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.

  • Article
  • Published:

The development of inducible bronchus-associated lymphoid tissue depends on IL-17

Abstract

Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4+CD3 lymphoid tissue–inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4+ T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-α-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Development of iBALT in neonatal mice rather than adult mice.
Figure 2: Formation of iBALT independently of CCR2 and CCR6.
Figure 3: LTi cells are not required for iBALT development.
Figure 4: Higher expression of IL-17 in neonatal lungs than in adult lungs.
Figure 5: The development of iBALT requires IL-17.
Figure 6: IL-17 acts early in iBALT formation but does not maintain iBALT structure.
Figure 7: IL-17-producing T cells promote iBALT formation.

Similar content being viewed by others

References

  1. Randall, T. Bronchus-associated lymphoid tissue: structure and function. Adv. Immunol. 107, 187–241 (2010).

    Article  CAS  Google Scholar 

  2. Carragher, D.M., Rangel-Moreno, J. & Randall, T.D. Ectopic lymphoid tissues and local immunity. Semin. Immunol. 20, 26–42 (2007).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Halle, S. et al. Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. J. Exp. Med. 206, 2593–2601 (2009).

    Article  CAS  Google Scholar 

  5. Moyron-Quiroz, J.E. et al. Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25, 643–654 (2006).

    Article  CAS  Google Scholar 

  6. GeurtsvanKessel, C.H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).

    Article  CAS  Google Scholar 

  7. Rangel-Moreno, J. et al. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J. Clin. Invest. 116, 3183–3194 (2006).

    Article  CAS  Google Scholar 

  8. Ulrichs, T. et al. Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J. Pathol. 204, 217–228 (2004).

    Article  Google Scholar 

  9. Hogg, J.C. et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 2645–2653 (2004).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Randall, T.D., Carragher, D.M. & Rangel-Moreno, J. Development of secondary lymphoid organs. Ann. Rev. Immunol. 26, 627–650 (2008).

    Article  CAS  Google Scholar 

  12. Cupedo, T., Kraal, G. & Mebius, R.E. The role of CD45+CD4+CD3 cells in lymphoid organ development. Immunol. Rev. 189, 41–50 (2002).

    Article  CAS  Google Scholar 

  13. van de Pavert, S.A. et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10, 1193–1199 (2009).

    Article  CAS  Google Scholar 

  14. Mebius, R.E., Rennert, P. & Weissman, I.L. Developing lymph nodes collect CD4+CD3LTb+ cells that can differentiate to APC, NK cells, and follicular cells, but not T or B cells. Immunity 7, 493–504 (1997).

    Article  CAS  Google Scholar 

  15. Ngo, V.N. et al. Lymphotoxin a/b 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 

  16. 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 

  17. 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 

  18. Rangel-Moreno, J., Moyron-Quiroz, J.E., Hartson, L., Kusser, K. & Randall, T.D. Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza. Proc. Natl. Acad. Sci. USA 104, 10577–10582 (2007).

    Article  CAS  Google Scholar 

  19. Gatumu, M.K. et al. Blockade of lymphotoxin-β receptor signaling reduces aspects of Sjogren's syndrome in salivary glands of non-obese diabetic mice. Arthritis Res. Ther. 11, 1–12 (2009).

    Article  Google Scholar 

  20. Furtado, G.C. et al. Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc. Natl. Acad. Sci. USA 104, 5026–5031 (2007).

    Article  CAS  Google Scholar 

  21. Cupedo, T., Jansen, W., Kraal, G. & Mebius, R.E. Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21, 655–667 (2004).

    Article  CAS  Google Scholar 

  22. Serbina, N.V. & Pamer, E.G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    Article  CAS  Google Scholar 

  23. Iwasaki, A. & Kelsall, B.L. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)3a, MIP-3b, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–1394 (2000).

    Article  CAS  Google Scholar 

  24. Mebius, R.E. et al. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+CD4+CD3 cells, as well as macrophages. J. Immunol. 166, 6593–6601 (2001).

    Article  CAS  Google Scholar 

  25. Cupedo, T. & Mebius, R.E. Cellular interactions in lymph node development. J. Immunol. 174, 21–25 (2005).

    Article  CAS  Google Scholar 

  26. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    Article  CAS  Google Scholar 

  27. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).

    Article  CAS  Google Scholar 

  28. Luther, S.A., Ansel, K.M. & Cyster, J.G. Overlapping roles of CXCL13, interleukin 7 receptor α, and CCR7 ligands in lymph node development. J. Exp. Med. 197, 1191–1198 (2003).

    Article  CAS  Google Scholar 

  29. 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 

  30. Zhou, L. et al. IL-6 programs TU-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).

    Article  CAS  Google Scholar 

  31. Marinkovic, T. et al. Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J. Clin. Invest. 116, 2622–2632 (2006).

    Article  CAS  Google Scholar 

  32. Nagatake, T. et al. Id2-, RORγt-, and LTβR-independent initiation of lymphoid organogenesis in ocular immunity. J. Exp. Med. 206, 2351–2364 (2009).

    Article  CAS  Google Scholar 

  33. Rangel-Moreno, J. et al. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30, 731–743 (2009).

    Article  CAS  Google Scholar 

  34. Harmsen, A. et al. Organogenesis of nasal associated lymphoid tissue (NALT) occurs independently of lymphotoxin-α (LTα) and retinoic acid receptor-related orphan receptor-γ, but the organization of NALT is LTα-dependent. J. Immunol. 168, 986–990 (2002).

    Article  CAS  Google Scholar 

  35. 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  Google Scholar 

  36. Yang, X.O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    Article  CAS  Google Scholar 

  37. 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 (2010).

    Article  Google Scholar 

  38. Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).

    Article  CAS  Google Scholar 

  39. Martin, B., Hirota, K., Cua, D.J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    Article  CAS  Google Scholar 

  40. Bagavant, H., Thompson, C., Ohno, K., Setiady, Y. & Tung, K.S. Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease. Int. Immunol. 14, 1397–1406 (2002).

    Article  CAS  Google Scholar 

  41. Kocks, J.R., Davalos-Misslitz, A.C., Hintzen, G., Ohl, L. & Forster, R. Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J. Exp. Med. 204, 723–734 (2007).

    Article  CAS  Google Scholar 

  42. Tshering, T. & Pabst, R. Bronchus associated lymphoid tissue (BALT) is not present in normal adult lung but in different diseases. Pathobiol. 68, 1–8 (2000).

    Article  Google Scholar 

  43. Sue-Chu, M. et al. Lymphoid aggregates in endobronchial biopsies from young elite cross-country skiers. Am. J. Respir. Crit. Care Med. 158, 597–601 (1998).

    Article  CAS  Google Scholar 

  44. Heier, I. et al. Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age. Thorax 63, 703–709 (2008).

    Article  CAS  Google Scholar 

  45. Ersch, J., Tschernig, T. & Stallmach, T. Frequency and potential cause of bronchus-associated lymphoid tissue in fetal lungs. Pediatr. Allergy Immunol. 16, 295–298 (2005).

    Article  Google Scholar 

  46. Kahnert, A. et al. Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. J. Infect. Dis. 195, 46–54 (2007).

    Article  CAS  Google Scholar 

  47. Chiavolini, D. et al. Bronchus-associated lymphoid tissue (BALT) and survival in a vaccine mouse model of tularemia. PLoS ONE 5, e11156 (2010).

    Article  Google Scholar 

  48. Escolar Castellon, J.D., Escolar Castellon, A., Roche Roche, P.A. & Minana Amada, C. Bronchial-associated lymphoid tissue (BALT) response to airway challenge with cigarette smoke, bovine antigen and anti-pulmonary serum. Histol. Histopathol. 7, 321–328 (1992).

    CAS  PubMed  Google Scholar 

  49. Wiley, J.A. et al. Inducible bronchus-associated lymphoid tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses. PLoS ONE 4, e7142 (2009).

    Article  Google Scholar 

  50. van den Berg, W.B. & Miossec, P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 549–553 (2009).

    Article  CAS  Google Scholar 

  51. Segal, B.M. Th17 cells in autoimmune demyelinating disease. Semin. Immunopathol. 32, 71–77 (2010).

    Article  CAS  Google Scholar 

  52. Khader, S.A., Gaffen, S.L. & Kolls, J.K. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2, 403–411 (2009).

    Article  CAS  Google Scholar 

  53. Ivanov, I.I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  Google Scholar 

  54. Wu, H.J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    Article  CAS  Google Scholar 

  55. Dewhirst, F.E. et al. Phylogeny of the defined murine microbiota: altered Schaedler flora. Appl. Environ. Microbiol. 65, 3287–3292 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank L. LaMere and A. Boucher for animal husbandry; S. Lira (Mount Sinai School of Medicine) for Ccr6−/− mice; D. Littman (New York University) for Rorc−/− and Id2−/− mice; J. Cyster (University of California, San Francisco) for Cxcl13−/− and plt/plt mice; L. Haynes (Trudeau Institute) for rederived OT-II mice; and J. Browning (Biogen Idec) for soluble LTβR. Supported by the University of Rochester, the US National Institutes of Health (HL069409, AI072689 and AI061511 to T.D.R.; and HL105427 to S.A.K.) and the Children's Hospital of Pittsburgh.

Author information

Authors and Affiliations

Authors

Contributions

J.R.-M., D.M.C., M.d.l.L.G.-H. and T.D.R. designed the experiments; J.R.-M., D.M.C., M.d.l.L.G.-H., J.Y.H., K.K. and L.H. did the experiments; J.R.-M. and T.D.R. wrote the paper; and J.K.K., S.A.K. and T.D.R. edited the paper and provided the funding.

Corresponding author

Correspondence to Troy D Randall.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rangel-Moreno, J., Carragher, D., de la Luz Garcia-Hernandez, M. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol 12, 639–646 (2011). https://doi.org/10.1038/ni.2053

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2053

This article is cited by

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