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The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

Cellular and Molecular Immunology volume 15, pages 216225 (2018) | Download Citation

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Abstract

Interleukin-17 (IL-17), IL-21, IL-22 and IL-23 can be grouped as T helper 17 (Th17)-related cytokines because they are either produced by Th17/Th22 cells or involved in their development. Here, we review Th17-related cytokines/Th17-like cells, networks/signals and their roles in immune responses or immunity against Mycobacterium tuberculosis (Mtb) infection. Published studies suggest that Th17-related cytokine pathways may be manipulated by Mtb microorganisms for their survival benefits in primary tuberculosis (TB). In addition, there is evidence that immune responses of the signal transducer and activator of transcription 3 (STAT3) signal pathway and Th17-like T-cell subsets are dysregulated or destroyed in patients with TB. Furthermore, Mtb infection can impact upstream cytokines in the STAT3 pathway of Th17-like responses. Based on these findings, we discuss the need for future studies and the rationale for targeting Th17-related cytokines/signals as a potential adjunctive treatment.

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References

  1. 1.

    , , , , . Diagnosis of opportunistic infections: HIV co-infections—tuberculosis. Curr Opin HIV AIDS 2017; 12: 129–138.

  2. 2.

    , . Molecular basis of mycobacterial survival in macrophages. Cell Mol Life Sci 2017; 74: 1625–1648.

  3. 3.

    , , . Latent tuberculosis infection. N Engl J Med 2002; 347: 1860–1866.

  4. 4.

    , , , , . Impairment of Wnt/β-catenin signaling in blood cells of patients with severe cavitary pulmonary tuberculosis. PLoS One 2017; 12: e0172549.

  5. 5.

    , . T regulatory cells as part of strategy of immune evasion by pathogens. Biochemistry (Moscow) 2015; 80: 957–971.

  6. 6.

    , . Down-regulation of CD1 on antigen-presenting cells by infection with Mycobacterium tuberculosis. J Immunol 1998; 161: 3582–3588.

  7. 7.

    , , , , , . Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31: 331–341.

  8. 8.

    , , , . The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell Mol Immunol 2016; 13: 418–431.

  9. 9.

    , , . IL-17+ γδ T cells as kick-starters of inflammation. Nat Immunol 2017; 18: 604–611.

  10. 10.

    , , , , , et al. IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J Immunol 2007; 178: 3786–3796.

  11. 11.

    , , , , , et al. IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease. Autophagy 2017; 13: 1191–1204.

  12. 12.

    , , , , . T-cell exhaustion in tuberculosis: pitfalls and prospects. Crit Rev Microbiol 2017; 43: 133–141.

  13. 13.

    , , , , , et al. A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host. Sci Rep 2016; 6: 23917.

  14. 14.

    , , , , , , et al. Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation with Mycobacterium tuberculosis. J Infect Dis 2011; 203: 1256–1263.

  15. 15.

    , , , , , et al. The characteristic profiles of PD-1 and PD-L1 expressions and dynamic changes during treatment in active tuberculosis. Tuberculosis (Edinb) 2016; 101: 146–150.

  16. 16.

    , , , , , et al. Phosphorylated STAT3 and PD-1 regulate IL-17 production and IL-23 receptor expression in Mycobacterium tuberculosis infection. Eur J Immunol 2014; 44: 2013–2024.

  17. 17.

    , , , , , et al. Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization. Sci Rep 2016; 6: 36923.

  18. 18.

    , , , , , et al. Single nucleotide polymorphisms in IL17A and IL6 are associated with decreased risk for pulmonary tuberculosis in Southern Brazilian Population. PLoS One 2016; 11: e0147814.

  19. 19.

    , , , , , et al. Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J Immunol 2010; 184: 4414–4422.

  20. 20.

    , , , , , 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 2007; 8: 369–377.

  21. 21.

    , , , , , et al. IL-17RA in non-hematopoietic cells controls CXCL-1 and 5 critical to recruit neutrophils to the lung of mycobacteria-infected mice during the adaptive immune response. PLoS One 2016; 11: e0149455.

  22. 22.

    , , , , , et al. Interleukin-17F and interleukin-6 gene polymorphisms in Asian Indian patients with Takayasu arteritis. Hum Immunol 2017; S0198-8859: 30070–30078.

  23. 23.

    , , , , , et al. Th17-related cytokines contribute to recall-like expansion/effector function of HMBPP-specific Vγ2Vδ2 T cells after M. tuberculosis infection or vaccination. Eur J Immunol 2015; 45: 442–451.

  24. 24.

    , , , , , et al. IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis. Mucosal Immunol 2016; 10: 1031–1042.

  25. 25.

    , , , , , . Antigen-specific human NKT cells from tuberculosis patients produce IL-21 to help B cells for the production of immunoglobulins. Oncotarget 2015; 6: 28633–28645.

  26. 26.

    , , , , , et al. Mycobacterium tuberculosis-specific IL-21+IFN-γ+CD4+ T cells are regulated by IL-12. PLoS One 2016; 11: e0147356.

  27. 27.

    , , , , , et al. IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection. Sci Rep 2016; 6: 36720.

  28. 28.

    , , , , , et al. The Functional response of B cells to antigenic stimulation: a preliminary report of latent tuberculosis. PLoS One 2016; 11: e0152710.

  29. 29.

    , , , , , et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J Immunol 2007; 179: 8180–8190.

  30. 30.

    , , , , , . Decreased frequencies of circulating CD4+ T follicular helper cells associated with diminished plasma IL-21 in active pulmonary tuberculosis. PLoS One 2014; 9: e111098.

  31. 31.

    , , , , , et al. Differentiation, distribution and gammadelta T cell-driven regulation of IL-22-producing T cells in tuberculosis. PLoS Pathog 2010; 6: e1000789.

  32. 32.

    , , , , , et al. Anti-tuberculosis treatment enhances the production of IL-22 through reducing the frequencies of regulatory B cell. Tuberculosis (Edinb) 2014; 94: 238–244.

  33. 33.

    , , , , , et al. Plasma biomarkers can predict treatment response in tuberculosis patients, a prospective observational study. Medicine (Baltimore) 2015; 94: e1628.

  34. 34.

    , , , , , . Comparison of interferon-γ-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection. Clin Exp Immunol 2012; 167: 317–329.

  35. 35.

    , , , , , et al. Distinct, specific IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol 2008; 180: 1962–1970.

  36. 36.

    , , , , , et al. Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence. Eur Respir J 2015; 46: 771–782.

  37. 37.

    , , , , , . CD4+ T cells are required to contain early extrathoracic TB dissemination and sustain multi-effector functions of CD8+ T and CD3− lymphocytes. J Immunol 2014; 192: 2120–2132.

  38. 38.

    , , , , , et al. IL-22 produced by human NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion. J Immunol 2009; 183: 6639–6645.

  39. 39.

    , , , . Mycobacterium tuberculosis promotes Th17 expansion via regulation of human dendritic cells toward a high CD14 and low IL-12p70 phenotype that reprograms upon exogenous IFN-γ. Int Immunol 2014; 26: 705–716.

  40. 40.

    , , , , , . Membrane-bound IL-22 after de novo production in tuberculosis and anti-Mycobacterium tuberculosis effector function of IL-22+ CD4+ T cells. J Immunol 2011; 187: 190–199.

  41. 41.

    , , , , . Depletion of IL-22 during culture enhanced antigen-driven IFN-γ production by CD4+T cells from patients with active TB. Immunol Lett 2013; 150: 48–53.

  42. 42.

    , , , , , et al. Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections. J Immunol 2010; 184: 4378–4390.

  43. 43.

    , , , , , et al. Severe tuberculosis induces unbalanced up-regulation of gene networks and overexpression of IL-22, MIP-1α, CCL27, IP-10, CCR4, CCR5, CXCR3, PD1, PDL2, IL-3, IFN-β, TIM1, and TLR2 but low antigen-specific cellular responses. J Infect Dis 2008; 198: 1514–1519.

  44. 44.

    , , , , , et al. Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection. Mucosal Immunol 2017; 10: 1069–1081.

  45. 45.

    , , , , , et al. An SNP selection strategy identified IL-22 associating with susceptibility to tuberculosis in Chinese. Sci Rep 2011; 1: 20.

  46. 46.

    , , , , , . Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti-inflammatory IL-22 and IL-10 response. PLoS One 2014; 9: e86466.

  47. 47.

    , , , , , et al. Intracellular network of phosphatidylinositol 3-kinase, mammalian target of the rapamycin/70 kDa ribosomal S6 kinase 1, and mitogen-activated protein kinases pathways for regulating mycobacteria-induced IL-23 expression in human macrophages. Cell Microbiol 2006; 8: 1158–1171.

  48. 48.

    , , , , . Interleukin-23-induced interleukin-23 receptor subunit expression is mediated by the Janus kinase/signal transducer and activation of transcription pathway in human CD4 T cells. J Interferon Cytokine Res 2011; 31: 363–371.

  49. 49.

    , , , , , et al. Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells. J Exp Med 2008; 205: 1447–1461.

  50. 50.

    , , , , , et al. Infection rate and tissue localization of murine IL-12p40-producing monocyte-derived CD103(+) lung dendritic cells during pulmonary tuberculosis. PLoS One 2013; 8: e69287.

  51. 51.

    , , , , , et al. Interleukin-23 dependent IL-17 drives Th1 responses following Mycobacterium bovis BCG vaccination. Eur J Immunol 2012; 42: 364–373.

  52. 52.

    , , , , , et al. IL-21 inhibits IL-17A-producing cd T-cell response after infection with Bacillus Calmette-Gue'rin via induction of apoptosis. Innate Immunity 2016; 22: 588–597.

  53. 53.

    , , , , , et al. Selective destruction of interleukin 23-induced expansion of a major antigen-specific γδ T-cell subset in patients with tuberculosis. J Infect Dis 2017; 215: 420–430.

  54. 54.

    , , , , , et al. Interplay between microRNAs and the STAT3 signaling pathway in human cancers. Physiol Genomics 2013; 45: 1206–1214.

  55. 55.

    . microRNAs: tiny regulators with great potential. Cell 2001; 107: 823–826.

  56. 56.

    , . Understanding the IL-23-IL-17 immune pathway. Trends Immunol 2006; 27: 17–23.

  57. 57.

    , , , , , et al. Development of Vgamma2Vdelta2+ T cell responses during active mycobacterial coinfection of simian immunodeficiency virus-infected macaques requires control of viral infection and immune competence of CD4+ T cells. J Infect Dis 2004; 190: 1438–1447.

  58. 58.

    , . Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science (New York, NY) 1994; 264: 95–98.

  59. 59.

    , , , , . STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells 2014; 32: 1149–1160.

  60. 60.

    , , , , , et al. SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases. Haematologica 2009; 94: 576–580.

  61. 61.

    , , , , . SOCS3 promotes inflammation and apoptosis via inhibiting JAK2/STAT3 signaling pathway in 3T3-L1 adipocyte. Immunobiology 2015; S0171-298500025-X.

  62. 62.

    , , , , , . Early secreted antigenic target of 6-kDa of Mycobacterium tuberculosis stimulates IL-6 production by macrophages through activation of STAT3. Sci Rep 2017; 7: 40984.

  63. 63.

    , , , , , . Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol 2003; 171: 4750–4757.

  64. 64.

    , , , , . ESX-1 exploits type I IFN-signalling to promote a regulatory macrophage phenotype refractory to IFNγ-mediated autophagy and growth restriction of intracellular mycobacteria. Cell Microbiol 2016; 18: 1471–1485.

  65. 65.

    , , , , , , et al. Latency-associated protein Acr1 impairs dendritic cell maturation and functionality: a possible mechanism of immune evasion by Mycobacterium tuberculosis. J Infect Dis 2014; 209: 1436–1445.

  66. 66.

    , , , , , et al. Mycobacterium tuberculosis cell wall released fragments by the action of the human lung mucosa modulate macrophages to control infection in an IL-10-dependent manner. Mucosal Immunol 2016; 10: 1248–1258.

  67. 67.

    , , , , , et al. Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis. Cell Res 2015; 25: 1333–1351.

  68. 68.

    , , , , , et al. Prolactin modulates cytokine production induced by culture filtrate proteins of M. bovis through different signaling mechanisms in THP1 cells. Cytokine 2015; 71: 1.

  69. 69.

    , , . Interferons and inflammasomes: cooperation and counterregulation in disease. J Allergy Clin Immunol 2016; 38: 37–46.

  70. 70.

    , , , , , , , . Investigation of JAK2, STAT3 and CCR6 polymorphisms and their gene-gene interactions in inflammatory bowel disease. Int J Immunogenet 2012; 39: 247–252.

  71. 71.

    , , , , , et al. Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat Microbiol 2017; 2: 17072.

  72. 72.

    , , , , , et al. Recruitment of IL-27-producing CD4(+) T cells and effect of IL-27 on pleural mesothelial cells in tuberculous pleurisy. Lung 2015; 193: 539–548.

  73. 73.

    , , , , , et al. The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J Immunol 2005; 174: 3534–3544.

  74. 74.

    , , , , , et al. MicroRNA 17-5p regulates autophagy in Mycobacterium tuberculosis-infected macrophages by targeting Mcl-1 and STAT3. Cell Microbiol 2016; 18: 679–691.

  75. 75.

    , , . Roles of mTOR and STAT3 in autophagy induced by telomere 3' overhang-specific DNA oligonucleotides. Autophagy 2007; 3: 496–498.

  76. 76.

    , , , , , et al. Autophagy in immunity against Mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy. Curr Top Microbiol Immunol 2009; 335: 169–188.

  77. 77.

    , , , , , et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci USA 2013; 110: E2480–E2489.

  78. 78.

    , , , , , et al. Adaptive immune response of Vγ2Vδ2+ T cells during mycobacterial infections. Science (New York, NY) 2002; 295: 2255–2258.

  79. 79.

    , , , , , et al. Chicago 2014—30years of γδ T cells. Cell Immunol 2015; 296: 3–9.

  80. 80.

    , , , , . IL-2 and IL-12 act in synergy to overcome antigen-specific T cell unresponsiveness in mycobacterial disease. J Immunol 1997; 159: 786–793.

  81. 81.

    , , , . IL-2 enhances cervical cancer cells proliferation and JAK3/STAT5 phosphorylation at low doses, while at high doses IL-2 has opposite effects. Cancer Invest 2014; 32: 115–125.

  82. 82.

    , , , , , et al. IL-2 simultaneously expands Foxp3+ T regulatory and T effector cells and confers resistance to severe tuberculosis (TB): implicative Treg-T effector cooperation in immunity to TB. J Immunol 2012; 199: 4278–4288.

  83. 83.

    , , , , , et al. PD-1 blockade can restore functions of T-Cells in Epstein–Barr virus-positive diffuse large B-cell lymphoma in vitro. PLoS One 2015; 10: e0136476.

  84. 84.

    , , , , , et al. Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17+ IFNγ− CD4+ T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis. Clin Exp Immunol 2017; 187: 160–173.

  85. 85.

    , , , , , et al. Cryptogenic organizing pneumonia: IL-1β, IL-6, IL-8, and TGF- β1 serum concentrations and response to clarithromycin treatment. Adv Exp Med Biol 2016; 911: 77–85.

  86. 86.

    , , , , , et al. Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy. Mol Immunol 2014; 62: 159–168.

  87. 87.

    , , , , , . Cytokines for monitoring anti-tuberculous therapy: a systematic review. Tuberculosis 2015; 95: 217–218.

  88. 88.

    , , , , , et al. IL-1β, but not programed death-1 and programed death ligand pathway, is critical for the human Th17 response to Mycobacterium tuberculosis. Front Immunol 2016; 7: 465.

  89. 89.

    , , , , . Regulation of interleukin-12/interleukin-23 production and the Thelper 17 response in humans. Immunol Rev 2008; 226: 112.

  90. 90.

    , , , , , et al. Tuberculous lymphadenitis is associated with enhanced baseline and antigen-specific induction of type 1 and type 17 cytokines and reduced interleukin-1β (IL-1β) and IL-18 at the site of infection. Clin Vaccine Immunol 2017; 24: e00045–00017.

  91. 91.

    , , , , , et al. IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J Immunol 2007; 179: 1178–1189.

  92. 92.

    , , , , , et al. The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling. PLoS One 2013; 8: e53531.

  93. 93.

    , . Th1 and Th17 cells in tuberculosis: protection, pathology, and biomarkers. Mediat Inflamm 2015; 2015: 854507.

  94. 94.

    , , , , , et al. An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J Immunol 2007; 179: 7791–7799.

  95. 95.

    , , , , , et al. PET CT identifies reactivation risk in cynomolgus macaques with latent M. tuberculosis. PLoS Pathog 2016; 12: e1005739.

  96. 96.

    , , , , , et al. Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis. Tuberculosis (Edinb) 2011; 91: 587–593.

  97. 97.

    , , , , , et al. Severe tuberculosis induces unbalanced up-regulation of gene networks and overexpression of IL-22, MIP-1alpha, CCL27, IP-10, CCR4, CCR5, CXCR3, PD1, PDL2, IL-3, IFN-beta, TIM1, and TLR2 but low antigen-specific cellular responses. J Infect Dis 2008; 198: 1514–1519.

  98. 98.

    , , , , , et al. IL-2 simultaneously expands Foxp3+ T regulatory and T effector cells and confers resistance to severe tuberculosis (TB): implicative Treg-T effector cooperation in immunity to TB. J Immunol 2012; 188: 4278–4288.

  99. 99.

    , , , , , et al. Harnessing the therapeutic potential of Th17 cells. Mediators Inflamm 2015; 2015: 205156.

  100. 100.

    , , , , , et al. Phosphoantigen/IL2 expansion and differentiation of Vgamma2Vdelta2 T cells increase resistance to tuberculosis in nonhuman primates. PLoS Pathog 2013; 9: e1003501.

  101. 101.

    , , , , . Treatment of experimental disseminated Mycobacterium avium complex infection in mice with recombinant IL-2 and tumor necrosis factor. J Immunol 1989; 143: 2996–3000.

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Acknowledgements

This work was supported by the following research grants: The National Key Research and Development Program of China (2016YFA0502204); the National Institutes of Health R01 grants (NIH R01 HL64560/OD015092/HL129887 to ZWC).

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Affiliations

  1. Unit of Anti-tuberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China

    • Hongbo Shen
  2. Department of Microbiology and Immunology and Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612, USA

    • Zheng W Chen

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The authors declare no conflict of interest.

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Correspondence to Hongbo Shen.

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https://doi.org/10.1038/cmi.2017.128