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IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge

Nature Immunology volume 8, pages 369–377 (2007)Cite this article

Abstract

Interferon-γ is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-γ response by CD4+ T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4+ T cell population in the lung. The recall response of the IL-17-producing CD4+ T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4+ T cells producing interferon-γ in the lung. We propose that vaccination induces IL-17-producing CD4+ T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4+ T cells producing interferon-γ, which ultimately restrict bacterial growth.

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Figure 1: Vaccination reduces bacterial burden and accelerates the accumulation of antigen-specific cytokine-producing T cells in the lung after challenge.
Figure 2: IL-12p40 but not IL-12p35 is essential for vaccine-induced reduced bacterial burden and the accelerated accumulation of antigen-specific cytokine-producing T cells in the lungs.
Figure 3: IL-23 is required for vaccine-induced reduced bacterial burden and the accelerated accumulation of antigen-specific cytokine-producing T cells in the lungs.
Figure 4: Cellular responses in the lung are accelerated in vaccinated mice.
Figure 5: Vaccinated mice show early IL-17- and IL-23-dependent chemokine production.
Figure 6: Vaccination-induced IL-23-dependent lung IL-17-producing CD4+ T cell population.
Figure 7: DDA drives the production of TGF-β and population expansion of IL-17-producing cells.

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References

  1. Corbett, E.L. et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch. Intern. Med. 163, 1009–1021 (2003).

    Article  Google Scholar 

  2. Nabeshima, S. et al. Kinetic analysis of Mycobacterium tuberculosis-specific cytokine production by PBMC in adults after BCG vaccination. J. Infect. Chemother. 11, 18–23 (2005).

    Article  Google Scholar 

  3. Colditz, G.A. et al. Efficacy of BCG vaccine in the prevention of tuberculosis. J. Am. Med. Assoc. 271, 698–702 (1994).

    Article  CAS  Google Scholar 

  4. Cooper, A.M., Callahan, J.E., Keen, M., Belisle, J.T. & Orme, I.M. Expression of memory immunity in the lung following re-exposure to Mycobacterium tuberculosis. Tuber. Lung Dis. 78, 67–73 (1997).

    Article  CAS  Google Scholar 

  5. Jung, Y.J., Ryan, L., Lacourse, R. & North, R. Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice. J. Exp. Med. 201, 1915–1924 (2005).

    Article  CAS  Google Scholar 

  6. Flynn, J.L. & Chan, J. Immunology of tuberculosis. Annu. Rev. Immunol. 19, 93–129 (2001).

    Article  CAS  Google Scholar 

  7. Akahoshi, M. et al. Influence of interleukin-12 receptor β1 polymorphisms on tuberculosis. Hum. Genet. 112, 237–243 (2003).

    CAS  PubMed  Google Scholar 

  8. Tso, H.W., Lau, Y.L., Tam, C.M., Wong, H.S. & Chiang, A.K. Associations between IL12β polymorphisms and tuberculosis in the Hong Kong chinese population. J. Infect. Dis. 190, 913–919 (2004).

    Article  CAS  Google Scholar 

  9. Cooper, A.M., Magram, J., Ferrante, J. & Orme, I.M. IL-12 is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J. Exp. Med. 186, 39–46 (1997).

    Article  CAS  Google Scholar 

  10. Holscher, C. et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J. Immunol. 167, 6957–6966 (2001).

    Article  CAS  Google Scholar 

  11. Cooper, A.M. et al. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168, 1322–1327 (2002).

    Article  CAS  Google Scholar 

  12. Leal, I.S., Smedegard, B., Andersen, P. & Appelberg, R. Interleukin-6 and interleukin-12 participate in induction of a type 1 protective T-cell response during vaccination with a tuberculosis subunit vaccine. Infect. Immun. 67, 5747–5754 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Stobie, L. et al. The role of antigen and IL-12 in sustaining Th1 memory cells in vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge. Proc. Natl. Acad. Sci. USA 97, 8427–8432 (2000).

    Article  CAS  Google Scholar 

  14. Khader, S.A. et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-γ responses if IL-12p70 is available. J. Immunol. 175, 788–795 (2005).

    Article  CAS  Google Scholar 

  15. Cruz, A. et al. CE:IFN-γ regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection1. J. Immunol. 177, 1416–1420 (2006).

    Article  CAS  Google Scholar 

  16. Veldhoen, M., Hocking, R., Atkins, C., Locksley, R. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  Google Scholar 

  17. Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  Google Scholar 

  18. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  Google Scholar 

  19. Aggarwal, S. & Gurney, A.L. IL-17: prototype member of an emerging cytokine family. J. Leukoc. Biol. 71, 1–8 (2002).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

    Article  CAS  Google Scholar 

  22. Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl. Acad. Sci. USA 100, 5986–5990 (2003).

    Article  CAS  Google Scholar 

  23. Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).

    Article  CAS  Google Scholar 

  24. Jones, C.E. & Chan, K. Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-α, and granulocyte-colony-stimulating factor by human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 26, 748–753 (2002).

    Article  CAS  Google Scholar 

  25. Ye, P. et al. Requirement of Interleukin-17 receptor signalling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recriutment, and host defense. J. Exp. Med. 194, 519–527 (2001).

    Article  CAS  Google Scholar 

  26. Kolls, J.K., Kanaly, S.T. & Ramsay, A.J. Interleukin-17: An emerging role in lung inflammation. Am. J. Respir. Cell Mol. Biol. 28, 9–11 (2003).

    Article  CAS  Google Scholar 

  27. Moseley, T.A., Haudenschild, D., Rose, L. & Reddi, A. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155–174 (2003).

    Article  CAS  Google Scholar 

  28. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    Article  CAS  Google Scholar 

  29. Harrington, L.E. et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  30. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    Article  CAS  Google Scholar 

  31. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    Article  CAS  Google Scholar 

  32. Aggarwal, S., Ghilardi, N., Xie, M-H., deSauvage, F. & Gurney, A. Interleukin 23 promotes a distinct CD4 T cell activation state characterized by the production of IL-17. J. Biol. Chem. 278, 1910–1914 (2003).

    Article  CAS  Google Scholar 

  33. Winslow, G.M., Roberts, A.D., Blackman, M.A. & Woodland, D.L. Persistence and turnover of antigen-specific CD4 T cells during chronic tuberculosis infection in the mouse. J. Immunol. 170, 2046–2052 (2003).

    Article  CAS  Google Scholar 

  34. Evans, J. et al. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev. Vaccines 2, 219–229 (2003).

    Article  CAS  Google Scholar 

  35. Geisel, R.E., Sakamoto, K., Russell, D. & Rhoades, E. In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette-Guerin is due principally to trehalose mycolates. J. Immunol. 174, 5007–5015 (2005).

    Article  CAS  Google Scholar 

  36. Kim, C.H. & Broxmeyer, H.E. Chemokines: signal lamps for trafficking of T and B cells for development and effector function. J. Leukoc. Biol. 65, 6–15 (1999).

    Article  CAS  Google Scholar 

  37. MacMicking, J.D., Taylor, G. & McKinney, J. Immune control of tuberculosis by IFN-γ-inducible LRG-47. Science 302, 654–659 (2003).

    Article  CAS  Google Scholar 

  38. Shen, F., Hu, Z., Goswami, J. & Gaffen, S. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 281, 24138–24148 (2006).

    Article  CAS  Google Scholar 

  39. Reinhardt, R.L., Hong, S., Kang, S., Wang, Z. & Locksley, R. Visualization of IL-12/23p40 in vivo reveals immunostimulatory dendritic cell migrants that promote Th1 differentiation. J. Immunol. 177, 1618–1627 (2006).

    Article  CAS  Google Scholar 

  40. Wozniak, T.M., Ryan, A. & Britton, W. Interleukin-23 restores immunity to Mycobacterium tuberculosis infection in IL-12p40-deficient mice and is not required for the development of IL-17-secreting T cell responses. J. Immunol. 177, 8684–8692 (2006).

    Article  CAS  Google Scholar 

  41. Veldhoen, M., Hocking, R., Flavell, R. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat. Immunol. 7, 1151–1156 (2006).

    Article  CAS  Google Scholar 

  42. Belladonna, M.L. et al. IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. J. Immunol. 168, 5448–5454 (2002).

    Article  CAS  Google Scholar 

  43. Higgins, S.C., Jarnicki, A., Lavelle, E. & Mills, K. TLR4 Mediates vaccine-Induced protective cellular immunity to Bordetella pertussis: role of IL-17-producing T cells. J. Immunol. 177, 7980–7989 (2006).

    Article  CAS  Google Scholar 

  44. Baekkevold, E.S. et al. A role for CCR4 in development of mature circulating cutaneous T helper memory cell populations. J. Exp. Med. 201, 1045–1051 (2005).

    Article  CAS  Google Scholar 

  45. Byersdorfer, C.A. & Chaplin, D. Visualization of early APC/T cell interactions in the mouse lung following intranasal challenge. J. Immunol. 167, 6756–6764 (2001).

    Article  CAS  Google Scholar 

  46. Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    Article  CAS  Google Scholar 

  47. Miyamoto, M. et al. Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways. J. Immunol. 170, 4665–4672 (2003).

    Article  CAS  Google Scholar 

  48. Appelberg, R. Neutrophils and intracellular pathogens: beyond phagocytosis and killing. Trends Microbiol. 15, 87–92 (2007).

    Article  CAS  Google Scholar 

  49. Chackerian, A.A. et al. Neutralization or absence of the interleukin-23 pathway does not compromise immunity to mycobacterial infection. Infect. Immun. 74, 6092–6099 (2006).

    Article  CAS  Google Scholar 

  50. Gaffen, S.L. Biology of recently discovered cytokines: interleukin-17–a unique inflammatory cytokine with roles in bone biology and arthritis. Arthritis Res. Ther. 6, 240–247 (2004).

    Article  CAS  Google Scholar 

  51. Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 172, 2827–2833 (2004).

    Article  CAS  Google Scholar 

  52. Khader, S.A. et al. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J. Exp. Med. 203, 1805–1815 (2006).

    Article  CAS  Google Scholar 

  53. Olsen, A.W., Hansen, P., Holm, A. & Andersen, P. Efficient protection against Mycobacterium tuberculosis by vaccination with a single immunodominant epitope from the ESAT-6 antigen. Eur. J. Immunol. 30, 1724–1732 (2000).

    Article  CAS  Google Scholar 

  54. Happel, K.I. et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005).

    Article  CAS  Google Scholar 

  55. Hollenbaugh, J.A. & Dutton, R. IFN-γ regulates donor CD8 T cell expansion, migration and leads to solid tumor apoptosis. J. Immunol. 177, 3004–3011 (2006).

    Article  CAS  Google Scholar 

  56. Flano, E., Kayhan, B., Woodland, D. & Blackman, M. Infection of dendritic cells by a γ2-herpesvirus induces functional modulation. J. Immunol. 175, 3225–3234 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Smiley, L. Johnson, M. Mohrs, M. Blackman, R. Dutton, G. Winslow and D. Woodland for critical reading of the manuscript, and B. Sells for cell sorting. IL-23p19-deficient mice (B6.Il23a−/−) were provided by N. Ghilardi and F. deSauvage (Genentech). Supported by the Trudeau Institute, the New York Community Trust–Heiser Fund (S.A.K.) and the National Institutes of Health (AI46530, AI067723 and AG028878 to A.M.C.; AR050458 to S.L.G.; AI030663 to R.M.L.; AG02160 and AG21054 to L.H.; and HL69409 to T.D.R.).

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Authors and Affiliations

  1. Trudeau Institute, Saranac Lake, New York, 12983, USA

    Shabaana A Khader, Guy K Bell, John E Pearl, Jeffrey J Fountain, Javier Rangel-Moreno, Garth E Cilley, Sheri M Eaton, Susan L Swain, Laura Haynes, Troy D Randall & Andrea M Cooper

  2. Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State Univeristy of New York, Buffalo, 14214, New York, USA

    Fang Shen & Sarah L Gaffen

  3. Department of Medicine and Microbiology & Immunology, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, 94143, California, USA

    Richard M Locksley

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Supplementary information

Supplementary Fig. 1

Protective responses in the lung are accelerated in vaccinated mice. (PDF 82 kb)

Supplementary Fig. 2

Vaccination-induced IL-23-dependent lung IL-17-producing CD4+ T cell population. (PDF 132 kb)

Supplementary Fig. 3

Model of the CD4+ T cell response to vaccination and challenge. (PDF 291 kb)

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Khader, S., Bell, G., Pearl, J. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8, 369–377 (2007). https://doi.org/10.1038/ni1449

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