Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lymphotoxin signalling in immune homeostasis and the control of microorganisms

Key Points

  • Lymphotoxin is best known for its roles in promoting lymphoid tissue development, but this cytokine also has other important immunological functions.

  • Lymphotoxin produced by dendritic cells has steady-state immunological functions, including roles in maintaining the cellularity of secondary lymphoid organs and in IgA production.

  • The coordination of the multicellular interactions that contribute to T helper cell and germinal centre responses depends on the lymphotoxin pathway.

  • Antiviral immunity requires the lymphotoxin pathway, both for the regulation of type I interferon production and for innate aspects of the B cell response.

  • Innate lymphoid cells produce lymphotoxin and this promotes interleukin-23 (IL-23)- and IL-22-dependent immune responses at mucosal surfaces. Lymphotoxin production at mucosal surfaces also regulates the microbiota and can contribute to metabolic disease.

  • The lymphotoxin pathway has a crucial role in active immune responses that occur in adult hosts, and a better understanding of these roles may help to guide the development of a new class of therapeutic agents to treat inflammatory diseases.

Abstract

Lymphotoxin (LT) is a member of the tumour necrosis factor (TNF) superfamily that was originally thought to be functionally redundant to TNF, but these proteins were later found to have independent roles in driving lymphoid organogenesis. More recently, LT-mediated signalling has been shown to actively contribute to effector immune responses. LT regulates dendritic cell and CD4+ T cell homeostasis in the steady state and determines the functions of these cells during pathogenic challenges. The LT receptor pathway is essential for controlling pathogens and even contributes to the regulation of the intestinal microbiota, with recent data suggesting that LT-induced changes in the microbiota promote metabolic disease. In this Review, we discuss these newly defined roles for LT, with a particular focus on how the LT receptor pathway regulates innate and adaptive immune responses to microorganisms.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The LT pathway regulates DC fates.
Figure 2: LT coordinates adaptive immunity.
Figure 3: Regulation of viral infections with LT.
Figure 4: LT regulates responses to microorganisms at mucosal surfaces.

References

  1. Eberl, G. A new vision of immunity: homeostasis of the superorganism. Mucosal Immunol. 3, 450–460 (2010).

    CAS  Article  PubMed  Google Scholar 

  2. 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 

  3. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    CAS  Article  PubMed  Google Scholar 

  6. De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  8. Zhu, M., Brown, N. K. & Fu, Y.-X. Direct and indirect roles of the LTβR pathway in central tolerance induction. Trends Immunol. 31, 325–331 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Chin, R. K. et al. Lymphotoxin pathway directs thymic Aire expression. Nature Immunol. 4, 1121–1127 (2003).

    CAS  Article  Google Scholar 

  10. Iizuka, K. et al. Requirement for membrane lymphotoxin in natural killer cell development. Proc. Natl Acad. Sci. USA 96, 6336–6340 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Fütterer, 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  PubMed  Google Scholar 

  12. Crowe, P. D. et al. A lymphotoxin-β-specific receptor. Science 264, 707–710 (1994).

    CAS  Article  PubMed  Google Scholar 

  13. Samstein, R. M., Josefowicz, S. Z., Arvey, A., Treuting, P. M. & Rudensky, A. Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150, 29–38 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nature Rev. Immunol. 10, 664–674 (2010).

    CAS  Article  Google Scholar 

  15. Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Zindl, C. L. et al. The lymphotoxin LT1β2 controls postnatal and adult spleen marginal sinus vascular structure and function. Immunity 30, 408–420 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  18. Moussion, C. & Girard, J.-P. Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479, 542–546 (2011). This is the first demonstration of LT being produced by a non-lymphoid cell type.

    CAS  Article  PubMed  Google Scholar 

  19. Schneider, K., Potter, K. G. & Ware, C. F. Lymphotoxin and LIGHT signaling pathways and target genes. Immunol. Rev. 202, 49–66 (2004).

    CAS  Article  PubMed  Google Scholar 

  20. Tamada, K. et al. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J. Immunol. 164, 4105–4110 (2000).

    CAS  Article  PubMed  Google Scholar 

  21. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    CAS  Article  PubMed  Google Scholar 

  22. Steinman, R. M. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1–22 (2012).

    CAS  Article  PubMed  Google Scholar 

  23. MartIn-Fontecha, A. et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615–621 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Girard, J.-P., Moussion, C. & Förster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Rev. Immunol. 12, 762–773 (2012).

    CAS  Article  Google Scholar 

  25. Uchimura, K. et al. A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nature Immunol. 6, 1105–1113 (2005).

    CAS  Article  Google Scholar 

  26. Kawashima, H. et al. N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nature Immunol. 6, 1096–1104 (2005).

    CAS  Article  Google Scholar 

  27. Browning, J. L. et al. Lymphotoxin-β receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity 23, 539–550 (2005).

    CAS  Article  PubMed  Google Scholar 

  28. León, B. et al. Regulation of TH2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells. Nature Immunol. 13, 681–690 (2012). This article provides a very clear demonstration of the ability of the LT pathway to coordinate key multicellular interactions that influence T H 2 cell development.

    Article  CAS  Google Scholar 

  29. Kabashima, K. et al. Intrinsic lymphotoxin-β receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22, 439–450 (2005).

    CAS  PubMed  Google Scholar 

  30. Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780–791 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Chow, A., Toomre, D., Garrett, W. & Mellman, I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418, 988–994 (2002).

    CAS  Article  PubMed  Google Scholar 

  33. Cella, M., Engering, A., Pinet, V., Pieters, J. & Lanzavecchia, A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388, 782–787 (1997).

    CAS  Article  PubMed  Google Scholar 

  34. Kaisho, T. & Akira, S. Dendritic-cell function in Toll-like receptor- and MyD88-knockout mice. Trends Immunol. 22, 78–83 (2001).

    CAS  Article  PubMed  Google Scholar 

  35. Suzuki, K. & Fagarasan, S. How host-bacterial interactions lead to IgA synthesis in the gut. Trends Immunol. 29, 523–531 (2008).

    CAS  Article  PubMed  Google Scholar 

  36. Fritz, J. H. et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481, 199–203 (2011). This paper further defines the mechanism by which LT controls IgA production through the LT-dependent regulation of iNOS+ DCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    CAS  Article  Google Scholar 

  38. Macpherson, A. J. S. et al. IgA production without μ or δ chain expression in developing B cells. Nature Immunol. 2, 625–631 (2001).

    CAS  Article  Google Scholar 

  39. Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008).

    CAS  Article  PubMed  Google Scholar 

  40. Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28, 243–273 (2010).

    CAS  Article  PubMed  Google Scholar 

  41. Lee, M.-R., Seo, G.-Y., Kim, Y.-M. & Kim, P.-H. iNOS potentiates mouse Ig isotype switching through AID expression. Biochem. Biophys. Res. Commun. 410, 602–607 (2011).

    CAS  Article  PubMed  Google Scholar 

  42. Tezuka, H. et al. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448, 929–933 (2007).

    CAS  Article  PubMed  Google Scholar 

  43. Cerutti, A. The regulation of IgA class switching. Nature Rev. Immunol. 8, 421–434 (2008).

    CAS  Article  Google Scholar 

  44. Fagarasan, S. et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 298, 1424–1427 (2002).

    CAS  Article  PubMed  Google Scholar 

  45. Kang, H.-S. et al. Lymphotoxin is required for maintaining physiological levels of serum IgE that minimizes Th1-mediated airway inflammation. J. Exp. Med. 198, 1643–1652 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Spahn, T. W. et al. The lymphotoxin-β receptor is critical for control of murine Citrobacter rodentium-induced colitis. Gastroenterology 127, 1463–1473 (2004).

    CAS  Article  PubMed  Google Scholar 

  47. Ehrchen, J. M. et al. The absence of cutaneous lymph nodes results in a Th2 response and increased susceptibility to Leishmania major infection in mice. Infect. Immun. 76, 4241–4250 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Dohi, T. et al. Elimination of colonic patches with lymphotoxin β receptor-Ig prevents Th2 cell-type colitis. J. Immunol. 167, 2781–2790 (2001).

    CAS  Article  PubMed  Google Scholar 

  49. 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 down-regulated by IL-4 during Th2 differentiation. J. Immunol. 162, 1333–1338 (1999).

    CAS  PubMed  Google Scholar 

  50. Morel, P. A. & Oriss, T. B. Crossregulation between Th1 and Th2 cells. Crit. Rev. Immunol. 18, 275–303 (1998).

    CAS  Article  PubMed  Google Scholar 

  51. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev. Immunol. 3, 133–146 (2003).

    CAS  Article  Google Scholar 

  52. Zhu, J. & Paul, W. E. Heterogeneity and plasticity of T helper cells. Cell Res. 20, 4–12 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Else, K. J. & Finkelman, F. D. Intestinal nematode parasites, cytokines and effector mechanisms. Int. J. Parasitol. 28, 1145–1158 (1998).

    CAS  Article  PubMed  Google Scholar 

  54. Matsumoto, M. et al. Affinity maturation without germinal centres in lymphotoxin-α-deficient mice. Nature 382, 462–466 (1996).

    CAS  Article  PubMed  Google Scholar 

  55. Thai, T.-H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007). A demonstration that a miRNA-dependent programme regulates LT expression to contribute to germinal centre formation.

    CAS  Article  PubMed  Google Scholar 

  56. Vu, F., Dianzani, U., Ware, C. F., Mak, T. & Gommerman, J. L. ICOS, CD40, and lymphotoxin β receptors signal sequentially and interdependently to initiate a germinal center reaction. J. Immunol. 180, 2284–2293 (2008).

    CAS  Article  PubMed  Google Scholar 

  57. Junt, T. et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450, 110–114 (2007).

    CAS  Article  PubMed  Google Scholar 

  58. Phan, T. G., Green, J. A., Gray, E. E., Xu, Y. & Cyster, J. G. Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation. Nature Immunol. 10, 786–793 (2009).

    CAS  Article  Google Scholar 

  59. Phan, T. G., Grigorova, I., Okada, T. & Cyster, J. G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nature Immunol. 8, 992–1000 (2007).

    CAS  Article  Google Scholar 

  60. Moseman, E. A. et al. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. Immunity 36, 415–426 (2012). A mechanistic demonstration that LT from B cells maintains the sentinel function of SCS macrophages and prevents the dissemination of lethal pathogens.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature Rev. Immunol. 5, 375–386 (2005).

    CAS  Article  Google Scholar 

  62. Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3, 67–76 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Banks, T. A. et al. A lymphotoxin-IFN-β axis essential for lymphocyte survival revealed during cytomegalovirus infection. J. Immunol. 174, 7217–7225 (2005).

    CAS  Article  PubMed  Google Scholar 

  64. Kumar, V. et al. Global lymphoid tissue remodeling during a viral infection is orchestrated by a B cell-lymphotoxin-dependent pathway. Blood 115, 4725–4733 (2010).

    CAS  Article  PubMed  Google Scholar 

  65. Louten, J., van Rooijen, N. & Biron, C. A. Type 1 IFN deficiency in the absence of normal splenic architecture during lymphocytic choriomeningitis virus infection. J. Immunol. 177, 3266–3272 (2006).

    CAS  Article  PubMed  Google Scholar 

  66. Heath, W. R. & Carbone, F. R. Cross-presentation in viral immunity and self-tolerance. Nature Rev. Immunol. 1, 126–135 (2001).

    CAS  Article  Google Scholar 

  67. Banks, T. A., Rickert, S. & Ware, C. F. Restoring immune defenses via lymphotoxin signaling: lessons from cytomegalovirus. Immunol. Res. 34, 243–254 (2006).

    CAS  Article  PubMed  Google Scholar 

  68. Summers deLuca, L. et al. LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+ T cells. Proc. Natl Acad. Sci. USA 108, 2046–2051 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Roozendaal, R. et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity 30, 264–276 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Iannacone, M. et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465, 1079–1083 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nature Med. 10, 927–934 (2004).

    CAS  Article  PubMed  Google Scholar 

  72. Ehlers, S. et al. The lymphotoxin β receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J. Immunol. 170, 5210–5218 (2003).

    CAS  Article  PubMed  Google Scholar 

  73. Barthel, M. et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839–2858 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Hapfelmeier, S. et al. The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms. J. Immunol. 174, 1675–1685 (2005).

    CAS  Article  PubMed  Google Scholar 

  75. Wang, Y. et al. Lymphotoxin β receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32, 403–413 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ota, N. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nature Immunol. 12, 941–948 (2011).

    CAS  Article  Google Scholar 

  77. Tumanov, A. V. et al. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10, 44–53 (2011). References 76 and 77 demonstrate the importance of the LT pathway in the regulation of the innate IL-23–IL-22 axis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Schlüter, D. et al. Both lymphotoxin-α and TNF are crucial for control of Toxoplasma gondii in the central nervous system. J. Immunol. 170, 6172–6182 (2003).

    Article  PubMed  Google Scholar 

  79. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nature Immunol. 5, 64–73 (2003).

    Article  CAS  Google Scholar 

  80. Eberl, G. & Lochner, M. The development of intestinal lymphoid tissues at the interface of self and microbiota. Mucosal Immunol. 2, 478–485 (2009).

    CAS  Article  PubMed  Google Scholar 

  81. Eberl, G. & Littman, D. R. Thymic origin of intestinal αβT cells revealed by fate mapping of RORγt+ cells. Sci. Signal. 305, 248–251 (2004).

    CAS  Google Scholar 

  82. Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    CAS  PubMed  Google Scholar 

  84. Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).

    CAS  Article  PubMed  Google Scholar 

  86. Cherrier, M., Sawa, S. & Eberl, G. Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J. Exp. Med. 209, 729–740 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Satoh-Takayama, N. et al. Lymphotoxin-β receptor-independent development of intestinal IL-22-producing NKp46+ innate lymphoid cells. Eur. J. Immunol. 41, 780–786 (2011).

    CAS  Article  PubMed  Google Scholar 

  89. Tumanov, A. V. et al. Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol. Rev. 195, 106–116 (2003).

    CAS  Article  PubMed  Google Scholar 

  90. Mahajan, A. et al. Obesity-dependent association of TNF-LTA locus with type 2 diabetes in North Indians. J. Mol. Med. 88, 515–522 (2010).

    CAS  Article  PubMed  Google Scholar 

  91. Lo, J. C. et al. Lymphotoxin β receptor-dependent control of lipid homeostasis. Science 316, 285–288 (2007).

    CAS  Article  PubMed  Google Scholar 

  92. Lotzer, K. et al. Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/Lymphotoxin β-receptor NF-κB signaling. Arterioscler. Thromb. Vasc. Biol. 30, 395–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tumanov, A. V., Christiansen, P. A. & Fu, Y.-X. The role of lymphotoxin receptor signaling in diseases. Curr. Mol. Med. 7, 567–578 (2007).

    CAS  Article  PubMed  Google Scholar 

  94. Norman, R., Bogardus, C. & Ravussin, E. Linkage between obesity and a marker near the tumor necrosis factor-α locus in Pima Indians. J. Clin. Invest. 96, 158–162 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Hamid, Y. H. et al. The common T60N polymorphism of the lymphotoxin-α gene is associated with type 2 diabetes and other phenotypes of the metabolic syndrome. Diabetologia 48, 445–451 (2005).

    CAS  Article  PubMed  Google Scholar 

  96. Upadhyay, V. et al. Lymphotoxin regulates commensal responses to enable diet-induced obesity. Nature Immunol. 13, 947–953 (2012). This paper demonstrates the ability of the LT pathway to regulate the commensal microbiota.

    CAS  Article  Google Scholar 

  97. Pamir, N., McMillen, T. S., Edgel, K. A., Kim, F. & LeBoeuf, R. C. Deficiency of Lymphotoxin-α does not exacerbate high fat diet induced obesity but does enhance inflammation in mice. Am. J. Physiol. Endocrinol. Metab. 302, e961–e971 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Spiegelman, B. M. & Flier, J. S. Obesity and the regulation of energy balance. Cell 104, 531–543 (2001).

    CAS  Article  PubMed  Google Scholar 

  99. Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    CAS  Article  PubMed  Google Scholar 

  101. Fava, R. A., Browning, J. L., Gatumu, M., Skarstein, K. & Bolstad, A.-I. LTBR-pathway in Sjogren's syndrome: CXCL13 levels and B-cell-enriched ectopic lymphoid aggregates in NOD mouse lacrimal glands are dependent on LTBR. Adv. Exp. Med. Biol. 691, 383–390 (2011).

    CAS  Article  PubMed  Google Scholar 

  102. Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 1–5 (2011).

    Article  CAS  Google Scholar 

  104. Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Dejardin, E. et al. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525–535 (2002).

    CAS  Article  PubMed  Google Scholar 

  106. Chang, Y.-H., Chao, Y., Hsieh, S.-L. & Lin, W.-W. Mechanism of LIGHT/interferon-γ-induced cell death in HT-29 cells. J. Cell. Biochem. 93, 1188–1202 (2004).

    CAS  Article  PubMed  Google Scholar 

  107. 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).

    CAS  Article  PubMed  Google Scholar 

  108. 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).

    CAS  Article  PubMed  Google Scholar 

  109. 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).

    CAS  Article  PubMed  Google Scholar 

  110. Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208, 125–134 (2011). This article demonstrates the LT-dependent formation of aberrant lymphoid structures near an epithelial surface.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1131 (2006).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank A. Tumanov and M. Zhu for their contribution to the lymphotoxin project. This work is partially supported by DK080736 and CA141975 to Y.-X.F.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yang-Xin Fu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Yang-Xin Fu's homepage

Glossary

Innate lymphoid cells

(ILCs). Populations of lymphoid cells that lack lineage markers typically associated with other immune cell subsets, but that express transcription factors and cytokines that are usually associated with differentiated CD4+ T helper cell subsets.

Cd11c–DTR system

A system in which mice express the diphtheria toxin receptor (DTR) under the control of the Cd11c gene promoter. This allows the conditional depletion of dendritic cells (and some other CD11c+ cells) in response to diphtheria toxin administration.

μMT−/− mice

Mice that contain a targeted mutation of Ighm; these mice lack mature, conventional B cells.

LTR-Ig and TNFR-Ig

LTR-Ig and TNFR-Ig are decoy receptors for the lymphotoxin receptor (LTR) and the tumour necrosis factor receptor (TNFR), respectively. Their administration prevents ligand–receptor interactions and circumvents signalling through these pathways. They block lymphoid organogenesis if delivered in utero.

Subcapsular sinus (SCS) macrophages

CD11b+CD169+ macrophages that populate the subcapsular sinus of lymph nodes.

Lymphoid tissue-inducer cells

A CD4+CD90+RORγt+CD3 subset of innate lymphoid cells that express lymphotoxin-α1β2 to enable the formation of lymph nodes and Peyer's patches during development.

16S rRNA

A component of the 30S subunit of the bacterial ribosome; a unique secondary structure characterized by stem and loop regions makes this target useful in the unbiased identification of currently uncultured commensal bacteria.

Segmented filamentous bacteria

(SFB). A bacterial species that lives in the terminal ileum in direct contact with intestinal epithelial cells and that induces the expression of interleukin-17A (IL-17A), IL-22 and IgA in the host. Candidatus savagella has been proposed as a name for this uncultured species.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Upadhyay, V., Fu, YX. Lymphotoxin signalling in immune homeostasis and the control of microorganisms. Nat Rev Immunol 13, 270–279 (2013). https://doi.org/10.1038/nri3406

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3406

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing