Is IL-17 required to control tuberculosis?

  • Andrea M. Cooper
Part of the Progress in Inflammation Research book series (PIR)


We review the state of knowledge regarding the role of IL-17 in tuberculosis (TB). IL-17 is clearly induced following exposure to mycobacteria in mice and humans and therefore its role in both protection and the immunopathological consequences of infection must be fully defined. IL-17-producing T cells can be seen in both mice and humans and these cytokine-producing cells are dependent to a large degree upon IL-23. Based on what we know of the function of IL-17 and the nature of TB, it would be surprising if this were a disease where IL-17 would have a dramatic impact; indeed the experimental data suggests that it is not required for control of bacterial growth. However, while it is clear that IL-17 is present during TB, its function(s) is not yet known. Key questions that will help elucidate function include - the role the mycobacteria plays in induction and regulation of the IL-17 response and the role IL-17 plays in modulating the inflammatory response during chronic disease.


Mycobacterium Tuberculosis Chronic Granulomatous Disease Mycobacterial Infection Bacterial Burden Granulomatous Response 


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  1. 1.
    Flynn J, Chan J (2001) Immunology of tuberculosis. Annu Rev Immunol 19: 93–129PubMedCrossRefGoogle Scholar
  2. 2.
    North R, Jung Y (2004) Immunity to tuberculosis. Annu Rev Immunol 22: 599–623PubMedCrossRefGoogle Scholar
  3. 3.
    Scott-Browne J, Shafiani S, Tucker-Heard G, Ishida-Tsubota K, Fontenot J, Rudensky A, Bevan M, Urdahl K (2007) Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med 204: 2159–2169PubMedCrossRefGoogle Scholar
  4. 4.
    Khader S, Pearl J, Sakamoto K, Gilmartin L, Bell G, Jelley-Gibbs D, Ghilardi N, deSauvage F, Cooper A (2005) 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 antigenspecific IFN-gamma responses if IL-12p70 is available. J Immunol 175: 788–795PubMedGoogle Scholar
  5. 5.
    Scriba T, Kalsdorf B, Abrahams D-A, Isaacs F, Hofmeister J, Black G, Hassan H, Wilkinson R, Walzl G, Gelderbloem S et al (2008) Distinct, specific IL-17 and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol 180: 1962–1970PubMedGoogle Scholar
  6. 6.
    Umemura M, Yahagi A, Hamada S, Begum M, Watanabe H, Kawakami K, Suda T, Sudo K, Nakae S, Iwakura Y et al (2007) IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis Bacille Calmette-Guerin infection. J Immunol 178: 3786–3796PubMedGoogle Scholar
  7. 7.
    Lockhart E, Green A, Flynn J (2006) IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 177: 4662–4669PubMedGoogle Scholar
  8. 8.
    D’Souza CD, Cooper AM, Frank AA, Mazzaccaro RJ, Bloom BR, Orme IM (1997) An anti-inflammatory role for γ δ T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J Immunol 158: 1217–1221PubMedGoogle Scholar
  9. 9.
    Romani L, Fallarino F, De Luca A, Montagnoli C, D’Angelo C, Zelante T, Vacca C, Bistoni F, Fioretti M, Grohmann U et al (2008) Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451: 211–215PubMedCrossRefGoogle Scholar
  10. 10.
    Cooper AM, Segal BH, Frank AA, Holland SM, Orme IM (2000) Transient loss of resistance to pulmonary tuberculosis in p47phox-/-mice. Infect Immun 68: 1231–1234PubMedCrossRefGoogle Scholar
  11. 11.
    Michel M, Keller A, Paget C, Fujio M, Trottein F, Savage P, Wong C, Schneider E, Dy M, Leite-de-Moraes M (2007) Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. J Exp Med 204: 995–1001PubMedCrossRefGoogle Scholar
  12. 12.
    Weaver C, Hatton R, Mangan P, Harrington L (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25: 821–852PubMedCrossRefGoogle Scholar
  13. 13.
    Stockinger B, Veldhoen M, Martin B (2007) Th17 T cells: Linking innate and adaptive immunity. Semin Immunol 19: 353–361PubMedCrossRefGoogle Scholar
  14. 14.
    Khader S, Bell G, Pearl J, Fountain J, Rangel-Moreno J, Cilley G, Shen F, Eaton S, Gaffen S, Swain S et al (2007) IL-23 and IL-17 in establishment of protective pulmonary CD4+ T cell responses upon vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8: 369–377PubMedCrossRefGoogle Scholar
  15. 15.
    Cruz A, Khader S, Torrado E, Fraga A, Pearl J, Pedrosa J, Cooper A, Castro A (2006) CE:IFN-γ regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol 177: 1416–1420PubMedGoogle Scholar
  16. 16.
    Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19: 281–286PubMedCrossRefGoogle Scholar
  17. 17.
    Ivanov I, Zhou L, Littman D (2007) Transcriptional regulation of Th17 cell differentiation. Semin Immunol 19: 409–417PubMedCrossRefGoogle Scholar
  18. 18.
    McGeachy M, Cua D (2007) The link between IL-23 and Th17 cell-mediated immune pathologies. Semin Immunol 19: 372–376PubMedCrossRefGoogle Scholar
  19. 19.
    Kano S, Sato K, Morishita Y, Vollstedt S, Kim S, Bishop K, Honda K, Kubo M, Taniguchi T (2008) The contribution of transcription factor IRF1 to the interferon-gammainterleukin 12 signaling axis and T(H)1 versus T(H)-17 differentiation of CD4(+) T cells. Nat Immunol 9: 34–41PubMedCrossRefGoogle Scholar
  20. 20.
    Acosta-Rodriguez E, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8: 639–646PubMedCrossRefGoogle Scholar
  21. 21.
    Stark M, Huo Y, Burcin T, Morris M, Olson T, Ley K (2005) Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22: 285–294PubMedCrossRefGoogle Scholar
  22. 22.
    Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J et al (2001) Requirement of Interleukin-17 receptor signalling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194: 519–527PubMedCrossRefGoogle Scholar
  23. 23.
    Kolls J, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21: 467–476PubMedCrossRefGoogle Scholar
  24. 24.
    Hsu H, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus A et al (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9: 166–175PubMedCrossRefGoogle Scholar
  25. 25.
    Mangan P, Harrington L, O’Quinn D, Helms W, Bullard D, Elson C, Hatton R, Wahl S, Schoeb T, Weaver C (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441: 231–234PubMedCrossRefGoogle Scholar
  26. 26.
    Huang W, Na L, Fidel P, Schwarzenberger P (2004) Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190: 624–631PubMedCrossRefGoogle Scholar
  27. 27.
    Wu Q, Martin R, Rino J, Breed R, Torres R, Chu H (2007) IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection. Microbes Infect 9: 78–86PubMedCrossRefGoogle Scholar
  28. 28.
    Chackerian A, Chen S, Brodie S, Mattson J, McClanahan T, Kastelein R, Bowman E (2006) Neutralization or absence of the interleukin-23 pathway does not compromise immunity to mycobacterial infection. Infect Immun 74: 6092–6099PubMedCrossRefGoogle Scholar
  29. 29.
    Happel K, Lockhart E, Mason C, Porretta E, Keoshkerian E, Odden A, Nelson S, Ramsay A (2005) Pulmonary interleukin-23 gene delivery increases local T-cell immunity and controls growth of Mycobacterium tuberculosis in the lungs. Infect Immun 73: 5782–5788PubMedCrossRefGoogle Scholar
  30. 30.
    Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, Jouanguy E, Boisson-Dupuis S, Fieschi C, Picard C et al (2006) Inborn errors of IL-12/23-and IFN-gamma-mediated immunity: Molecular, cellular, and clinical features. Semin Immunol 18: 347–361PubMedCrossRefGoogle Scholar
  31. 31.
    Hoeve M, de Boer T, Langenberg D, Sanal O, Verreck F, Ottenhoff T (2003) IL-12 receptor deficiency revisited: IL-23-mediated signaling is also impaired in human genetic IL-12 receptor beta1 deficiency. Eur J Immunol 33: 3393–3397PubMedCrossRefGoogle Scholar
  32. 32.
    Hoeve M, Savage N, de Boer T, Langenberg D, de Waal Malefyt R, Ottenhoff T, Verreck F (2006) Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 36: 661–670PubMedCrossRefGoogle Scholar
  33. 33.
    Cargill M, Schrodi S, Chang M, Garcia V, Brandon R, Callis K, Matsunami N, Ardlie K, Civello D, Catanese J et al (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273–290PubMedCrossRefGoogle Scholar
  34. 34.
    Duerr R, Taylor K, Brant S, Rioux J, Silverberg M, Daly M, Steinhart A, Abraham C, Regueiro M, Griffiths A et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461–1463PubMedCrossRefGoogle Scholar
  35. 35.
    Wozniak T, Ryan A, Triccas J, Britton W (2006) Plasmid interleukin-23 (IL-23), but not plasmid IL-27, enhances the protective efficacy of a DNA vaccine against Mycobacterium tuberculosis infection. Infect Immun 74: 557–565PubMedCrossRefGoogle Scholar
  36. 36.
    Wozniak T, Ryan A, Britton W (2006) 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: 8684–8692PubMedGoogle Scholar
  37. 37.
    Stumhofer J, Laurence A, Wilson E, Huang E, Tato C, Johnson L, Villarino A, Huang Q, Yoshimura A, Sehy D et al (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7: 937–945PubMedCrossRefGoogle Scholar
  38. 38.
    Batten M, Li J, Yi S, Kljavin N, Danilenko D, Lucas S, Lee J, de Sauvage F, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7: 929–936PubMedCrossRefGoogle Scholar
  39. 39.
    Rhoades ER, Frank AA, Orme IM (1997) Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent Mycobacterium tuberculosis. Tuber Lung Dis 78: 57–66PubMedCrossRefGoogle Scholar
  40. 40.
    Aujla S, Dubin P, Kolls J (2007) Th17 cells and mucosal host defense. Semin Immunol 19: 377–382PubMedCrossRefGoogle Scholar
  41. 41.
    Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S, Belladonna M, Vacca C, Conte C, Mosci P et al (2007) The IL-23and the IL-17 pathway promotes inflammation and impairs antifungal immune resistance. Eur J Immunol 37: 2695–2706PubMedCrossRefGoogle Scholar
  42. 42.
    Seiler P, Aichele P, Bandermann S, Hauser A, Lu B, Gerard N, Gerard C, Ehlers S, Mollenkopf H, Kaufmann S (2003) Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines. Eur J Immunol 33: 2676–2686PubMedCrossRefGoogle Scholar
  43. 43.
    Keller C, Hoffmann R, Lang R, Brandau S, Hermann C, Ehlers S (2006) Genetically determined susceptibility to tuberculosis in mice causally involves accelerated and enhanced recruitment of granulocytes. Infect Immun 74: 4295–4309PubMedCrossRefGoogle Scholar
  44. 44.
    Ulrichs T, Kosmiadi G, Trusov V, Jörg S, Pradl L, Titukhina M, Mishenko V, Gushina N, Kaufmann S (2004) Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol 204: 217–228PubMedCrossRefGoogle Scholar
  45. 45.
    Tsai M, Chakravarty S, Zhu G, Xu J, Tanaka K, Koch C, Tufariello J, Flynn J, Chan J (2006) Characterization of the tuberculous granuloma in murine and human lungs: Cellular composition and relative tissue oxygen tension. Cell Microbiol 8: 218–232PubMedCrossRefGoogle Scholar
  46. 46.
    Kahnert A, Höpken U, Stein M, Bandermann S, Lipp M, Kaufmann S (2007) Mycobac terium tuberculosis triggers formation of lymphoid structure in murine lungs. J Infect Dis 195: 46–54PubMedCrossRefGoogle Scholar
  47. 47.
    Bosio C, Gardner D, Elkins K (2000) Infection of B cell-deficient mice with CDC 1551, a clinical isolate of Mycobacterium tuberculosis: Delay in dissemination and development of lung pathology. J Immunol 164: 6417–6425PubMedGoogle Scholar
  48. 48.
    Maglione P, Xu J, Chan J (2007) B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis. J Immunol 178: 7222–7234PubMedGoogle Scholar
  49. 49.
    Aggarwal S, Ghilardi N, Xie M, de Sauvage FJ, Gurney AL (2002) Interleukin-23 promotes a distinct CD4+ T cell activation state characterised by the production of IL-17. J Biol Chem 278: 1910–1914PubMedCrossRefGoogle Scholar
  50. 50.
    Leibundgut-Landmann S, Groß O, Robinson M, Osorio F, Slack E, Tsoni S, Schweighoffer E, Tybulewicz V, Brown G, Ruland J et al (2007) Syk-and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 8: 630–638PubMedCrossRefGoogle Scholar
  51. 51.
    Yadav M, Schorey J (2006) The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108: 3168–3175PubMedCrossRefGoogle Scholar
  52. 52.
    Rothfuchs A, Bafica A, Feng C, Egen J, Williams D, Brown G, Sher A (2007) Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells. J Immunol 179: 3463–3471PubMedGoogle Scholar
  53. 53.
    Hohl T, Van Epps H, Rivera A, Morgan L, Chen P, Feldmesser M, Pamer E (2005) Aspergillus fumigatus triggers inflammatory responses by stage-specific beta-glucan display. PLoS Pathog 1: e30CrossRefGoogle Scholar
  54. 54.
    Steele C, Rapaka R, Metz A, Pop S, Williams D, Gordon S, Kolls J, Brown G (2005) The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog 1: e42CrossRefGoogle Scholar
  55. 55.
    Rao V, Fujiwara N, Porcelli S, Glickman M (2005) Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J Exp Med 201: 535–543PubMedCrossRefGoogle Scholar
  56. 56.
    Kursar M, Koch M, Mittrücker H, Nouailles G, Bonhagen K, Kamradt T, Kaufmann S (2007) Cutting edge: Regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol 178: 2661–2665PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Andrea M. Cooper
    • 1
  1. 1.Trudeau Institute, Inc.Saranac LakeUSA

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