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Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity

Abstract

Bronchus-associated lymphoid tissue (BALT) is occasionally found in the lungs of mice and humans; however, its role in respiratory immunity is unknown. Here we show that mice lacking spleen, lymph nodes and Peyer's patches generate unexpectedly robust primary B- and T-cell responses to influenza, which seem to be initiated at sites of induced BALT (iBALT). Areas of iBALT have distinct B-cell follicles and T-cell areas, and support T and B-cell proliferation. The homeostatic chemokines CXCL13 and CCL21 are expressed independently of TNFα and lymphotoxin at sites of iBALT formation. In addition, mice with iBALT, but lacking peripheral lymphoid organs, clear influenza infection and survive higher doses of virus than do normal mice, indicating that immune responses generated in iBALT are not only protective, but potentially less pathologic, than systemic immune responses. Thus, iBALT functions as an inducible secondary lymphoid tissue for respiratory immune responses.

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Figure 1: Influenza-specific CD8+ T cells are generated in mice lacking peripheral lymphoid organs.
Figure 2: Influenza-specific CD8+ effector T cells accumulate in the lungs of mice lacking peripheral lymphoid organs.
Figure 3: Influenza-specific IgG and germinal-center B cells are generated in mice lacking peripheral lymphoid organs.
Figure 4: iBALT is formed in influenza-infected SLP mice and supports T- and B-cell proliferation.
Figure 5: CXCL13 and CCL21 are induced in the lungs of influenza-infected mice and are found in areas of iBALT.
Figure 6: Viral clearance is slightly delayed in SLP mice, but survival is enhanced.

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    Barker, C.F. & Billingham, R.E. The role of afferent lymphatics in the rejection of skin homografts. J. Exp. Med. 128, 197–221 (1968).

    CAS  Article  Google Scholar 

  3. 3

    Zinkernagel, R.M. et al. Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol. Rev. 156, 199–209 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Weninger, W., Crowley, M.A., Manjunath, N. & von Andrian, U.H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Roman, E. et al. CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function. J. Exp. Med. 196, 957–968 (2002).

    CAS  Article  Google Scholar 

  6. 6

    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 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Miyawaki, S. et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 24, 429–434 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Shinkura, R. et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding NFκB-inducing kinase. Nat. Genet. 22, 74–77 (1999).

    CAS  Article  Google Scholar 

  10. 10

    Karrer, U. et al. On the key role of secondary organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox 11−/−) mutant mice. J. Exp. Med. 185, 2157–2170 (1997).

    CAS  Article  Google Scholar 

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    Lakkis, F.G., Arakelov, A., Konieczny, B.T. & Inoue, Y. Immunological 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat. Med. 6, 686–688 (2000).

    CAS  Article  Google Scholar 

  13. 13

    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  Google Scholar 

  14. 14

    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 gammaherpesvirus 68 but fail to develop splenomegaly or lymphocytosis. J. Virol. 74, 2786–2792 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Feuerer, M. et al. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat. Med. 9, 1151–1157 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Tripp, R.A., Topham, D.J., Watson, S.R. & Doherty, P.C. Bone marrow can function as a lymphoid organ during a primary immune response under conditions of disrupted lymphocyte trafficking. J. Immunol. 158, 3716–3720 (1997).

    CAS  PubMed  Google Scholar 

  17. 17

    Bienenstock, J., Rudzik, O., Clancy, R.L. & Perey, D.Y. Bronchial lymphoid tissue. Adv. Exp. Med. Biol. 45, 47–56 (1974).

    CAS  PubMed  Google Scholar 

  18. 18

    Delventhal, S., Hensel, A., Petzoldt, K. & Pabst, R. Effects of microbial stimulation on the number, size and activity of bronchus-associated lymphoid tissue (BALT) structures in the pig. Int. J. Exp. Path. 73, 351–357 (1992).

    CAS  Google Scholar 

  19. 19

    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 

  20. 20

    Chvatchko, Y., Kosco-Vilbois, M.H., Herren, S., Lefort, J. & Bonnefoy, J.-Y. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J. Exp. Med. 184, 2353–2360 (1996).

    CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 22

    Bienenstock, J. & Johnston, N. A morphologic study of rabbit bronchial lymphoid aggregates and lymphoepithelium. Lab. Invest. 35, 343–348 (1976).

    CAS  PubMed  Google Scholar 

  23. 23

    Plesch, B.E.C., van der Brugge-Gamelkoorn, G.J. & van de Ende, M.B. Development of bronchus associated lymphoid tissue (BALT) in the rat, with special reference to T and B cells. Dev. Comp. Immunol. 7, 79–84 (1983).

    Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    Matsumoto, M. et al. Role of lymphotoxin and the type 1 TNF receptor in the formation of germinal centers. Science 271, 1289–1291 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Fu, Y.-X., Huang, G., Matsumoto, M., Molina, H. & Chaplin, D.D. Independent signals regulate development of primary and secondary follicular structure in spleen and mesenteric lymph node. Proc. Natl. Acad. Sci. 94, 5739–5743 (1997).

    CAS  Article  Google Scholar 

  28. 28

    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  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    Hussell, T., Pennycook, A. & Openshaw, P.J. Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur. J. Immunol. 31, 2566–2573 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Constant, S.L. et al. Resident lung antigen-presenting cells have the capacity to promote Th2 T cell differentiation in situ. J. Clin. Invest. 110, 1441–1448 (2002).

    CAS  Article  Google Scholar 

  33. 33

    Chen, H.D. et al. Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung. Nat. Immunol. 2, 1067–1076 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Brimnes, M.K., Bonifaz, L., Steinman, R.M. & Moran, T.M. Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein. J. Exp. Med. 198, 133–144 (2003).

    CAS  Article  Google Scholar 

  35. 35

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

    CAS  Article  Google Scholar 

  36. 36

    Xu, B. et al. Lymphocyte homing to bronchus-associated lymphoid tissue (BALT) is mediated by L-selectin/PNAd, α4β1 integrin/VCAM-1, and LFA-1 adhesion pathways. J. Exp. Med. 197, 1255–1267 (2003).

    CAS  Article  Google Scholar 

  37. 37

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

    CAS  Article  Google Scholar 

  38. 38

    Futterer, A., Mink, K., Luz, A., Kosco-Vilbois, M.H. & Pfeffer, K. The lymphotoxin b receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9, 59–70 (1998).

    CAS  Article  Google Scholar 

  39. 39

    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  Google Scholar 

  40. 40

    Lo, J.C. et al. Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues. J. Clin. Invest. 112, 1495–1505 (2003).

    CAS  Article  Google Scholar 

  41. 41

    Guo, Z. et al. Cutting edge: membrane lymphotoxin regulates CD8+ T cell-mediated intestinal allograft rejection. J. Immunol. 167, 4796–4800 (2001).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Trudeau Institute and US National Institutes of Health grants HL69409 and HL63925 (T.D.R.), HL63925 and AI57158 (D.L.W.) and AI50844 and HL63925 (F.E.L.).

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Correspondence to Troy D Randall.

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Supplementary information

Supplementary Fig. 1

Generation of BM chimeric mice. (PDF 513 kb)

Supplementary Fig. 2

Splenectomized Rorγ−/− mice rapidly generate influenza-specific CD8 responses after infection. (PDF 72 kb)

Supplementary Fig. 3

Splenectomized Rorγ−/− mice rapidly generate influenza-specific antibody responses after infection. (PDF 42 kb)

Supplementary Fig. 4

Germinal center B cells are generated in mice lacking all peripheral lymphoid organs. (PDF 83 kb)

Supplementary Fig. 5

Expression of CXCL13 and CCL21 is induced in the lung after influenza infection. (PDF 394 kb)

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Moyron-Quiroz, J., Rangel-Moreno, J., Kusser, K. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10, 927–934 (2004). https://doi.org/10.1038/nm1091

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