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  • Review Article
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Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease

Key Points

  • 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.

Abstract

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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Figure 1: Ligands and receptors of the tumour-necrosis factor/lymphotoxin system.
Figure 2: Maintenance of follicular dendritic cells — a model for lymphotoxin–stromal-cell interactions.
Figure 3: What is the role of lymphotoxin/LIGHT in T-cell function in the lymph nodes?
Figure 4: Organized lymphoid tissue is seen in inflamed ectopic sites.

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References

  1. Goodnow, C. C. Chance encounters and organized rendezvous. Immunol. Rev. 156, 5–10 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Aggarwal, B. B. & Natarajan, K. Tumor necrosis factors: developments during the last decade. Eur. Cytokine Netw. 7, 93–124 (1996).

    CAS  PubMed  Google Scholar 

  3. 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).

    CAS  PubMed  Google Scholar 

  4. Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).

    Article  CAS  Google Scholar 

  5. Muller, G. & Lipp, M. Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Curr. Opin. Immunol. 15, 217–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Ruddle, N. H. Lymphoid neo-organogenesis: lymphotoxin's role in inflammation and development. Immunol. Res. 19, 119–125 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. Granger, S. W. & Ware, C. F. Turning on LIGHT. J. Clin. Invest. 108, 1741–1742 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Browning, J. L. et al. Characterization of lymphotoxin-αβ complexes on the surface of mouse lymphocytes. J. Immunol. 159, 3288–3298 (1997).

    CAS  PubMed  Google Scholar 

  12. Browning, J. L. & French, L. E. Visualization of lymphotoxin-β and lymphotoxin-β receptor expression in mouse embryos. J. Immunol. 168, 5079–5087 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Rennert, P. D. TNF family ligands and receptors control the development of secondary lymphoid organs. Recent Res. Devel. Immunity 1, 33–43 (2003).

    CAS  Google Scholar 

  15. Finke, D. & Kraehenbuhl, J. P. Formation of Peyer's patches. Curr. Opin. Genet. Dev. 11, 561–567 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Fu, Y. X. & Chaplin, D. D. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17, 399–433 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Ye, Q. et al. Modulation of LIGHT–HVEM co-stimulation prolongs cardiac allograft survival. J. Exp. Med. 195, 795–800 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cyster, J. G. et al. Follicular stromal cells and lymphocyte homing to follicles. Immunol. Rev. 176, 181–193 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Husson, H. et al. Functional effects of TNF and lymphotoxin α1β2 on FDC-like cells. Cell. Immunol. 203, 134–143 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Martin, F. & Kearney, J. F. Marginal-zone B cells. Nature Rev. Immunol. 2, 323–335 (2002).

    Article  CAS  Google Scholar 

  36. Lu, T. T. & Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. Ngo, V. N., Cornall, R. J. & Cyster, J. G. Splenic T zone development is B cell dependent. J. Exp. Med. 194, 1649–1660 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cyster, J. G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cyster, J. G. Leukocyte migration: scent of the T zone. Curr. Biol. 10, R30–R33 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Neutra, M. R., Mantis, N. J. & Kraehenbuhl, J. P. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nature Immunol. 2, 1004–1009 (2001).

    Article  CAS  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Jacob, E., Baker, S. J. & Swaminathan, S. P. 'M' cells in the follicle-associated epithelium of the human colon. Histopathology 11, 941–952 (1987).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Takemura, S. et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

  56. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003).

    Article  CAS  Google Scholar 

  57. 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).

    CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Pomerantz, J. L. & Baltimore, D. Two pathways to NF-κB. Mol. Cell 10, 693–695 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. de Vinuesa, C. G. et al. Germinal centers without T cells. J. Exp. Med. 191, 485–494 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. Maccioni, M. et al. Arthritogenic monoclonal antibodies from K/BxN mice. J. Exp. Med. 195, 1071–1077 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Holmdahl, R. et al. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol. Rev. 118, 193–232 (1990).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. Constant, S. L. & Bottomly, K. Induction of TH1 and TH2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15, 297–322 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. 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.

    Article  CAS  PubMed  Google Scholar 

  76. Suresh, M. et al. Role of Lymphotoxin α in T-cell responses during an acute viral infection. J. Virol. 76, 3943–3951 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    Article  PubMed  Google Scholar 

  78. Benedict, C. A. et al. Lymphotoxins and cytomegalovirus cooperatively induce interferon-β, establishing host-virus detente. Immunity 15, 617–626 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    Article  CAS  PubMed  Google Scholar 

  81. Muller, S. et al. Role of an intact splenic microarchitecture in early lymphocytic choriomeningitis virus production. J. Virol. 76, 2375–2383 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Berger, D. P. et al. Lymphotoxin-β-deficient mice show defective antiviral immunity. Virology 260, 136–147 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. 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.

    Article  CAS  PubMed  Google Scholar 

  85. Wu, Q. et al. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J. Exp. Med. 193, 1327–1332 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gommerman, J. L. et al. A role for surface lymphotoxin in experimental autoimmune encephalitis indepdendent of LIGHT. J. Clin. Invest. (in the press).

  89. 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).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

  94. Weyand, C. M., Kurtin, P. J. & Goronzy, J. J. Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am. J. Pathol. 159, 787–793 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mabbott, N. A. & Bruce, M. E. Follicular dendritic cells as targets for intervention in transmissible spongiform encephalopathies. Semin. Immunol. 14, 285–293 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. 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).

    Article  CAS  PubMed  Google Scholar 

  100. Pitti, R. M. et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699–703 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Baud, V. & Karin, M. Signal transduction by tumor necrosis and its relatives. Trends Cell Biol. 11, 372–377 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. MacEwan, D. J. TNF ligands and receptors — a matter of life and death. Br. J. Pharmacol. 135, 855–875 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mackay, C. R. Follicular homing T helper (TH) cells and the TH1/TH2 paradigm. J. Exp. Med. 192, F31–F34 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  Google Scholar 

  112. 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).

    Article  CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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).

    Article  CAS  PubMed  Google Scholar 

  115. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    Article  CAS  PubMed  Google Scholar 

  117. 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).

    Article  CAS  PubMed  Google Scholar 

  118. van Nierop, K. & de Groot, C. Human follicular dendritic cells: function, origin and development. Semin. Immunol. 14, 251–257 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. 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).

    CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sankary, H. et al. Daily determinations of serum lymphotoxin allows for accurate early diagnosis of hepatic allograft rejection. Transplant. Proc. 25, 928–930 (1993).

    CAS  PubMed  Google Scholar 

  122. Ishibashi, K., Kodama, M., Hanada, S. & Arima, T. Tumor necrosis factor-β and hypercalcemia. Leuk. Lymphoma 7, 409–417 (1992).

    Article  CAS  PubMed  Google Scholar 

  123. Mackay, F. et al. Cytotoxic activities of recombinant soluble murine lymphotoxin-α and lymphotoxin-αβ complexes. J. Immunol. 159, 3299–3310 (1997).

    CAS  PubMed  Google Scholar 

  124. 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).

    CAS  PubMed  Google Scholar 

  125. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. 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).

    Article  CAS  PubMed  Google Scholar 

  129. 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).

    Article  CAS  PubMed  Google Scholar 

  130. 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 CD3CD4+CD45+ cells. Immunity 17, 31–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Lian, R. H. & Kumar, V. Murine natural killer cell progenitors and their requirements for development. Semin. Immunol. 14, 453–460 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. 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).

    Article  CAS  PubMed  Google Scholar 

  133. 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.

    Article  CAS  PubMed  Google Scholar 

  134. 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).

    Article  CAS  PubMed  Google Scholar 

  135. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Castenholz, A. Architecture of the lymph node with regard to its function. Curr. Top. Pathol. 84, 1–32 (1990).

    PubMed  Google Scholar 

  137. 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).

    CAS  PubMed  Google Scholar 

  138. Ohshima, Y. et al. Naive human CD4+ T cells are a major source of lymphotoxin α. J. Immunol. 162, 3790–3794 (1999).

    CAS  PubMed  Google Scholar 

  139. 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).

    Article  CAS  PubMed  Google Scholar 

  140. 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).

    CAS  PubMed  Google Scholar 

  141. 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).

    CAS  PubMed  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. Agyekum, S. et al. Expression of lymphotoxin-β (LT-β) in chronic inflammatory conditions. J. Pathol. 199, 115–121 (2003).

    Article  PubMed  CAS  Google Scholar 

  144. 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.

    Article  CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  Google Scholar 

  146. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 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).

    CAS  PubMed  Google Scholar 

  148. 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).

    Article  CAS  PubMed  Google Scholar 

  149. Muller, P., Mannel, D. N. & Hehlgans, T. Functional characterization of the mouse lymphotoxin-β receptor promoter. Eur. Cytokine. Netw. 12, 325–330 (2001).

    CAS  PubMed  Google Scholar 

  150. 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).

    Article  CAS  PubMed  Google Scholar 

  151. 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).

    Article  CAS  PubMed  Google Scholar 

  152. 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).

    Article  CAS  PubMed  Google Scholar 

  153. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 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).

    Article  CAS  PubMed  Google Scholar 

  155. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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.

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Correspondence to Jeffrey L. Browning.

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DATABASES

Entrez

HSV

LCMV

LocusLink

CCL19

CCL21

CCR7

CD157

CXCL9

CXCL10

CXCL11

CXCL12

CXCL13

CXCR3

HVEM

ICAM1

IFN-γ

IL-12

LIGHT

LTα

LTβ

LTβR

Rag

TNF

VCAM1

Glossary

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'.

MICROENVIRONMENT

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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