Lymph nodes (LNs) are subdivided into three compartments: the lymphatic system, the blood circulation and the parenchyma, which is further subdivided into B-cell follicles and the T-cell area that together form the cortex, and the medulla. Cellular and molecular traffic between these compartments is an essential aspect of LN physiology.
Afferent lymph transports antigen and antigen-presenting dendritic cells (DCs) from peripheral tissues to draining LNs. The lymphatic system also functions as a one-way communication system along which molecular messages, such as chemokines, are transmitted to the cellular constituents of LNs.
Naive and central memory lymphocytes continuously enter LNs through high endothelial venules (HEVs) and return to the circulation by way of the efferent lymphatics.
Lymphocyte recruitment in HEVs involves a multi-step adhesion cascade that requires specific traffic molecules on both lymphocytes and HEVs. The respective T-cell and endothelial-cell-expressed homing molecules are: L-selectin and peripheral node addressin (for rolling); CC-chemokine ligand 21 (CCL21) and CC-chemokine receptor 7 (CCR7) (chemokine signal); and leukocyte function-associated antigen 1 (LFA1) and intercellular adhesion molecule 1 (ICAM1) or ICAM2 (for firm arrest).
DCs and their precursors enter LNs through afferent lymphatics and possibly also through HEVs. They process and present antigen from peripheral tissues and are essential for antigen-specific priming of naive T cells in LNs.
After entering the paracortex of LNs, T cells migrate rapidly and in random directions, contacting numerous DCs in search for a stimulating antigen. This behaviour seems to be cell autonomous and does not seem to be controlled by long-range chemotactic gradients.
Recent evidence indicates that the overall cellularity of LNs and, in particular, the egress of T cells from the cortex into efferent lymph vessels is tightly regulated and might involve sphingosine-1-phosphate and its receptors.
Lymph nodes (LNs) are the organs where innate immune responses lead to acquired immunity, where some of our most devastating pathogens evade immunity, and where autoreactive lymphocytes first encounter tissue-specific self-antigens and are either tolerized or activated. The many roles of LNs depend on the coordinated migration of its cellular constituents. This article covers new insights into the organization and microvascular specialization of LNs, the guidance mechanisms that allow lymphocytes and antigen-presenting cells to find their correct place in the nodal parenchyma; and the role of afferent lymph flow in LN function.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Communications Open Access 02 December 2022
Nature Communications Open Access 10 November 2022
Bulletin of Mathematical Biology Open Access 01 November 2022
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gowans, J. L. & Knight, E. J. The route of re-circulation of lymphocytes in the rat. Proc. R. Soc. Lond. B 159, 257–282 (1964). A classic study that provided the first clear experimental evidence for lymphocyte recirculation from blood to lymph nodes (LNs) and through the thoracic duct, back to the blood.
Marchesi, V. T. & Gowans, J. L. The migration of lymphocytes through the endothelium of venules in lymph nodes: an electron microscope study. Proc. R. Soc. B 159, 283–290 (1964).
Girard, J. -P. & Springer, T. A. High endothelial venules (HEVs): Specialized endothelium for lymphocyte migration. Immunol. Today 16, 449–457 (1995).
Pabst, R. The spleen in lymphocyte migration. Immunol. Today 9, 43–45 (1988).
Gesner, B. M. & Gowans, J. L. The output of lymphocytes from the thoracic duct of unanaesthetized mice. Br. J. Exp. Path. 43, 424 (1962).
Scheinecker, C., McHugh, R., Shevach, E. M. & Germain, R. N. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J. Exp. Med. 196, 1079–1090 (2002).
Butcher, E. C. & Picker, L. J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).
von Andrian, U. H. & Mackay, C. R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).
Kantele, A., Westerholm, M., Kantele, J. M., Makela, P. H. & Savilahti, E. Homing potentials of circulating antibody-secreting cells after administration of oral or parenteral protein or polysaccharide vaccine in humans. Vaccine 17, 229–236 (1999).
Kantele, A., Zivny, J., Hakkinen, M., Elson, C. O. & Mestecky, J. Differential homing commitments of antigen-specific T cells after oral or parenteral immunization in humans. J. Immunol. 162, 5173–5177 (1999).
Campbell, D. J. & Butcher, E. C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002). This study shows that intraperitoneal injection of a model antigen rapidly induces antigen-specific effector cells in peripheral LNs and gut-associated lymphoid tissues, which have a skin-homing and gut-homing phenotype, respectively.
Stagg, A. J., Kamm, M. A. & Knight, S. C. Intestinal dendritic cells increase T cell expression of α4β7 integrin. Eur. J. Immunol. 32, 1445–1454 (2002).
Mora, J. R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999). This study shows that memory T cells can be subdivided into CC-chemokine receptor 7 (CCR7)+L-selectin+ central memory cells and CCR7−L-selectin− effector memory cells, which show distinct responses to recall antigens.
Weninger, W., Crowley, M. A., Manjunath, N. & von Andrian, U. H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).
Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).
Mondino, A., Khoruts, A. & Jenkins, M. K. The anatomy of T-cell activation and tolerance. Proc. Natl Acad. Sci. USA 93, 2245–2252 (1996).
Fossum, S. & Ford, W. L. The organization of cell populations within lymph nodes: their origin, life history and functional relationships. Histopathology 9, 469–499 (1985).
Pabst, R. & Binns, R. M. Heterogeneity of lymphocyte homing physiology: several mechanisms operate in the control of migration to lymphoid and non-lymphoid organs in vivo. Immunol. Rev. 108, 83–109 (1989).
Sainte-Marie, G. & Peng, F. S. High endothelial venules of the rat lymph node. A review and a question: is their activity antigen specific? Anat. Rec. 245, 593–620 (1996).
Gretz, J. E., Anderson, A. O. & Shaw, S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156, 11–24 (1997).
Kelly, R. H. Functional anatomy of lymph nodes. I. The paracortical cords. Int. Arch. Allergy Appl. Immunol. 48, 836–849 (1975).
von Andrian, U. H. Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirc. 3, 287–300 (1996).
M'Rini, C. et al. A novel endothelial L-selectin ligand activity in lymph node medulla that is regulated by α(1,3)-fucosyltransferase-IV. J. Exp. Med. (in the press).
Mebius, R. E., Streeter, P. R., Michie, S., Butcher, E. C. & Weissman, I. L. A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+CD3− cells to colonize lymph nodes. Proc. Natl Acad. Sci. USA 93, 11019–11024 (1996).
Hendriks, H. R., Eestermans, I. L. & Hoefsmit, E. C. Depletion of macrophages and disappearance of postcapillary high endothelial venules in lymph nodes deprived of afferent lymphatic vessels. Cell Tissue Res. 211, 375–389 (1980).
Hendriks, H. R., Duijvestijn, A. M. & Kraal, G. Rapid decrease in lymphocyte adherence to high endothelial venules in lymph nodes deprived of afferent lymphatic vessels. Eur. J. Immunol. 17, 1691–1695 (1987).
Mebius, R. E., Bauer, J., Agaath, J. T. T., Brevé, J. & Kraal, G. The functional activity of high endothelial venules: a role for the subcapsular sinus macrophages in the lymph node. Immunobiology 182, 277–291 (1991).
Hendriks, H. R., von Hemert, N. A. & van der Heijden, M. The effect of stimulated macrophages on high endothelial venules and germinal centres in lymph nodes of rat. Adv. Exp. Med. Biol. 149, 207–212 (1982).
Mebius, R. E., Streeter, P. R., Breve, J., Duijvestijn, A. M. & Kraal, G. The influence of afferent lymphatic vessel interruption on vascular addressin expression. J. Cell Biol. 115, 85–95 (1991).
Kratz, A., Campos-Neto, A., Hanson, M. S. & Ruddle, N. H. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J. Exp. Med. 183, 1461–1472 (1996).
Fan, L., Reilly, C. R., Luo, Y., Dorf, M. E. & Lo, D. Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J. Immunol. 164, 3955–3959 (2000).
Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424–433 (2002).
Chen, S. C. et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J. Immunol. 168, 1001–1008 (2002).
Schrama, D. et al. Targeting of lymphotoxin-α to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14, 111–121 (2001).
De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).
Koni, P. A. et al. Distinct roles in lymphoid organogenesis for lymphotoxins α and β revealed in lymphotoxin β-deficient mice. Immunity 6, 491–500 (1997).
Uccini, S. et al. Kaposi's sarcoma cells express the macrophage-associated antigen mannose receptor and develop in peripheral blood cultures of Kaposi's sarcoma patients. Am. J. Pathol. 150, 929–938 (1997).
Irjala, H. et al. Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. J. Exp. Med. 194, 1033–1042 (2001).
Ingulli, E., Ulman, D. R., Lucido, M. M. & Jenkins, M. K. In situ analysis reveals physical interactions between CD11b+ dendritic cells and antigen-specific CD4+ T cells after subcutaneous injection of antigen. J. Immunol. 169, 2247–2252 (2002).
Gretz, J. E., Norbury, C. C., Anderson, A. O., Proudfoot, A. E. & Shaw, S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J. Exp. Med. 192, 1425–1440 (2000).
Anderson, A. O. & Shaw, S. T cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node. Semin. Immunol. 5, 271–282 (1993).
Stein, J. V. et al. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J. Exp. Med. 191, 61–76 (2000). Intravital microscopy was used to show that CC-chemokine ligand 21 (CCL21) induces the activation of leukocyte function-associated antigen 1 (LFA1) on rolling naive T cells in LN high endothelial venules (HEVs). This paper also shows that a chemokine can be transported from the skin to the draining LNs and presented in HEVs.
Baekkevold, E. S. et al. The CCR7 ligand ELC (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J. Exp. Med. 193, 1105–1112 (2001).
Palframan, R. T. et al. Inflammatory chemokine transport and presentation in HEV: A remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1374 (2001).
Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).
Titball, R. W. & Leary, S. E. Plague. Br. Med. Bull. 54, 625–633 (1998).
Smith, J. & Reisner, B. in Pathology of infectious diseases (ed. Connor, D. H.) 729–738 (Appleton and Lange, Stamford, 1997).
Cloyd, M. W., Chen, J. J. & Wang, I. How does HIV cause AIDS? The homing theory. Mol. Med. Today 6, 108–111 (2000).
Mock, M. & Fouet, A. Anthrax. Annu. Rev. Microbiol. 55, 647–671 (2001).
Mackay, C. R., Marston, W. L. & Dudler, L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171, 801–817 (1990). This study shows that afferent lymph contains memory but not naive T cells, indicating that the latter can only home to LNs through HEVs, whereas (a subset of) the former migrate through peripheral tissues.
Cahill, R. N. P., Frost, H. & Trnka, Z. The effects of antigen on the migration of recirculating lymphocytes through single lymph nodes. J. Exp. Med. 143, 870–888 (1976).
Ford, W. L., Simmonds, S. J. & Atkins, R. C. Early cellular events in a systemic graft-vs-host reaction. II. Autoradiographic estimates of the frequency of donor lymphocytes which respond to each Ag-B-determined antigenic complex. J. Exp. Med. 141, 681–696 (1975).
Mackay, C. R., Marston, W. & Dudler, L. Altered patterns of T cell migration through lymph nodes and skin following antigen challenge. Eur. J. Immunol. 22, 2205–2210 (1992).
Springer, T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multi-step paradigm. Cell 76, 301–314 (1994).
Warnock, R. A., Askari, S., Butcher, E. C. & von Andrian, U. H. Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J. Exp. Med. 187, 205–216 (1998).
Okada, T. et al. Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. J. Exp. Med. 196, 65–75 (2002). This study shows that both CCR7 and CXC-chemokine receptor 4 (CXCR4) transmit integrin-activating signals in rolling B cells in LN HEVs.
Streeter, P. R., Rouse, B. T. N. & Butcher, E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J. Cell Biol. 107, 1853–1862 (1988).
Berg, E. L., Robinson, M. K., Warnock, R. A. & Butcher, E. C. The human peripheral lymph node vascular addressin is a ligand for LECAM-1, the peripheral lymph node homing receptor. J. Cell Biol. 114, 343–349 (1991).
Clark, R. A., Fuhlbrigge, R. C. & Springer, T. A. L-selectin ligands that are O-glycoprotease-resistant and distinct from MECA-79 antigen are sufficient for tethering and rolling of lymphocytes on human high endothelial venules. J. Cell Biol. 140, 721–731 (1998).
Lowe, J. B. Glycosylation, immunity, and autoimmunity. Cell 104, 809–812 (2001).
Vestweber, D. & Blanks, J. E. Mechanisms that regulate the function of the selectins and their ligands. Physiol. Rev. 79, 181–213 (1999).
Hamann, A. et al. Evidence for an accessory role of LFA-1 in lymphocyte-high endothelium interaction during homing. J. Immunol. 140, 693–699 (1988).
Andrew, D. P. et al. Transendothelial migration and trafficking of leukocytes in LFA-1-deficient mice. Eur. J. Immunol. 28, 1959–1969 (1998).
Berlin-Rufenach, C. et al. Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice. J. Exp. Med. 189, 1467–1478 (1999).
Gunn, M. D. et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes Proc. Natl Acad. Sci. USA. 95, 258–263 (1998). Using in situ hybridization, this study discovered that CCL21 is highly expressed by HEVs. CCL21 is also shown to be a potent chemoattractant for naive T cells.
Campbell, J. J. et al. Chemokines and the arrest of lymphoyctes rolling under flow conditions. Science 279, 381–384 (1998).
Campbell, J. J. et al. 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3β receptor CCR7. J. Cell Biol. 141, 1053–1059 (1998).
Vassileva, G. et al. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190, 1183–1188 (1999).
Nakano, H. & Gunn, M. D. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166, 361–369 (2001).
Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999). This study reports that CCR7-deficient mice have markedly disorganized secondary lymphoid tissues and are defective in lymphocyte homing.
Gunn, M. D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).
Cinamon, G., Shinder, V. & Alon, R. Shear forces promote lymphocyte migration across vascular endothelium bearing apical chemokines. Nature Immunol. 2, 515–522 (2001).
Weninger, W. et al. Naive T cell recruitment to non-lymphoid tissues: a role for endothelium-expressed CCL21 in autoimmune disease and lymphoid neogenesis. J. Immunol. 170, 4638–4648 (2003).
Tang, M. L., Steeber, D. A., Zhang, X. Q. & Tedder, T. F. Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways. J. Immunol. 160, 5113–5121 (1998).
Stein, J. V. et al. L-selectin-mediated leukocyte adhesion in vivo: microvillous distribution determines tethering efficiency, but not rolling velocity. J. Exp. Med. 189, 37–50 (1999).
Robert, C. et al. Gene therapy to target dendritic cells from blood to lymph nodes. Gene Therapy 10, 1479–1486 (2003).
Streeter, P. R., Lakey-Berg, E., Rouse, B. T. N., Bargatze, R. F. & Butcher, E. C. A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 331, 41–46 (1988).
Berlin, C. et al. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185–195 (1993).
Bargatze, R. F., Jutila, M. A. & Butcher, E. C. Distinct roles of L-selectin and integrins α4β7 and LFA-1 in lymphocyte homing to Peyer's patch-HEV in situ: The multistep model confirmed and refined. Immunity 3, 99–108 (1995).
Arbones, M. L. et al. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity 1, 247–260 (1994). The first detailed phenotypic characterization of L-selectin-deficient mice.
Wagner, N. et al. Critical role for β7 integrins in formation of the gut-associated lymphoid tissue. Nature 382, 366–370 (1996).
Kunkel, E. J. et al. The roles of L-selectin, β7 integrins, and P-selectin in leukocyte rolling and adhesion in high endothelial venules of Peyer's patches. J. Immunol. 161, 2449–2456 (1998).
Diacovo, T. G., Puri, K. D., Warnock, R. A., Springer, T. A. & von Andrian, U. H. Platelet-mediated lymphocyte delivery to high endothelial venules. Science 273, 252–255 (1996).
Salmi, M. & Jalkanen, S. VAP-1: an adhesin and an enzyme. Trends Immunol. 22, 211–216 (2001).
McEvoy, L. M., Sun, H., Frelinger, J. G. & Butcher, E. C. Anti-CD43 inhibition of T cell homing. J. Exp. Med. 185, 1493–1498 (1997).
Stockton, B. M., Cheng, G., Manjunath, N., Ardman, B. & von Andrian, U. H. Negative regulation of T cell homing by CD43. Immunity 8, 373–381 (1998).
Jalkanen, S. T., Bargatze, R. F., Herron, L. R. & Butcher, E. C. A lymphoid cell surface glycoprotein involved in endothelial cell recognition and lymphocyte homing in man. Eur. J. Immunol. 16, 1195–1202 (1986).
Stoop, R., Gal, I., Glant, T. T., McNeish, J. D. & Mikecz, K. Trafficking of CD44-deficient murine lymphocytes under normal and inflammatory conditions. Eur. J. Immunol. 32, 2532–2542 (2002).
Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 1001–1011 (1997). This study shows that extravascular chemokines can be transported in caveoli to the luminal surface of endothelial cells where they are presented to passing leukocytes.
Gu, L., Tseng, S. C. & Rollins, B. J. Monocyte chemoattractant protein-1. Chem. Immunol. 72, 7–29 (1999).
Janatpour, M. J., Hudak, S., Sathe, M., Sedgwick, J. D. & McEvoy, L. M. Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment. J. Exp. Med. 194, 1375–1384 (2001).
Nibbs, R. J. et al. The β-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. Am. J. Pathol. 158, 867–877 (2001).
Fra, A. M. et al. Cutting edge: scavenging of inflammatory CC chemokines by the promiscuous putatively silent chemokine receptor D6. J. Immunol. 170, 2279–2282 (2003).
Girard, J. P. et al. Heterogeneity of endothelial cells: the specialized phenotype of human high endothelial venules characterized by suppression subtractive hybridization. Am. J. Pathol. 155, 2043–2055 (1999).
De Bruyn, P. P. H. & Cho, Y. in Reaction Patterns of the Lymph Node (eds Grundman, E. & Vollmer, T.) 85–103 (Springer–Verlag, Berlin, 1990).
Anderson, A. O. & Anderson, N. D. Lymphocyte emigration from high endothelial venules in rat lymph nodes. Immunology 31, 731–748 (1976).
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Sallusto, F. & Lanzavecchia, A. Mobilizing dendritic cells for tolerance, priming, and chronic inflammation. J. Exp. Med. 189, 611–614 (1999).
Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).
Itano, A. A. et al. Distinct dendritic cell populations sequentially present a subcutaneous antigen to CD4+ T cells and stimulate different aspects of cell-mediated immunity. Immunity 19, 47–57 (2003).
Henri, S. et al. The dendritic cell populations of mouse lymph nodes. J. Immunol. 167, 741–748 (2001).
Nakano, H., Yanagita, M. & Gunn, M. D. CD11c+B220+Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194, 1171–1178 (2001).
Stoitzner, P. et al. Visualization and characterization of migratory Langerhans cells in murine skin and lymph nodes by antibodies against Langerin/CD207. J. Invest. Dermatol. 120, 266–274 (2003).
Merad, M., Fong, L., Bogenberger, J. & Engleman, E. G. Differentiation of myeloid dendritic cells into CD8α-positive dendritic cells in vivo. Blood 96, 1865–1872 (2000).
Cella, M. et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nature Med. 5, 919–923 (1999).
Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunol. 3, 1135–1141 (2002).
Robert, C. et al. Interaction of dendritic cells with skin endothelium: a new perspective on immunosurveillance. J. Exp. Med. 189, 627–636 (1999).
Randolph, G. J., Inaba, K., Robbiani, D. F., Steinman, R. M. & Muller, W. A. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761 (1999).
Sallusto, F. et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28, 2760–2769 (1998).
Adema, G. J. et al. A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells. Nature 387, 713–717 (1997).
Hieshima, K. et al. A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1α/LD78α and chemotactic for T lymphocytes, but not for monocytes. J. Immunol. 159, 1140–1149 (1997).
Godiska, R. et al. Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells J. Exp. Med. 185, 1595–1604 (1997).
Ngo, V. N., Tang, H. L. & Cyster, J. G. Epstein–Barr-virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells. J. Exp. Med. 188, 181–191 (1998).
Kabashima, K. et al. Thromboxane A2 modulates interaction of dendritic cells and T cells and regulates acquired immunity. Nature Immunol. 4, 694–701 (2003).
Robbiani, D. F. et al. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103, 757–768 (2000).
Xu, H. et al. The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur. J. Immunol. 31, 3085–3093 (2001).
Steinman, R. M. & Nussenzweig, M. C. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl Acad. Sci. USA 99, 351–358 (2002).
Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998). This study uses immunohistochemistry to characterize the kinetics and interstitial location of interactions between antigen-specific B and T cells in lymph nodes.
Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).
Cahalan, M. D., Parker, I., Wei, S. H. & Miller, M. J. Two-photon tissue imaging: seeing the immune system in a fresh light. Nature Rev. Immunol. 2, 872–880 (2002).
Miller, M. J., Wei, S. H., Parker, I. & Cahalan, M. D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296, 1869–1873 (2002). This study uses time-lapse two-photon microscopy to study the dynamics of T-cell migration in excised LNs.
Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell–dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).
Bousso, P. & Robey, E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nature Immunol. 4, 579–585 (2003).
von Andrian, U. H. Immunology. T cell activation in six dimensions. Science 296, 1815–1817 (2002).
Torres Filho, I. P., Leunig, M., Yuan, F., Intaglietta, M. & Jain, R. K. Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice. Proc. Natl Acad. Sci. USA 91, 2081–2085 (1994).
Bogdan, C., Rollinghoff, M. & Diefenbach, A. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr. Opin. Immunol. 12, 64–76 (2000).
Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).
Madden, K. S. & Felten, D. L. Experimental basis for neural-immune interactions. Physiol. Rev. 75, 77–106 (1995).
Miller, M. J., Wei, S. H., Cahalan, M. D. & Parker, I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc. Natl Acad. Sci. USA 100, 2604–2609 (2003). This is the first two-photon microscopy study on T-cell migration in LNs in vivo . The data indicate that T cells migrate rapidly and without apparent directionality in the T-cell area immediately after having undergone diapedesis across the HEVs.
Legler, D. F. et al. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J. Exp. Med. 187, 655–660 (1998).
Forster, R. et al. A putative chemokine receptor, BLRI, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).
Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).
Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).
Irjala, H. et al. The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels. Eur. J. Immunol. 33, 815–824 (2003).
Napoli, K. L. The FTY720 story. Ther. Drug Monit. 22, 47–51 (2000).
Brinkmann, V. & Lynch, K. FTY720: targeting G-protein-coupled receptors for sphingosine-1-phosphate in transplantation and autoimmunity. Curr. Opin. Immunol. 14, 569–575 (2002).
Enosawa, S., Suzuki, S., Kakefuda, T., Li, X. K. & Amemiya, H. Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720. Immunopharmacology 34, 171–179 (1996).
Pinschewer, D. D. et al. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J. Immunol. 164, 5761–5770 (2000).
Chiba, K. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol. 160, 5037–5044 (1998).
Henning, G. et al. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J. Exp. Med. 194, 1875–1881 (2001).
Yagi, H. et al. Immunosuppressant FTY720 inhibits thymocyte emigration. Eur. J. Immunol. 30, 1435–1444 (2000).
Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002). This study shows that the immunosuppressive drug FTY720 is rapidly phosphorylated in vivo and then binds to sphingosine-1-phosphate (S1P) receptors. S1P-receptor agonists cause lymphopaenia and block lymphocyte exit from the LN parenchyma to the medullary sinuses.
Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).
Graeler, M., Shankar, G. & Goetzl, E. J. Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate. J. Immunol. 169, 4084–4087 (2002).
Honig, S. M. et al. FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes. J. Clin. Invest. 111, 627–637 (2003).
von Andrian, U. H., Hasslen, S. R., Nelson, R. D., Erlandsen, S. L. & Butcher, E. C. A central role for microvillous receptor presentation in leukocyte adhesion under flow. Cell 82, 989–999 (1995).
Zoumi, A., Yeh, A. & Tromberg, B. J. Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two–photon excited fluorescence. Proc. Natl Acad. Sci. USA 99, 11014–11019 (2002).
We thank the members of the von Andrian lab for critical reading of this article. This work was supported by grants from the National Institutes of Health and the Dana Foundation.
Movie 1 | | Lymph-node microcirculation. This movie shows the location of B cells (green) and T cells (red) in the lymph node, relative to the microcirculation (which has been visualized by injection of a mixture of red and green fluorescent dextrans, and appears yellow). B cells are located in the distal B-cell follicles, whereas T cells remain in the paracortex. (MOV 4604 kb)
Movie 2 || Lymph conduits. Injection of fluorescent dextran (green) into the skin allows visualization of the afferent lymph vessel in a mouse popliteal lymph node. The lymph fluid accumulates below the lymph-node capsule (blue). (MOV 3901 kb)
Movie 3 || Exclusion of large molecules from the lymph-node parenchyma. This movie shows that the fluorescent lymph remains confined to the subcapsular sinus and does not penetrate the lymph-node parenchyma. (MOV 2414 kb)
- FOLLICULAR DENDRITIC CELLS
(FDCs). Stromal cells of non-haemopoietic origin in B-cell follicles that present intact antigen to B cells and function in the selection of memory B cells during germinal-centre reactions.
- HIGH ENDOTHELIAL VENULES
(HEVs). A specialized type of postcapillary venule that is lined by cuboid or high endothelial cells. HEVs are only found in secondary lymphoid organs, except the spleen. They are the main site of lymphocyte entry from the blood.
- INTEGRIN ACTIVATION
The process by which integrins are triggered, often by chemokines or other signals (for example, T-cell receptor stimulation), to switch from a low- to a high-affinity ligand-binding state. This entails a conformational change in the extracellular domain of the integrin heterodimer. In addition, integrins might be redistributed into clusters on the cell surface to enhance binding avidity.
The passage of cells across a cellular barrier, such as the monolayer of tightly apposed endothelial cells in postcapillary venules.
- DENDRITIC-CELL MATURATION
The process by which dendritic cells (DCs) are reprogrammed from a mainly antigen collecting to an antigen presenting, immunostimulatory mode. Maturation can be induced by signals associated with tissue damage, inflammation or infection, resulting in enhanced cell-surface presentation of MHC complexes and co-stimulatory molecules and altered trafficking, enabling them to enter the T-cell area of secondary lymphoid tissues.
About this article
Cite this article
von Andrian, U., Mempel, T. Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3, 867–878 (2003). https://doi.org/10.1038/nri1222
This article is cited by
Immunity & Ageing (2022)
Nature Communications (2022)
A single-cell atlas of non-haematopoietic cells in human lymph nodes and lymphoma reveals a landscape of stromal remodelling
Nature Cell Biology (2022)
Nature Immunology (2022)
Nature Communications (2022)