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. 1996 Nov 1;184(5):1999–2006. doi: 10.1084/jem.184.5.1999

Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs

PMCID: PMC2192901  PMID: 8920886

Abstract

For more than a decade, the biological roles and the apparent redundancy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) have been debated. LT alpha exists in its soluble form as a homotrimer, which like TNF only binds the TNF receptors, TNF-R55 or TNF- R75. The cell surface form of LT exists as a heteromer of LT alpha and LT beta subunits and this complex specifically binds the LT beta receptor (LT beta-R). To discriminate the functions of the LT and TNF systems, soluble LT beta-R-immunoglobulin (Ig) or TNF-R-Ig fusion proteins were introduced into embryonic circulation by injecting pregnant mice. Exposure to LT beta-R-Ig during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LT alpha/beta complex. These data are the first to identify a cell surface ligand involved in immune organ morphogenesis. Moreover, they unambiguously discriminate the functions of the various TNF/LT ligands, provide a unique model to study compartmentalization of immune responses and illustrate the generic utility of receptor-Ig fusion proteins for dissecting/ordering ontogenetic events in the absence of genetic modifications.

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Selected References

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  1. Ahouse J. J., Hagerman C. L., Mittal P., Gilbert D. J., Copeland N. G., Jenkins N. A., Simister N. E. Mouse MHC class I-like Fc receptor encoded outside the MHC. J Immunol. 1993 Dec 1;151(11):6076–6088. [PubMed] [Google Scholar]
  2. Banks T. A., Rouse B. T., Kerley M. K., Blair P. J., Godfrey V. L., Kuklin N. A., Bouley D. M., Thomas J., Kanangat S., Mucenski M. L. Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol. 1995 Aug 15;155(4):1685–1693. [PubMed] [Google Scholar]
  3. Browning J. L., Dougas I., Ngam-ek A., Bourdon P. R., Ehrenfels B. N., Miatkowski K., Zafari M., Yampaglia A. M., Lawton P., Meier W. Characterization of surface lymphotoxin forms. Use of specific monoclonal antibodies and soluble receptors. J Immunol. 1995 Jan 1;154(1):33–46. [PubMed] [Google Scholar]
  4. Browning J. L., Miatkowski K., Sizing I., Griffiths D., Zafari M., Benjamin C. D., Meier W., Mackay F. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J Exp Med. 1996 Mar 1;183(3):867–878. doi: 10.1084/jem.183.3.867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Browning J. L., Ngam-ek A., Lawton P., DeMarinis J., Tizard R., Chow E. P., Hession C., O'Brine-Greco B., Foley S. F., Ware C. F. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell. 1993 Mar 26;72(6):847–856. doi: 10.1016/0092-8674(93)90574-a. [DOI] [PubMed] [Google Scholar]
  6. Burkly L., Hession C., Ogata L., Reilly C., Marconi L. A., Olson D., Tizard R., Cate R., Lo D. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 1995 Feb 9;373(6514):531–536. doi: 10.1038/373531a0. [DOI] [PubMed] [Google Scholar]
  7. De Togni P., Goellner J., Ruddle N. H., Streeter P. R., Fick A., Mariathasan S., Smith S. C., Carlson R., Shornick L. P., Strauss-Schoenberger J. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994 Apr 29;264(5159):703–707. doi: 10.1126/science.8171322. [DOI] [PubMed] [Google Scholar]
  8. Eikelenboom P., Nassy J. J., Post J., Versteeg J. C., Langevoort H. L. The histogenesis of lymph nodes in rat and rabbit. Anat Rec. 1978 Feb;190(2):201–215. doi: 10.1002/ar.1091900204. [DOI] [PubMed] [Google Scholar]
  9. Erickson S. L., de Sauvage F. J., Kikly K., Carver-Moore K., Pitts-Meek S., Gillett N., Sheehan K. C., Schreiber R. D., Goeddel D. V., Moore M. W. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature. 1994 Dec 8;372(6506):560–563. doi: 10.1038/372560a0. [DOI] [PubMed] [Google Scholar]
  10. Force W. R., Walter B. N., Hession C., Tizard R., Kozak C. A., Browning J. L., Ware C. F. Mouse lymphotoxin-beta receptor. Molecular genetics, ligand binding, and expression. J Immunol. 1995 Dec 1;155(11):5280–5288. [PubMed] [Google Scholar]
  11. Georgopoulos K., Bigby M., Wang J. H., Molnar A., Wu P., Winandy S., Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994 Oct 7;79(1):143–156. doi: 10.1016/0092-8674(94)90407-3. [DOI] [PubMed] [Google Scholar]
  12. Gruss H. J., Dower S. K. Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas. Blood. 1995 Jun 15;85(12):3378–3404. [PubMed] [Google Scholar]
  13. Han S., Hathcock K., Zheng B., Kepler T. B., Hodes R., Kelsoe G. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J Immunol. 1995 Jul 15;155(2):556–567. [PubMed] [Google Scholar]
  14. 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. 1995;46(4):220–234. [PubMed] [Google Scholar]
  15. Koike R., Nishimura T., Yasumizu R., Tanaka H., Hataba Y., Hataba Y., Watanabe T., Miyawaki S., Miyasaka M. The splenic marginal zone is absent in alymphoplastic aly mutant mice. Eur J Immunol. 1996 Mar;26(3):669–675. doi: 10.1002/eji.1830260324. [DOI] [PubMed] [Google Scholar]
  16. Kratz A., Campos-Neto A., Hanson M. S., Ruddle N. H. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J Exp Med. 1996 Apr 1;183(4):1461–1472. doi: 10.1084/jem.183.4.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Matsumoto M., Mariathasan S., Nahm M. H., Baranyay F., Peschon J. J., Chaplin D. D. Role of lymphotoxin and the type I TNF receptor in the formation of germinal centers. Science. 1996 Mar 1;271(5253):1289–1291. doi: 10.1126/science.271.5253.1289. [DOI] [PubMed] [Google Scholar]
  18. Miller G. T., Hochman P. S., Meier W., Tizard R., Bixler S. A., Rosa M. D., Wallner B. P. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med. 1993 Jul 1;178(1):211–222. doi: 10.1084/jem.178.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miyawaki S., Nakamura Y., Suzuka H., Koba M., Yasumizu R., Ikehara S., Shibata Y. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur J Immunol. 1994 Feb;24(2):429–434. doi: 10.1002/eji.1830240224. [DOI] [PubMed] [Google Scholar]
  20. Mosialos G., Birkenbach M., Yalamanchili R., VanArsdale T., Ware C., Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995 Feb 10;80(3):389–399. doi: 10.1016/0092-8674(95)90489-1. [DOI] [PubMed] [Google Scholar]
  21. Nakamura T., Tashiro K., Nazarea M., Nakano T., Sasayama S., Honjo T. The murine lymphotoxin-beta receptor cDNA: isolation by the signal sequence trap and chromosomal mapping. Genomics. 1995 Nov 20;30(2):312–319. doi: 10.1006/geno.1995.9872. [DOI] [PubMed] [Google Scholar]
  22. Neumann B., Luz A., Pfeffer K., Holzmann B. Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. J Exp Med. 1996 Jul 1;184(1):259–264. doi: 10.1084/jem.184.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Neumann B., Machleidt T., Lifka A., Pfeffer K., Vestweber D., Mak T. W., Holzmann B., Krönke M. Crucial role of 55-kilodalton TNF receptor in TNF-induced adhesion molecule expression and leukocyte organ infiltration. J Immunol. 1996 Feb 15;156(4):1587–1593. [PubMed] [Google Scholar]
  24. Peppel K., Poltorak A., Melhado I., Jirik F., Beutler B. Expression of a TNF inhibitor in transgenic mice. J Immunol. 1993 Nov 15;151(10):5699–5703. [PubMed] [Google Scholar]
  25. Pfeffer K., Matsuyama T., Kündig T. M., Wakeham A., Kishihara K., Shahinian A., Wiegmann K., Ohashi P. S., Krönke M., Mak T. W. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993 May 7;73(3):457–467. doi: 10.1016/0092-8674(93)90134-c. [DOI] [PubMed] [Google Scholar]
  26. Roberts C. W., Shutter J. R., Korsmeyer S. J. Hox11 controls the genesis of the spleen. Nature. 1994 Apr 21;368(6473):747–749. doi: 10.1038/368747a0. [DOI] [PubMed] [Google Scholar]
  27. Rothe J., Lesslauer W., Lötscher H., Lang Y., Koebel P., Köntgen F., Althage A., Zinkernagel R., Steinmetz M., Bluethmann H. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993 Aug 26;364(6440):798–802. doi: 10.1038/364798a0. [DOI] [PubMed] [Google Scholar]
  28. Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
  29. Van Kooten C., Banchereau J. CD40-CD40 ligand: a multifunctional receptor-ligand pair. Adv Immunol. 1996;61:1–77. doi: 10.1016/s0065-2776(08)60865-2. [DOI] [PubMed] [Google Scholar]
  30. Vandenabeele P., Declercq W., Beyaert R., Fiers W. Two tumour necrosis factor receptors: structure and function. Trends Cell Biol. 1995 Oct;5(10):392–399. doi: 10.1016/s0962-8924(00)89088-1. [DOI] [PubMed] [Google Scholar]
  31. Ware C. F., VanArsdale T. L., Crowe P. D., Browning J. L. The ligands and receptors of the lymphotoxin system. Curr Top Microbiol Immunol. 1995;198:175–218. doi: 10.1007/978-3-642-79414-8_11. [DOI] [PubMed] [Google Scholar]
  32. Weih F., Carrasco D., Durham S. K., Barton D. S., Rizzo C. A., Ryseck R. P., Lira S. A., Bravo R. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell. 1995 Jan 27;80(2):331–340. doi: 10.1016/0092-8674(95)90416-6. [DOI] [PubMed] [Google Scholar]
  33. Worm M., Geha R. S. CD40 ligation induces lymphotoxin alpha gene expression in human B cells. Int Immunol. 1994 Dec;6(12):1883–1890. doi: 10.1093/intimm/6.12.1883. [DOI] [PubMed] [Google Scholar]
  34. Yang J. T., Rayburn H., Hynes R. O. Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development. 1995 Feb;121(2):549–560. doi: 10.1242/dev.121.2.549. [DOI] [PubMed] [Google Scholar]
  35. van Rooijen N., Kors N., Kraal G. Macrophage subset repopulation in the spleen: differential kinetics after liposome-mediated elimination. J Leukoc Biol. 1989 Feb;45(2):97–104. doi: 10.1002/jlb.45.2.97. [DOI] [PubMed] [Google Scholar]

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