To facilitate the encounter between lymphocytes and pathogens, the immune system has developed highly structured environments in the lymph nodes and marginal zones of the spleen.
Signalling through the lymphotoxin (LT)/LIGHT pathways are crucial for the maintenance of these environments. These interactions are complex and, although the role of LT in the spleen has been well described, our understanding of its role in lymph nodes and mucosal sites is preliminary.
Analysis of the effects of inhibitors of the LT/LIGHT system, which have been shown to reduce disease in many autoimmune models, can help us to understand the influence of lymphoid microenvironments on immune responses.
Here, our understanding of the role of LT/LIGHT signalling in the regulation of lymphoid microenvironments in the spleen, lymph nodes and mucosal system, in B- and T-cell function and in disease is discussed. The potential therapeutic benefits of blocking LT/LIGHT signalling is also discussed.
Much of the efficiency of the immune system is attributed to the high degree of spatial and temporal organization in the secondary lymphoid organs. Signalling through the lymphotoxin (LT) pathway is a crucial element in the maintenance of this organized microenvironment. The effect of altering lymphoid microenvironments on immune responses remains relatively unexplored. Inhibitors of the LT and LIGHT pathways have been shown to reduce disease in a wide range of autoimmune models. This approach has provided a tool to probe the effect of manipulation of the microenvironment on both normal and pathological immune responses.
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Goodnow, C. C. Chance encounters and organized rendezvous. Immunol. Rev. 156, 5–10 (1997).
Aggarwal, B. B. & Natarajan, K. Tumor necrosis factors: developments during the last decade. Eur. Cytokine Netw. 7, 93–124 (1996).
Ware, C. F., VanArsdale, T. L., Crowe, P. D. & Browning, J. L. The ligands and receptors of the lymphotoxin system. Curr. Top. Microbiol. Immunol. 198, 175–218 (1995).
Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).
Muller, G. & Lipp, M. Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Curr. Opin. Immunol. 15, 217–224 (2003).
Luther, S. A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J. G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000). This paper nicely shows that ectopic expression of a chemokine was sufficient to induce organized lymphoid structures.
Ruddle, N. H. Lymphoid neo-organogenesis: lymphotoxin's role in inflammation and development. Immunol. Res. 19, 119–125 (1999).
Vinuesa, C. G. & Cook, M. C. The molecular basis of lymphoid architecture and B cell responses: implications for immunodeficiency and immunopathology. Curr. Mol. Med. 1, 689–725 (2001).
Granger, S. W. & Ware, C. F. Turning on LIGHT. J. Clin. Invest. 108, 1741–1742 (2001).
Murphy, M. et al. Expression of the lymphotoxin-β receptor on follicular stromal cells in human lymphoid tissues. Cell Death Differ. 5, 497–505 (1998).
Browning, J. L. et al. Characterization of lymphotoxin-αβ complexes on the surface of mouse lymphocytes. J. Immunol. 159, 3288–3298 (1997).
Browning, J. L. & French, L. E. Visualization of lymphotoxin-β and lymphotoxin-β receptor expression in mouse embryos. J. Immunol. 168, 5079–5087 (2002).
De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994). The first study that linked lymphotoxin (LT) to lymph-node development.
Rennert, P. D. TNF family ligands and receptors control the development of secondary lymphoid organs. Recent Res. Devel. Immunity 1, 33–43 (2003).
Finke, D. & Kraehenbuhl, J. P. Formation of Peyer's patches. Curr. Opin. Genet. Dev. 11, 561–567 (2001).
Fu, Y. X. & Chaplin, D. D. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17, 399–433 (1999).
Scheu, S. et al. Targeted disruption of LIGHT causes defects in co-stimulatory T cell activation and reveals cooperation with lymphotoxin β in mesenteric lymph node genesis. J. Exp. Med. 195, 1613–1624 (2002).
Zhang, M., Guo, R., Zhai, Y., Fu, X. Y. & Yang, D. Light stimulates IFN-γ-mediated intercellular adhesion molecule-1 upregulation of cancer cells. Hum Immunol. 64, 416–426 (2003).
Ye, Q. et al. Modulation of LIGHT–HVEM co-stimulation prolongs cardiac allograft survival. J. Exp. Med. 195, 795–800 (2002).
Shaikh, R. B. et al. Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J. Immunol. 167, 6330–6337 (2001).
Wang, J. et al. The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J. Clin. Invest. 108, 1771–1780 (2001). This work, together with reference 20, using genetically altered mice, provided the first insights into the potential linkage between LIGHT and autoimmunity.
Cyster, J. G. et al. Follicular stromal cells and lymphocyte homing to follicles. Immunol. Rev. 176, 181–193 (2000).
Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).
Fu, Y. X., Huang, G., Wang, Y. & Chaplin, D. D. B lymphocytes induce the formation of follicular dendritic cell clusters in a lymphotoxin-α-dependent fashion. J. Exp. Med. 187, 1009–1018 (1998).
Gonzalez, M., Mackay, F., Browning, J. L., Kosco-Vilbois, M. H. & Noelle, R. J. The sequential role of lymphotoxin and B cells in the development of splenic follicles. J. Exp. Med. 187, 997–1007 (1998).
Endres, R. et al. Mature follicular dendritic cell networks depend on expression of lymphotoxin-β receptor by radioresistant stromal cells and of lymphotoxin-β and tumor necrosis factor by B cells. J. Exp. Med. 189, 159–168 (1999).
Wu, Q. et al. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J. Exp. Med. 190, 629–638 (1999).
Tumanov, A. et al. Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity 17, 239–250 (2002).
Mackay, F. & Browning, J. L. Turning off follicular dendritic cells. Nature 395, 26–27 (1998). This study showed that follicular dendritic-cell (FDC) networks were not static, but highly plastic even when fully developed.
Gommerman, J. L. et al. Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway. J. Clin. Invest. 110, 1359–1369 (2002).
Husson, H. et al. Functional effects of TNF and lymphotoxin α1β2 on FDC-like cells. Cell. Immunol. 203, 134–143 (2000).
Balogh, P., Aydar, Y., Tew, J. G. & Szakal, A. K. Appearance and phenotype of murine follicular dendritic cells expressing VCAM-1. Anat. Rec. 268, 160–168 (2002).
Matsushima, A. et al. Essential role of nuclear factor (NF)-κB-inducing kinase and inhibitor of κB (IκB) kinase α in NF-κB activation through lymphotoxin β receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 193, 631–636 (2001).
Yoshida, H. et al. Expression of α4β7 integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J. Immunol. 167, 2511–2521 (2001).
Martin, F. & Kearney, J. F. Marginal-zone B cells. Nature Rev. Immunol. 2, 323–335 (2002).
Lu, T. T. & Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).
Ettinger, R. et al. A critical role for lymphotoxin-β receptor in the development of diabetes in nonobese diabetic mice. J. Exp. Med. 193, 1333–1340 (2001). This study and a related study (reference 85) indicated a crucial role for the LT/LIGHT pathway in the development of diabetes in non-obese diabetic (NOD) mice.
Korner, H. et al. Recirculating and marginal zone B cell populations can be established and maintained independently of primary and secondary follicles. Immunol. Cell. Biol. 79, 54–61 (2001).
Mackay, F., Majeau, G. R., Lawton, P., Hochman, P. S. & Browning, J. L. Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Eur. J. Immunol. 27, 2033–2042 (1997).
Ngo, V. N., Cornall, R. J. & Cyster, J. G. Splenic T zone development is B cell dependent. J. Exp. Med. 194, 1649–1660 (2001).
Cyster, J. G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).
Ngo, V. N. et al. Lymphotoxin α/β and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189, 403–412 (1999). In this work, lymphotoxin was directly linked to the release of several of the homeostatic chemokines.
Cyster, J. G. Leukocyte migration: scent of the T zone. Curr. Biol. 10, R30–R33 (2000).
Neutra, M. R., Mantis, N. J. & Kraehenbuhl, J. P. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nature Immunol. 2, 1004–1009 (2001).
Dohi, T. et al. Elimination of colonic patches with lymphotoxin β receptor–Ig prevents TH2 cell-type colitis. J. Immunol. 167, 2781–2790 (2001). The first paper to show that Peyer's-patch and colonic-patch cellularity was affected by LTβ receptor (LTβR) signalling in adult mice.
Debard, N., Sierro, F., Browning, J. & Kraehenbuhl, J. P. Effect of mature lymphocytes and lymphotoxin on the development of the follicle-associated epithelium and M cells in mouse Peyer's patches. Gastroenterology. 120, 1173–1182 (2001).
Spahn, T. W. et al. Induction of colitis in mice deficient of Peyer's patches and mesenteric lymph nodes is associated with increased disease severity and formation of colonic lymphoid patches. Am. J. Pathol. 161, 2273–2282 (2002).
Jacob, E., Baker, S. J. & Swaminathan, S. P. 'M' cells in the follicle-associated epithelium of the human colon. Histopathology 11, 941–952 (1987).
Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J Immunol 168, 57–64. (2002).
Lorenz, R. G., Chaplin, D. D., McDonald, K. G., McDonough, J. S. & Newberry, R. D. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin-β receptor, and TNF receptor I function. J. Immunol. 170, 5475–5482 (2003).
Takemura, S. et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).
Banks, T. A. et al. Lymphotoxin-α-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155, 1685–1693 (1995).
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).
Kang, H. S. et al. Signaling via LTβR on the lamina propria stromal cells of the gut is required for IgA production. Nature Immunol. 3, 576–582 (2002). This study directly linked LTβR-mediated control of a mucosal microenvironment to the production of immunoglobulin A.
Newberry, R. D., McDonough, J. S., McDonald, K. G. & Lorenz, R. G. Postgestational lymphotoxin/lymphotoxin β receptor interactions are essential for the presence of intestinal B lymphocytes. J. Immunol. 168, 4988–4997 (2002).
Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003).
Itoh, M. et al. Deletion of bone marrow stromal cell antigen-1 (CD157) gene impaired systemic thymus independent-2 antigen-induced IgG3 and mucosal TD antigen-elicited IgA responses. J. Immunol. 161, 3974–3983 (1998).
Wang, J. et al. The complementation of lymphotoxin deficiency with LIGHT, a newly discovered TNF family member, for the restoration of secondary lymphoid structure and function. Eur. J. Immunol. 32, 1969–1979 (2002).
Yamada, T. et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-κ B-inducing kinase. J. Immunol. 165, 804–812 (2000).
Karrer, U., Althage, A., Odermatt, B., Hengartner, H. & Zinkernagel, R. M. Immunodeficiency of alymphoplasia mice (aly/aly) in vivo: structural defect of secondary lymphoid organs and functional B cell defect. Eur. J. Immunol. 30, 2799–2807 (2000).
Pomerantz, J. L. & Baltimore, D. Two pathways to NF-κB. Mol. Cell 10, 693–695 (2002).
Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).
Rennert, P. D. et al. Essential role of lymph nodes in contact hypersensitivity revealed in lymphotoxin-α-deficient mice. J. Exp. Med. 193, 1227–1238 (2001).
Koni, P. A. & Flavell, R. A. Lymph node germinal centers form in the absence of follicular dendritic cell networks. J. Exp. Med. 189, 855–864 (1999).
de Vinuesa, C. G. et al. Germinal centers without T cells. J. Exp. Med. 191, 485–494 (2000).
Futterer, A., Mink, K., Luz, A., Kosco-Vilbois, M. H. & Pfeffer, K. The lymphotoxin β receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9, 59–70 (1998).
Matsumoto, M. et al. Affinity maturation without germinal centres in lymphotoxin-α-deficient mice. Nature 382, 462–466 (1996). These authors showed that FDC networks and germinal centres do not form in the absence of expression of LT.
Hannum, L. G., Haberman, A. M., Anderson, S. M. & Shlomchik, M. J. Germinal center initiation, variable gene region hypermutation, and mutant B cell selection without detectable immune complexes on follicular dendritic cells. J. Exp. Med. 192, 931–942 (2000).
William, J., Euler, C., Christensen, S. & Shlomchik, M. J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066–2070 (2002).
Maccioni, M. et al. Arthritogenic monoclonal antibodies from K/BxN mice. J. Exp. Med. 195, 1071–1077 (2002).
Holmdahl, R. et al. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol. Rev. 118, 193–232 (1990).
Fava, R. F. et al. A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen induced arthritis. J. Immunol. 171, 115–126 (2003).
Constant, S. L. & Bottomly, K. Induction of TH1 and TH2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15, 297–322 (1997).
Gramaglia, I., Mauri, D. N., Miner, K. T., Ware, C. F. & Croft, M. Lymphotoxin αβ is expressed on recently activated naive and TH1-like CD4 cells but is downregulated by IL-4 during TH2 differentiation. J. Immunol. 162, 1333–1338 (1999).
Mackay, F. et al. Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis. Gastroenterology 115, 1464–1475 (1998). This work on colitis provided one of the first hints of a role for the LT/LIGHT system in T-cell function, as opposed to the many lines of evidence that link LT to B-cell function.
Suresh, M. et al. Role of Lymphotoxin α in T-cell responses during an acute viral infection. J. Virol. 76, 3943–3951 (2002).
Lund, F. E. et al. Lymphotoxin-α-deficient mice make delayed, but effective, T and B cell responses to influenza. J. Immunol. 169, 5236–5243 (2002).
Benedict, C. A. et al. Lymphotoxins and cytomegalovirus cooperatively induce interferon-β, establishing host-virus detente. Immunity 15, 617–626 (2001).
Lee, B. J., Santee, S., Von Gesjen, S., Ware, C. F. & Sarawar, S. R. Lymphotoxin-α-deficient mice can clear a productive infection with murine γ-herpesvirus 68 but fail to develop splenomegaly or lymphocytosis. J. Virol. 74, 2786–2792 (2000).
Kumaraguru, U., Davis, I. A., Deshpande, S., Tevethia, S. S. & Rouse, B. T. Lymphotoxin α−/− mice develop functionally impaired CD8+ T cell responses and fail to contain virus infection of the central nervous system. J. Immunol. 166, 1066–1074 (2001).
Muller, S. et al. Role of an intact splenic microarchitecture in early lymphocytic choriomeningitis virus production. J. Virol. 76, 2375–2383 (2002).
Berger, D. P. et al. Lymphotoxin-β-deficient mice show defective antiviral immunity. Virology 260, 136–147 (1999).
Puglielli, M. T. et al. Reversal of virus-induced systemic shock and respiratory failure by blockade of the lymphotoxin pathway. Nature Med. 5, 1370–1374 (1999). This paper and reference 82 highlighted the role of the LT pathway in the development of a CD8+ T-cell response to lymphocytic choriomeningitis virus (LCMV).
Guo, Z. et al. Membrane lymphotoxin regulates CD8+ T cell-mediated intestinal allograft rejection. J. Immunol. 167, 4796–4800 (2001). This work described a role for LT in CD8+ T-cell-mediated graft rejection that was independent from LIGHT, thereby showing that not all T-cell mediated events inhibited by a LTβR–immunoglobulin fusion protein were due to the loss of LIGHT signalling.
Wu, Q. et al. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J. Exp. Med. 193, 1327–1332 (2001).
Rimington, S. D. et al. Challenging cytokine redundancy: inflammatory cell movement and clinical course of experimental autoimmune encephalomyelitis are normal in lymphotoxin-deficient, but not tumor necrosis factor-deficient, mice. J. Exp. Med. 187, 1517–1528 (1998).
Suen, W. E., Bergman, C. M., Hjelmstrom, P. & Ruddle, N. H. A critical role for lymphotoxin in experimental allergic encephalomyelitis. J. Exp. Med. 186, 1233–1240 (1997).
Gommerman, J. L. et al. A role for surface lymphotoxin in experimental autoimmune encephalitis indepdendent of LIGHT. J. Clin. Invest. (in the press).
Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nature Med. 6, 283–289 (2000).
Tamada, K. et al. Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J. Clin. Invest. 109, 549–557 (2002).
Tamada, K. et al. Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGHT. J. Immunol. 168, 4832–4835 (2002).
Kassiotis, G. & Kollias, G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J. Exp. Med. 193, 427–434 (2001).
TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept multiple sclerosis study group and the University of British Columbia MS/MRI analysis group. Neurology 53, 457–465 (1999).
Weyand, C. M., Kurtin, P. J. & Goronzy, J. J. Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am. J. Pathol. 159, 787–793 (2001).
Mazzucchelli, L. et al. BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma. J. Clin. Invest. 104, R49–R54 (1999).
Mabbott, N. A. & Bruce, M. E. Follicular dendritic cells as targets for intervention in transmissible spongiform encephalopathies. Semin. Immunol. 14, 285–293 (2002).
Mabbott, N. A., Young, J., McConnell, I. & Bruce, M. E. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphtoxin pathway dramatically reduces scrapie susceptability. J. Virol. 77, 6845–6854 (2003).
Burton, G. F., Keele, B. F., Estes, J. D., Thacker, T. C. & Gartner, S. Follicular dendritic cell contributions to HIV pathogenesis. Semin. Immunol. 14, 275–284 (2002).
Montgomery, R. I., Warner, M. S., Lum, B. J. & Spear, P. G. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436 (1996).
Pitti, R. M. et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699–703 (1998).
Yu, K. Y. et al. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J. Biol. Chem. 274, 13733–13736 (1999).
Migone, T. S. et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell co-stimulator. Immunity 16, 479–492 (2002).
Baud, V. & Karin, M. Signal transduction by tumor necrosis and its relatives. Trends Cell Biol. 11, 372–377 (2001).
Chen, M. C. et al. The role of apoptosis signal-regulating kinase 1 in lymphotoxin-β receptor-mediated cell death. J. Biol. Chem. 278, 16073–16081 (2003).
MacEwan, D. J. TNF ligands and receptors — a matter of life and death. Br. J. Pharmacol. 135, 855–875 (2002).
Mackay, C. R. Follicular homing T helper (TH) cells and the TH1/TH2 paradigm. J. Exp. Med. 192, F31–F34 (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).
Vissers, J. L. M., Hartgers, F. C., Lindhout, E., Figdor, C. G. & Adema, G. J. BLC (CXCL13) is expressed by different dendritic cell subsets in vitro and in vivo. Eur. J. Immunol. 31, 1544–1549 (2001).
Ishikawa, S. et al. Aberrant high expression of B lymphocyte chemokine (BLC/CXCL13) by CD11b+CD11c+ dendritic cells in murine lupus and preferential chemotaxis of B1 cells towards BLC. J. Exp. Med. 193, 1393–1402 (2001).
Ansel, K. M., Harris, R. B. & Cyster, J. G. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 16, 67–76 (2002).
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).
Okada, S., Albrecht, R. M., Aharinejad, S. & Schraufnagel, D. E. Structural aspects of the lymphocyte traffic in rat submandibular lymph node. Microsc. Microanal. 8, 116–133 (2002).
Drayton, D. I., Ying, X., Lee, J., Lesslauer, W. & Ruddle, N. H. Ectopic LTαβ directs lymphoid organ neogenesis with concomitant expression of peripheral lymph node addressin and a HEV-restricted sulfotransferase. J. Exp. Med. 197, 1153–1163 (2003).
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).
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). A good introduction to the problems of lymph flow and compartments in the lymph node.
Fan, L., Reilly, C. R., Luo, Y., Dorf, M. E. & Lo, D. Ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J. Immunol. 164, 3955–3959 (2000).
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).
van Nierop, K. & de Groot, C. Human follicular dendritic cells: function, origin and development. Semin. Immunol. 14, 251–257 (2002).
Kim, H. J., Krenn, V., Steinhauser, G. & Berek, C. Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J. Immunol. 162, 3053–3062 (1999).
Noguchi, M., Hiwatashi, N., Liu, Z. & Toyota, T. Secretion imbalance between tumour necrosis factor and its inhibitor in inflammatory bowel disease. Gut 43, 203–209 (1998).
Sankary, H. et al. Daily determinations of serum lymphotoxin allows for accurate early diagnosis of hepatic allograft rejection. Transplant. Proc. 25, 928–930 (1993).
Ishibashi, K., Kodama, M., Hanada, S. & Arima, T. Tumor necrosis factor-β and hypercalcemia. Leuk. Lymphoma 7, 409–417 (1992).
Mackay, F. et al. Cytotoxic activities of recombinant soluble murine lymphotoxin-α and lymphotoxin-αβ complexes. J. Immunol. 159, 3299–3310 (1997).
Cuff, C. A., Sacca, R. & Ruddle, N. H. Differential induction of adhesion molecule and chemokine expression by LTα3 and LTαβ in inflammation elucidates potential mechanisms of mesenteric and peripheral lymph node development. J. Immunol. 162, 5965–5972 (1999).
Roach, D. R. et al. Secreted lymphotoxin-α is essential for the control of an intracellular bacterial infection. J. Exp. Med. 193, 239–246 (2001).
Kuprash, D. V. et al. Redundancy in tumor necrosis factor (TNF) and lymphotoxin (LT) signaling in vivo: mice with inactivation of the entire TNF/LT locus versus single-knockout mice. Mol. Cell. Biol. 22, 8626–8634 (2002).
Chicheportiche, Y. et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J. Biol. Chem. 272, 32401–32410 (1997).
Mauri, D. N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).
Harmsen, A. et al. Cutting edge: organogenesis of nasal-associated lymphoid tissue (NALT) occurs independently of lymphotoxin-α (LTα) and retinoic acid receptor-related orphan receptor-gamma, but the organization of NALT is LTα dependent. J. Immunol. 168, 986–990 (2002).
Fukuyama, S. et al. Initiation of NALT organogenesis is independent of the IL-7R, LTβR, and NIK signaling pathways but requires the Id2 gene and CD3−CD4+CD45+ cells. Immunity 17, 31–40 (2002).
Lian, R. H. & Kumar, V. Murine natural killer cell progenitors and their requirements for development. Semin. Immunol. 14, 453–460 (2002).
Yu, P. et al. B cells control the migration of a subset of dendritic cells into B cell follicles via CXC ligand 13 in a lymphotoxin-dependent fashion. J. Immunol. 168, 5117–5123 (2002).
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). The key paper that first described the ability of ectopic expression of LT to drive the formation of organized lymphoid structures.
Wang, J. & Fu, Y. X. LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)-mediated thymocyte deletion is dependent on the interaction between TCR and MHC/self-peptide. J. Immunol. 170, 3986–3993 (2003).
Steiniger, B., Barth, P. & Hellinger, A. The perifollicular and marginal zones of the human splenic white pulp: do fibroblasts guide lymphocyte immigration? Am. J. Pathol. 159, 501–512 (2001).
Castenholz, A. Architecture of the lymph node with regard to its function. Curr. Top. Pathol. 84, 1–32 (1990).
Millet, I. & Ruddle, N. H. Differential regulation of lymphotoxin (LT), lymphotoxin-β (LT-β), and TNF-α in murine T cell clones activated through the TCR. J. Immunol. 152, 4336–4346 (1994).
Ohshima, Y. et al. Naive human CD4+ T cells are a major source of lymphotoxin α. J. Immunol. 162, 3790–3794 (1999).
Voon, D. C., Subrata, L. S. & Abraham, L. J. Regulation of lymphotoxin-β by tumor necrosis factor, phorbol myristate acetate, and ionomycin in Jurkat T cells. J. Interferon Cytokine Res. 21, 921–930 (2001).
Kuprash, D. V. et al. Cyclosporin A blocks the expression of lymphotoxin α, but not lymphotoxin β, in human peripheral blood mononuclear cells. Blood 100, 1721–1727 (2002).
Kashii, Y., Giorda, R., Herberman, R. B., Whiteside, T. L. & Vujanovic, N. L. Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. J. Immunol. 163, 5358–5366 (1999).
Yoshida, H. et al. Different cytokines induce surface lymphotoxin-αβ on IL-7 receptor-α cells that differentially engender lymph nodes and Peyer's patches. Immunity 17, 823–833 (2002).
Agyekum, S. et al. Expression of lymphotoxin-β (LT-β) in chronic inflammatory conditions. J. Pathol. 199, 115–121 (2003).
Tamada, K. et al. LIGHT, a TNF-like molecule, co-stimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J. Immunol. 164, 4105–4110 (2000). An important study that links LIGHT to acute graft-versus-host disease.
Pakala, S. V., Ilic, A., Chen, L. & Sarvetnick, N. TNF-α receptor 1 (p55) on islets is necessary for the expression of LIGHT on diabetogenic T cells. Clin. Immunol. 100, 198–207 (2001).
Zhai, Y. et al. LIGHT, a novel ligand for lymphotoxin β receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J. Clin. Invest. 102, 1142–1151 (1998).
Hochman, P. S., Majeau, G. R., Mackay, F. & Browning, J. L. Proinflammatory responses are efficiently induced by homotrimeric but not heterotrimeric lymphotoxin ligands. J. Inflamm. 46, 220–234 (1995).
Browning, J. L. et al. Signaling through the lymphotoxin β receptor induces the death of some adenocarcinoma tumor lines. J. Exp. Med. 183, 867–878 (1996).
Muller, P., Mannel, D. N. & Hehlgans, T. Functional characterization of the mouse lymphotoxin-β receptor promoter. Eur. Cytokine. Netw. 12, 325–330 (2001).
Morel, Y., Truneh, A., Sweet, R. W., Olive, D. & Costello, R. T. The TNF superfamily members LIGHT and CD154 (CD40 ligand) co-stimulate induction of dendritic cell maturation and elicit specific CTL activity. J. Immunol. 167, 2479–2486 (2001).
Lee, W. H. et al. Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. Arterioscler. Thromb. Vasc. Biol. 21, 2004–2010 (2001).
Matsui, H., Hikichi, Y., Tsuji, I., Yamada, T. & Shintani, Y. LIGHT, a member of the tumor necrosis factor ligand superfamily, prevents tumor necrosis factor-mediated human primary hepatocyte apoptosis, but not Fas mediated apoptosis. J. Biol. Chem. 277, 50054–50061 (2002).
Bai, C. et al. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc. Natl Acad. Sci. USA 97, 1230–1235 (2000).
Goluszko, E. et al. Lymphotoxin-α deficiency completely protects C57BL/6 mice from developing clinical experimental autoimmune myasthenia gravis. J. Neuroimmunol. 113, 109–118 (2001).
Frei, K. et al. Tumor necrosis factor α and lymphotoxin α are not requied for induction of acute experimental autoimmune encephalomyelitis. J. Exp. Med. 185, 2177–2182 (1997).
We wish to thank E. Notidis and P. Hochman for critical reading and C. Ware, P. Rennert, Y-Z. Fu and J. Cyster for many helpful discussions.
- MARGINAL ZONE
A specialized microenvironment that surrounds the B-cell follicles of the spleen. This compartment is rich in monocytic and dendritic cells that function to capture blood-borne pathogens and present these antigens to both the marginal-zone and memory B cells that reside in this space.
- LYMPHOID ARCHITECTURE
The anatomical framework of the lymphoid organs, including the vascular and lymphatic conduits, extracellular matrix, reticular divisions between various regions and the compartmentalization of cellular subsets.
- ECTOPIC LYMPHOID STRUCTURES
Organized lymphocytic aggregates that form in sites of chronic inflammation. Typically, T- and B-cell-rich zones are segregated, and dendritic cells (DCs), germinal centres with follicular DC (FDC) networks and specialized endothelia are present. These structures are also known as the 'tertiary immune system' and their formation is termed 'lymphoid neogenesis'.
The generic term used to describe the local interplay between mobile lymphocytes and the fixed reticular/stromal cells, and includes cell adhesion, trafficking, chemokine function and cellular positioning.
- LYMPHOID FOLLICLE
A region in organized lymphoid environments that is composed of B cells. Typically, a follicular dendritic-cell (FDC) reticular network marks this region. Germinal-centre reactions occur in this region. The term primary follicle (or mantle in humans) refers to the region that contains follicular B cells that remain outside the germinal centres.
- GERMINAL CENTRE
Also known as a secondary follicle, this highly specialized and dynamic microenvironment occurs in the lymphoid follicles during an immune response. This environment is designed to promote the presentation of unprocessed antigen, the rapid clonal expansion of activated B cells, somatic hypermutation and affinity maturation that culminates in the generation of memory B cells and antibody-secreting plasma cells.
- FOLLICULAR DENDRITIC-CELL NETWORK
(FDC network). A meshwork of specialized reticular fibroblasts that has the unique ability to retain and present intact antigen to B cells, as well as to provide specific survival and positioning signals.
- CROHN'S DISEASE
One of the two main forms of inflammatory bowel disease that afflicts human patients. The pathophysiology is unknown, but is presumed to stem from a dysequilibrium between the gut flora and the mucosal immune system.
- ALTERNATIVE NUCLEAR FACTOR-κB PATHWAY (NF-κB).
Signalling through lymphotoxin-β receptor can activate NF-κB through a non-canonical NF-κB-inducing kinase (NIK)–inhibitor of NF-κB kinase-α (IKKα)-dependent route that results in the activation of RelB/NF-κB2. The repertoire of RelB/NF-κB2-activated genes is presumably different from those that are activated by the classic NF-κB complexes.
- AFFINITY MATURATION
The mutation of antibody variable-region genes followed by the selection of higher-affinity variants in the germinal centre leads to an increase in antibody affinity as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with free antibody to capture decreasing amounts of antigen.
- SOMATIC HYPERMUTATION
The accumulation of point mutations in the variable-region genes encoding immunoglobulin heavy and light chains, giving rise to high-affinity antibodies that are specific for a given antigen — a process known as affinity maturation. B cells that express high-affinity immunoglobulins on their cell surface are selected by limited amounts of the antigens.
- NON-OBESE DIABETIC MICE
(NOD mice). A strain of mice that normally develop idiopathic autoimmune diabetes that closely resembles type I diabetes in humans. The target antigen(s) that is recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic-islet cells, but its identity has remained elusive.
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Gommerman, J., Browning, J. Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 3, 642–655 (2003). https://doi.org/10.1038/nri1151
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