The Fibroblastic Reticular Cell Conduit

The FRCC rapidly conducts soluble materials across lymphatic tissues, including
chemokines and antigens. It also displays ECM & adhesion proteins that support
T- and B-cell migration past dendritic cells to lymphatic tissue compartments. [TR-04-476]



See the Structure of the FRCC which serves as a conduit to transmit signals across the lymph node cortex to dendritic cells and the HEV wall.
This image is from my 1975 paper where the "FRC Conduit" was first described.

See Anderson and Shaw, Sem. Immunol. 5:271-282. for full description of how the FRC Conduit works in the lymph node cortex.

The FRC Conduit is a reticular fiber surrounded by basement membrane and the cytoplasmic process of an FRC. Its 3D structure as a compartment defining network is nicely revealed in the SEM image of LN Reticulum by Ushiki

The FRC Conduit carries both chemokine signals and soluble antigens to mature dendritic cells that are attached along the course of FRCC connecting the subcapsular sinus lining cells with the walls of HEV in the deep cortex. This is regarded as the anatomical basis for the highly orchestrated waves of lymphocyte emigration and antigen presentation that occur in the LN Cortex after soluble antigen enters in from afferent lymph. Later a second wave of antigen presentation follows entry of antigen laden dendritic cells that crawl into the cortex across the floor of the subcapsular lymphatic sinus.

What drives the fluid transudates and soluble materials down the FRCC from the SCS to a High Endothelial Venule and across its wall and into the lumen?

The membranes of lymphatic endothelium lining the subcapsular, intermediate, and cortical sinus networks, along with key blood vascular structures such as the capillaries in the floor of the SCS and the endothelium of HEV deep in the cortex are rich in Aquaporin-1 activity. The presence of aquaporin "pumps" in these structures is intrigueing. Rapid water fluxes across vascular endothelium and across fibroblastic reticular cell membranes might support unidirectional flow of fluids down the FRC Conduit. But, how aquaporins function in lymph nodes will need to be investigated before it can explain FRC Conduit fluid flow.

The FRCC may also be a target of infection by Ebola viruses that can rapidly cross lymphatic tissues or subcutaneous reticular connective tissue via FRC Conduit to enter the blood at postcapillary venules.


Learn more about polarization and locomotion of lymphocytes

Return to Previous page about Lymphocyte Migration on the FRCC Stroma in Lymph Node Cortex


References:

Clark, S 1962. The Reticulum of Lymph Nodes in Mice Studied with the Electron Microscope. Am. J. Anat. 110: 217-257. (first electron microscopic study of FRC structure)

Moe, RE. 1964. Electron Microscopic Appearance of the Parenchyma of Lymph Nodes. Am J Anat 114:341-369. (first to speculate that FRC might conduct antigens)

Anderson, AO, and ND Anderson. 1975. Studies on the structure and permeability of the microvasculature in normal rat lymph nodes. Amer. J. Path. 80:387-418. (first evidence that FRC Conduit conducted 40KDa Horse Radish Peroxidase tracer from LN Subcapsular Sinus to HEV wall and lumen within a minute after intralymphatic inoculation)

Anderson, ND, AO Anderson, and RG Wyllie. 1976. Specialized structure and metabolic activities of high endothelial venules in rat lymphatic tissues. Immunology 31:455-473.

Anderson, AO and ND Anderson. 1976. Lymphocyte emigration from high endothelial venules in rat lymph nodes. Immunology 31:731-748.

Chang, TW, E Celis, HN Eisen and F Solomon. 1979. Crawling movements of lymphocytes on and beneath fibroblasts in culture. Proc Natl Acad Sci U S A. 76(6): 2917?2921.

Anderson, AO and ND Anderson. 1981. Structure and Physiology of the Lymphatic System. In: Cellular Functions in Immunity and Inflammation, Chapter 2, pp. 29-72, Oppenheim, JJ, Rosenstreich, DA, and Potter M (eds.), Elsevier-North Holland Publishers, NY. [Author's PDF] (Reticular Cells and Conduit function described on pp58-60.)

Sainte-Marie G, Peng FS. 1986. Diffusion of a lymph-carried antigen in the fiber network of the lymph node of the rat. Cell Tissue Res. 245:481-486. (ex vivo demonstration that fluorescent antigen entered reticular fibers from SCS)

Larsen, CG, AO Anderson, E Appella, JJ Oppenheim, and K Matsushima. 1989. The Neutrophil-Activating Protein (NAP-1) is also chemotactic for T lymphocytes. Science 243:1464-1466. [Author's PDF] (first indication how fast chemokine injected in periphery might change rate of cell traffic at HEV in draining lymph node)

Anderson, AO. 1990. "Structure and organization of the lymphatic system." In Immunophysiology. The role of cells and cytokines in immunity and inflammation. Oppenheim, JJ and E Shevach (eds.), pp. 14-45, Oxford University Press, NY. [Author's PDF]

Anderson, AO and S Shaw. 1993. T cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node. Sem. Immunol. 5:271-282.

Anderson, AO, and S Shaw. 1995. "Lymphocyte Trafficking." Chapter 3, In Clinical Immunology, Principles and Practice. RR Rich, TA Fleisher, BD Schwartz, WT Shearer, and W Strober (eds.), pp 39-49, Mosby-Year Book, Inc., St. Louis, MO.

Ebnet, K., E.P. Kaldjian, A.O. Anderson, and S. Shaw. 1995. Orchestrated information transfer underlying leukocyte endothelial interactions. Ann. Rev. Immunol. 14:155-177.

Gretz, JE, EP Kaldjian, AO Anderson, and S Shaw. 1996. Sophisticated strategies for information encounter in the lymph node: The reticular network as a conduit of soluble information and a highway for cell traffic. ("Cutting Edge") J. Immunol. 157:495-499.

Gretz, JE, AO Anderson, and S Shaw. 1997. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156:11-24.

Kuprash, DV, MB Alimzhanov, AV Tumanov, AO Anderson, K Pfeffer, and SA Nedospasov. 1999. TNF and Lymphotoxin beta Cooperate in the Maintenance of Secondary Lymphoid Tissue Microarchitecture But Not in the Development of Lymph Nodes. J. Immunol 163: 6575-6580.

Gunn, MD, S Kyuwa, C Tam, T Kakiuchi, A Matsuzawa, LT Williams and H Nakonoi. 1999. Mice Lacking Expression of Secondary Lymphoid Organ Chemokine Have Defects in Lymphocyte Homing and Dendritic Cell Localization. J. Exp. Med. 189: 451-460.

Gretz, JE, CC Norbury, AO Anderson, AEI Proudfoot, and S Shaw. 2000. Lymph-borne Chemokines and Other Low Molecular Weight Molecules Reach High Endothelial Venules via Specialized Conduits While a Functional Barrier Isolates the Lymphocyte Microenvironments in Lymph Node Cortex. J. Exp. Med. 192:1425-1440.

Kaldjian, EP, JE Gretz, AO Anderson, Y Shi, S Shaw. 2001. Spatial and molecular organization of lymph node T cell cortex: A labyrinthine cavity bounded by an epithelial sheet of fibroblastic reticular cells anchored to basement membrane-like extracellular matrix. Int Immunol 13:1243-1253.

Palframan, R.T., Jung, S., Cheng, G., Weninger, W., Luo, Y., Dorf, M., Littman, D.R,, Rollins, B.J., Zweerink, H., Rot, A. and von Andrian, U.H. 2001. Inflammatory Chemokine Transport and Presentation in HEV : A Remote Control Mechanism for Monocyte Recruitment to Lymph Nodes in Inflamed Tissues, J. Exp. Med. V194(9): 1361-1374.

Baekkevold, E.S., Yamanaka, T., Palframan, R.T., Carlsen, H.S., Reinholt, F.P., von Andrian, U.H., Brandtzaeg, P., and Haraldsen, G. 2001. The CCR7 Ligand ELC (CCL19) Is Transcytosed in High Endothelial Venules and Mediates T Cell Recruitment. J. Exp. Med., v193(9):1105-1112.

Penna, G., Sozzani, S. and Adorini, L. 2001. Cutting Edge: Selective Usage of Chemokine Receptors by Plasmacytoid Dendritic Cells. J. Immunol. 167: 1862-1866.

Kuprash, DV, MB Alimzhanov, AV Tumanov, SI Grivennikov, AN Shakkov, LN Drutskaya, MW Marino, RL Turetskaya, AO. Anderson, K Rajewsky, K Pfeffer and S A Nedospasov. 2002. Redundancy in TNF and LT signaling in vivo: mice with inactivation of the entire TNF/LT locus versus single knockout mice. Mol. Cell. Biol. 22:8626-8634.

Ingulli, E, DR Ulman, MM Lucido, and Marc K Jenkins. 2002. In Situ Analysis Reveals Physical Interactions Between CD11b+ Dendtritic Cells and Antigen-Specific CD4 T Cells After Subcutaneous Injection of Antigen. J. Immunol. 169: 2247-2252.

Ohtani, O, Ohtani, Y, Carati, CJ, and Gannon, BJ. 2003. Fluid and Cellular Pathways of Rat Lymph Nodes in Relation to Lymphatic Labyrinths and Aquaporin-1 Expression. Arch. Histol. Cytol. 66(3):261-273.

Nolte, MA, JAM Belien, I Schadee-Eestermans, W. Jansen, WWJ Unger, N van Rooijen, G Kraal and RE Mebius. 2003. A Conduit System Distributes Chemokines and Small Blood-borne Molecules through the Splenic White Pulp. J. Exp. Med 198:505-512

Bajenoff, M, S Granjeaud and S Guerder. 2003. The Strategy of T Cell Antigen-presenting Cell Encounter in Antigen-draining Lymph Nodes Revealed by Imaging of Initial T Cell Activation. J. Exp. Med. 198:715-724

Itano AA, SJ McSorley, RL Reinhardt, BD Ehst, E Ingulli, AY, Rudentsky and Marc K Jenkins. 2003. Distinct Dendritic Cell Populations Sequentially Present Antigen to CD4 T Cells and Stimulate Different Aspects of Cell-Mediated Immunity. Immunity 19: 47-57.

Itano AA, and MK Jenkins. 2003. Antigen Presentation to naive CD4 T cells in the lymph node. Nature Immunology 4: 733-739.

von Andrian, UH and T Mempel. 2003. Homing and Cellular Traffic in Lymph Nodes. Nature Reviews Immunology 3: 867-878. [PubMed]

Thomazy VA, Vega F, Medeiros LJ, Davies PJ and Jones D. 2003. Phenotypic modulation of the stromal reticular network in normal and neoplastic lymph nodes: tissue transglutaminase reveals coordinate regulation of multiple cell types. Am J Pathol. 63: 165-74.

Mempel, TR, SE Henrickson, and UH von Andrian. 2004. T cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427: 154-159. [PubMed]

Pribila JT, AA Itano, KL Mueller, Y Shimizu. 2004. The alpha1beta1 and alphaEbeta7 integrins define a subset of dendritic cells in peripheral lymph nodes with unique adhesive and antigen uptake properties. J Immunol. 172: 282-91

Katakai, T, T Hara, J-H Lee, H Gonda, M Sugai, and A Shimizu. 2004. A novel reticular stromal structure in lymph node cortex: an immuno-platform for interactions among dendritic cells, T cells and B cells. Int Immunol 16(8):1133-1142.

Katakai T, T Hara, M Sugai, H Gonda, and A Shimizu. 2004. Lymph Node Fibroblastic Reticular Cells Construct the Stromal Reticulum via Contact with Lymphocytes. J Exp Med 200: 783-795

MacPherson, G, S Milling, U Yrlid, L Cousins, E Turnbull, and F-P Huang. December 1, 2004. Uptake of Antigens from the Intestine by Dendritic Cells. Ann. N.Y. Acad. Sci., 1029: 75 - 82.

Carragher, D, Johal, R, Button, A, White, A, Eliopoulos, A, Jenkinson, E, Anderson, G, and J Caamano. 2004. A Stroma-Derived Defect in NF-{kappa}B2-/- Mice Causes Impaired Lymph Node Development and Lymphocyte Recruitment. J. Immunol. v173(4) pp2271-2279.

Sixt, M, N Kanazawa, M Selg, T Samson, G Roos, DP Reinhardt, R Pabst, MB Lutz and L Sorokin. 2005. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity v22, pp19-29.

Anderson, AO and S Shaw. 2005. Conduit for Privileged Communications In the Lymph Node. Preview. Immunity v22 pp3-5. [PDF]

Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, et al. 2005. Antigen-Engaged B Cells Undergo Chemotaxis toward the T Zone and Form Motile Conjugates with Helper T Cells. PLoS Biol 3(6): e150

Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, Romani N, Tripp CH, Douillard P, Leserman L, Kaiserlian D, Saeland S, Davoust J, Malissen B. 2005. Dynamics and Function of Langerhans Cells In Vivo Dermal Dendritic Cells Colonize Lymph Node AreasDistinct from Slower Migrating Langerhans Cells. Immunity v22(5):643-654.

Pabst, O., Peters, T., Czeloth, N., Bernhardt, G., Scharffetter-Kochanek K., and F?er, R. Cutting Edge: Egress of Newly Generated Plasma Cells from Peripheral Lymph Nodes Depends on beta 2 Integrin. J. Immunol. 174: 7492-7495.

Drumea-Mirancea M, Wessels JT, Muller CA, Essl M, Eble JA, Tolosa E, Koch M, Reinhardt DP, Sixt M, Sorokin L, Stierhof YD, Schwarz H, Klein G. 2006. Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules. J Cell Sci. 119(7): 1396-1405

Qi, H., Egen, J.G., Huang, A.Y.C., and Germain, R.N. 2006. Extrafollicular Activation of Lymph Node B Cells by Antigen-Bearing Dendritic Cells. Science Vol. 312. no. 5780, pp.1672-1676

Bajenoff, M., J.G., Egen, L.Y. Koo, Laugier, J.P., Brau, F., Glaichenhaus, N., and Germain, R.N.. 2006. Stromal Cell Networks Regulate Lymphocyte Entry, Migration, and Territoriality in Lymph Nodes. Immunity 25(6) pp.989-1001.

Liao S, Ruddle NH. 2006. Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J. Immunol. 177: 3369-3379

Reinhardt RL,et al. 2006.Visualization of IL-12/23p40 in vivo reveals immunostimulatory dendritic cell migrants that promote Th1 differentiation. J Immunol. 177(3):1618-1627

Wikstrom ME, et al. 2006. Influence of mucosal adjuvants on antigen passage and CD4+ T cell activation during the primary response to airborne allergen. J Immunol. 2006 177(2):913-924

McKenzie EJ, et al 2007. Mannose Receptor Expression and Function Define a New Population of Murine Dendritic Cells. J. Immunol. 178: 4975-4983

Mueller SN, et al. 2007. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl. Acad. Sci. USA 104: 15430-15435

Richter MV, et al. 2007. The {alpha}1beta1 Integrin and TNF Receptor II Protect Airway CD8+ Effector T Cells from Apoptosis during Influenza Infection. J. Immunol. 179: 5054-5063

Halin C, et al. 2007. VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 110: 3158-3167

Manzo A, et al. 2007. CCL21 Expression Pattern of Human Secondary Lymphoid Organ Stroma Is Conserved in Inflammatory Lesions with Lymphoid Neogenesis. Am. J. Pathol. 171: 1549-1562

Bourges D, et al. 2007. Targeting the Gut Vascular Endothelium Induces Gut Effector CD8 T Cell Responses Via Cross-Presentation by Dendritic Cells. J. Immunol. 179: 5678-5685

Roozendaal, R, Mebius, RE, Kraal, G. 2008. The Conduit System of the Lymph Node. Int Immunol 20: 1483-1487


Recirculation | Emigration at HEV | FRC Conduit | Locomotion | Chemotaxis & Links

Dendritic Cells in TDL | Dendritic cells in Tissue | Immune System Lecture Notes | Mucosal Immunity

Links to Homing Articles | Art Anderson's CV | Google Scholar AO Anderson | Contact Art

See who's visiting this page.View Page Stats