martinez-Valdez H (1996) Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4:241–250

    Article  PubMed  CAS  Google Scholar 

  • Mabbott NA, Bruce ME, Botto M, Walport MJ, Pepys MB (2001) Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 7:485–487

    Article  PubMed  CAS  Google Scholar 

  • MacLennan ICM (1991) The centre of hypermutation. Nature 354:352–353

    Article  PubMed  CAS  Google Scholar 

  • MacLennan IC (1994a) Germinal centers. Annu Rev Immunol 12:117–139

    Article  PubMed  CAS  Google Scholar 

  • MacLennan IC (1994b) Somatic mutation. From the dark zone to the light. Curr Biol 4:70–72

    Article  PubMed  CAS  Google Scholar 

  • MacLennan ICM, Gray D (1986) Antigen-driven selection of virgin and memory B cells. Immunol Rev 91:61–85

    Article  PubMed  CAS  Google Scholar 

  • Mandel TE, Phipps RP, Abbot A, Tew JG (1980) The follicular dendritic cell: long term antigen retention during immunity. Immunol Rev 53:29–59

    Article  PubMed  CAS  Google Scholar 

  • Mandel TE, Phipps RP, Abbot AP, Tew JG (1981) Long-term antigen retention by dendritic cells in the popliteal lymph node of immunized mice. Immunology 43:353–362

    PubMed  CAS  Google Scholar 

  • Muller J, Tvrdik D, Dvorak R, Djaborkhel R, Mandys V, Bednar B, Raska I, Lojda Z (2000) Expression of beta-catenins and cadherins by follicular dendritic cells in human lymph nodes. Acta Histochem 102:369–380

    Article  PubMed  CAS  Google Scholar 

  • Nossal GJV, Abbot A, Mitchell J, Lummus Z (1968) Antigen in immunity. XV. Ultrastructural features of antigen capture in primary and secondary lymphoid follicles. J Exp Med 127:277–290

    Article  PubMed  CAS  Google Scholar 

  • Schmitz J, Petrasch S, van Lunzen J, Racz P, Kleine HD, Hufert F, Kern P, Schmitz H, Tenner-Racz K (1993) Optimizing follicular dendritic cell isolation by discontinuous gradient centrifugation and use of the magnetic cell sorter (MACS). J Immunol Methods 159:189–196

    Article  PubMed  CAS  Google Scholar 

  • 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 134:1360–1368

    PubMed  CAS  Google Scholar 

  • Schriever F, Freedman AS, Freeman G, Messner E, Lee G, Daley J, nadler LM (1989) Isolated human follicular dendritic cells display a unique antigenic phenotype. J Exp Med 169:2043

    Article  PubMed  CAS  Google Scholar 

  • Smith BA, Gartner S, Liu Y, Perelson AS, Stilianakis NI, Keele BF, Kerkering TM, Ferreira-Gonzalez A, Szakal AK, Tew JG, Burton GF (2001) Persistence of infectious HIV on follicular dendritic cells. J Immunol 166:690–696

    PubMed  CAS  Google Scholar 

  • Sukumar S, Conrad DH, Szakal AK, Tew JG (2006a) Differential T cell-mediated regulation of CD23 (Fc epsilonRII) in B cells and follicular dendritic cells. J Immunol 176:4811–4817

    PubMed  CAS  Google Scholar 

  • Sukumar S, Szakal AK, Tew JG (2006b) Isolation of functionally active murine follicular dendritic cells. J Immunol Methods 313:81–95

    Article  PubMed  CAS  Google Scholar 

  • Szakal AK, Hanna MG Jr (1968) The ultrastructure of antigen localization and virus-like particles in mouse spleen germinal centers. Exp Mol Pathol 8:75–89

    Article  PubMed  CAS  Google Scholar 

  • Szakal AK, Holmes KL, 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. J Immunol 131:1714–1727

    PubMed  CAS  Google Scholar 

  • Szakal AK, Gieringer RL, Kosco MH, Tew JG (1985) Isolated follicular dendritic cells: cytochemical antigen localization, Nomarski, SEM, and TEM morphology. J Immunol 134:1349–1359

    PubMed  CAS  Google Scholar 

  • 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 140:341–353

    PubMed  CAS  Google Scholar 

  • Szakal AK, Kosco MH, Tew JG (1989) Microanatomy of lymphoid tissue during the induction and maintenance of humoral immune responses: structure function relationships. Annu Rev Immunol 7:91–109

    Article  PubMed  CAS  Google Scholar 

  • Tenner-Racz K, Racz P, Gartner S, Ramsauer J, Dietrich M, Gluckman JC, Popovic M (1989) Ultrastructural analysis of germinal centers in lymph nodes of patients with HIV-1-induced persistent generalized lymphadenopathy: evidence for persistence of infection. Prog AIDS Pathol 1:29–40

    PubMed  CAS  Google Scholar 

  • Tew JG, Mandel TE, Phipps RP, Szakal AK (1984) Tissue localization and retention of antigen in relation to the immune response. Am J Anat 170:407–420

    Article  PubMed  CAS  Google Scholar 

  • Tew JG, Wu J, Fakher M, Szakal AK, Qin D (2001) Follicular dendritic cells: beyond the necessity of T-cell help. Trends Immunol 22:361–367

    Article  PubMed  CAS  Google Scholar 

  • Wu J, Qin D, Burton GF, Szakal AK, Tew JG (1996) Follicular dendritic cell (FDC) derived Ag and accessory activity in initiation of memory IgG responses in vitro. J Immunol 157:3404–3411

    PubMed  CAS  Google Scholar 

  • Wu Y, Sukumar S, El Shikh ME, Best AM, Szakal AK, Tew JG (2008) Immune complex-bearing follicular dendritic cells deliver a late antigenic signal that promotes somatic hypermutation. J Immunol 180:281–290

    Article  PubMed  CAS  Google Scholar 

  • Yoshida T, Takaya K (1989) Follicular dendritic reticular cells in the germinal center of the rat lymph node as studied by immuno-electron microscopy. Arch Histol Cytol 52:327–335

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Mrs. Judy Williamson for her excellent technical assistance in preparing samples for transmission electron microscopy. We also thank Ms. Natasha Purdie for her assistance with the confocal microscopy.

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Correspondence to John G. Tew.

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This work was supported by National Institutes of Health Grant AI-17142. Electron microscopy and confocal microscopy were performed at the VCU Department of Neurobiology and Anatomy Microscopy Facility supported, in part, by funding from an NIH-NINDS Center core grant (5P30NS047463).

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Sukumar, S., El Shikh, M.E., Tew, J.G. et al. Ultrastructural study of highly enriched follicular dendritic cells reveals their morphology and the periodicity of immune complex binding. Cell Tissue Res 332, 89–99 (2008). https://doi.org/10.1007/s00441-007-0566-4

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