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Generation of a synthetic lymphoid tissue–like organoid in mice

Nature Biotechnology volume 22, pages 1539–1545 (2004)Cite this article

Abstract

Stromal cells play an important role in the formation of the normal organized microarchitecture of secondary lymphoid organs. Here we demonstrate that a tissue-engineered, lymphoid tissue–like organoid, which was constructed by transplantation of stromal cells embedded in biocompatible scaffolds into the renal subcapsular space in mice, had an organized tissue structure similar to secondary lymphoid organs. This organoid contained compartmentalized B-cell and T-cell clusters, high endothelial venule-like vessels, germinal centers and follicular dendritic cell networks. Furthermore, the organoid was transplantable to naive normal or severe combined immunodeficiency (SCID) mice, and antigen-specific, IgG-isotype antibody formation could be induced soon after intravenous administration of the antigen. This simplified system of lymphoid tissue–like organoid construction will facilitate analyses of cell-cell interactions required for development of secondary lymphoid organs and efficient induction of adaptive immune responses, and may have possible applications in the treatment of immune deficiency.

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Figure 1: Inclusion of activated DCs in collagenous scaffold in which TEL-2-LTα cells are embedded for renal subcapsular transplantation accelerates lymphocyte accumulation in the transplants.
Figure 2: Tissue-engineered transplants have structure similar to secondary lymphoid organs.
Figure 3: HEV and blood vessels are formed in tissue-engineered transplants.
Figure 4: Antigen-specific IgG1 antibody formation by the tissue-engineered lymphoid tissue–like organoid.

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References

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

    Article  CAS  Google Scholar 

  2. Nishikawa, S.-I., Hashi, H., Honda, K., Fraser, S. & Yoshida, H. Inflammation, a prototype for organogenesis of the lymphopoietic/hematopoietic system: Commentary. Curr. Opin. Immunol. 12, 342–345 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Ansel, K.M. & Cyster, J.G. Chemokines in lymphopoiesis and lymphoid organ development. Curr. Opin. Immunol. 13, 172–179 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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 

  8. 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  Google Scholar 

  9. 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  Google Scholar 

  10. Rennert, P.D., Browning, J.L., Mebius, R., Mackay, F. & Hochman, P.S. Surface lymphotoxin α/β complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184, 1999–2006 (1996).

    Article  CAS  Google Scholar 

  11. Rennert, P.D., James, D., Mackay, F., Browning, J.L. & Hochman, P.S. Lymph node genesis is induced by signaling through the lymphotoxin β receptor. Immunity 9, 71–79 (1998).

    Article  CAS  Google Scholar 

  12. 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  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Luther, S.A., Tang, H.L., Hyman, P.L., Farr, A.G. & Cyster, J.G. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl. Acad. Sci. USA 97, 12694–12699 (2000).

    Article  CAS  Google Scholar 

  15. Gunn, M.D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).

    Article  CAS  Google Scholar 

  16. Vassileva, G. et al. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190, 1183–1188 (1999).

    Article  CAS  Google Scholar 

  17. Nakano, H. & Gunn, M.D. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166, 361–369 (2001).

    Article  CAS  Google Scholar 

  18. Gunn, M.D. et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl. Acad. Sci. USA 95, 258–263 (1998).

    Article  CAS  Google Scholar 

  19. Okada, T. et al. Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. J. Exp. Med. 196, 65–75 (2002).

    Article  CAS  Google Scholar 

  20. Baekkevold, E.S. et al. The CCR7 ligand ELC (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J. Exp. Med. 193, 1105–1111 (2001).

    Article  CAS  Google Scholar 

  21. Ebisuno, Y. et al. Cutting edge: the B cell chemokine CXC chemokine ligand 13/B lymphocyte chemoattractant is expressed in the high endothelial venules of lymph nodes and Peyer's patches and affects B cell trafficking across high endothelial venules. J. Immunol. 171, 1642–1646 (2003).

    Article  CAS  Google Scholar 

  22. Kratz, A., Campos-Neto, A., Hanson, M. & Ruddle, N. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J. Exp. Med. 183, 1461–1472 (1996).

    Article  CAS  Google Scholar 

  23. Fan, L., Reilly, C.R., Luo, Y., Dorf, M.E. & Lo, D. Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J. Immunol. 164, 3955–3959 (2000).

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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  Google Scholar 

  27. Drayton, D.L., Ying, X., Lee, J., Lesslauer, W. & Ruddle, N.H. Ectopic LTαβ directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J. Exp. Med. 197, 1153–1163 (2003).

    Article  CAS  Google Scholar 

  28. Schrama, D. et al. Targeting of lymphotoxin-α to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14, 111–121 (2001).

    Article  CAS  Google Scholar 

  29. Nakashima, M. et al. Selective elimination of double-positive immature thymocytes by a thymic epithelial cell line. Eur. J. Immunol. 20, 47–53 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C. & Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 20, 621–667 (2002).

    Article  CAS  Google Scholar 

  32. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  Google Scholar 

  33. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991).

    Article  CAS  Google Scholar 

  34. Lutz, M.B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Takehisa Matsuda for fruitful discussions and biocompatible materials, Peter Burrows for critical reading and suggestions. This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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  1. Research Unit for Immune Surveillance, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, 230-0045, Kanagawa, Japan

    Sachiko Suematsu & Takeshi Watanabe

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  2. Takeshi Watanabe
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Correspondence to Sachiko Suematsu.

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Suematsu, S., Watanabe, T. Generation of a synthetic lymphoid tissue–like organoid in mice. Nat Biotechnol 22, 1539–1545 (2004). https://doi.org/10.1038/nbt1039

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