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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References
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).
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).
Colditz, G.A. et al. Efficacy of BCG vaccine in the prevention of tuberculosis. J. Am. Med. Assoc. 271, 698–702 (1994).
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).
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).
Flynn, J.L. & Chan, J. Immunology of tuberculosis. Annu. Rev. Immunol. 19, 93–129 (2001).
Akahoshi, M. et al. Influence of interleukin-12 receptor β1 polymorphisms on tuberculosis. Hum. Genet. 112, 237–243 (2003).
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).
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).
Holscher, C. et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J. Immunol. 167, 6957–6966 (2001).
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).
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).
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).
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).
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).
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).
Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Aggarwal, S. & Gurney, A.L. IL-17: prototype member of an emerging cytokine family. J. Leukoc. Biol. 71, 1–8 (2002).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
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).
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).
Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).
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).
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).
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).
Moseley, T.A., Haudenschild, D., Rose, L. & Reddi, A. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155–174 (2003).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
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).
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).
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).
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).
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).
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).
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).
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).
MacMicking, J.D., Taylor, G. & McKinney, J. Immune control of tuberculosis by IFN-γ-inducible LRG-47. Science 302, 654–659 (2003).
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).
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).
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).
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).
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).
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).
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).
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).
Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).
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).
Appelberg, R. Neutrophils and intracellular pathogens: beyond phagocytosis and killing. Trends Microbiol. 15, 87–92 (2007).
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).
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).
Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 172, 2827–2833 (2004).
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).
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).
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).
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).
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).
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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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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DOI: https://doi.org/10.1038/ni1449
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