Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Respective IL-17A production by γδ T and Th17 cells and its implication in host defense against chlamydial lung infection

Abstract

The role of IL-17A is important in protection against lung infection with Chlamydiae, an obligate intracellular bacterial pathogen. In this study, we explored the producers of IL-17A in chlamydial lung infection and specifically tested the role of major IL-17A producers in protective immunity. We found that γδT cells and Th17 cells are the major producers of IL-17A at the early and later stages of chlamydial infection, respectively. Depletion of γδT cells in vivo at the early postinfection (p.i.) stage, when most γδT cells produce IL-17A, failed to alter Th1 responses and bacterial clearance. In contrast, the blockade of IL-17A at the time when IL-17A was mainly produced by Th17 (day 7 p.i.) markedly reduced the Th1 response and increased chlamydial growth. The data suggest that the γδ T cell is the highest producer of IL-17A in the very early stages of infection, but the protection conferred by IL-17A is mainly mediated by Th17 cells. In addition, we found that depletion of γδ T cells reduced IL-1α production by dendritic cells, which was associated with a reduced Th17 response. This finding is helpful to understand the variable role of IL-17A in different infections and to develop preventive and therapeutic approaches against infectious diseases by targeting IL-17A.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 2005; 202: 761–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009; 30: 108–119.

    Article  CAS  Google Scholar 

  3. Dubin PJ, Kolls JK . IL-23 mediates inflammatory responses to mucoid Pseudomonas aeruginosa lung infection in mice. Am J Physiol Lung Cell Mol Physiol 2007; 292: L519–L528.

    Article  CAS  PubMed  Google Scholar 

  4. Song X, He X, Li X, Qian Y . The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell Mol Immunol 2016; 13: 418–431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Khader SA, Pearl JE, Sakamoto K, Gilmartin L, Bell GK, Jelley-Gibbs DM 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-gamma responses if IL-12p70 is available. J Immunol 2005; 175: 788–795.

    Article  CAS  PubMed  Google Scholar 

  6. Lin Y, Ritchea S, Logar A, Slight S, Messmer M, Rangel-Moreno J et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity 2009; 31: 799–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bai H, Cheng J, Gao X, Joyee AG, Fan Y, Wang S et al. IL-17/Th17 promotes type 1T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function. J Immunol 2009; 183: 5886–5895.

    Article  CAS  PubMed  Google Scholar 

  8. Gao X, Gigoux M, Yang J, Leconte J, Yang X, Suh WK . Anti-chlamydial Th17 responses are controlled by the inducible costimulator partially through phosphoinositide 3-kinase signaling. PloS One 2012; 7: e52657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang Y, Wang H, Ren J, Tang X, Jing Y, Xing D et al. IL-17A synergizes with IFN-gamma to upregulate iNOS and NO production and inhibit chlamydial growth. PloS One 2012; 7: e39214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khader SA, Gopal R . IL-17 in protective immunity to intracellular pathogens. Virulence 2010; 1: 423–427.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang X, Gao L, Lei L, Zhong Y, Dube P, Berton MT et al. A MyD88-dependent early IL-17 production protects mice against airway infection with the obligate intracellular pathogen Chlamydia muridarum. J Immunol 2009; 183: 1291–1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu H, Jiang X, Shen C, Karunakaran KP, Jiang J, Rosin NL et al. Chlamydia muridarum T-cell antigens formulated with the adjuvant DDA/TDB induce immunity against infection that correlates with a high frequency of gamma interferon (IFN-gamma)/tumor necrosis factor alpha and IFN-gamma/interleukin-17 double-positive CD4+ T cells. Infect Immun 2010; 78: 2272–2282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dejima T, Shibata K, Yamada H, Hara H, Iwakura Y, Naito S et al. Protective role of naturally occurring interleukin-17A-producing gammadelta T cells in the lung at the early stage of systemic candidiasis in mice. Infect Immun 2011; 79: 4503–4510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hedges JF, Graff JC, Jutila MA . Transcriptional profiling of gamma delta T cells. J Immunol 2003; 171: 4959–4964.

    Article  CAS  PubMed  Google Scholar 

  15. Lockhart E, Green AM, Flynn JL . IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 2006; 177: 4662–4669.

    Article  CAS  PubMed  Google Scholar 

  16. Hamada S, Umemura M, Shiono T, Tanaka K, Yahagi A, Begum MD et al. IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver. J Immunol 2008; 181: 3456–3463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schulz SM, Kohler G, Holscher C, Iwakura Y, Alber G . IL-17A is produced by Th17, gammadelta T cells and other CD4- lymphocytes during infection with Salmonella enterica serovar Enteritidis and has a mild effect in bacterial clearance. Int Immunol 2008; 20: 1129–1138.

    Article  CAS  PubMed  Google Scholar 

  18. Peng MY, Wang ZH, Yao CY, Jiang LN, Jin QL, Wang J et al. Interleukin 17-producing gamma delta T cells increased in patients with active pulmonary tuberculosis. Cell Mol Immunol 2008; 5: 203–208.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Curtis MM, Way SS, Wilson CB . IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. J Immunol 2009; 183: 381–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Passos ST, Silver JS, O'Hara AC, Sehy D, Stumhofer JS, Hunter CA . IL-6 promotes NK cell production of IL-17 during toxoplasmosis. J Immunol 184 1776-83.

    Article  CAS  PubMed  Google Scholar 

  21. Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM et al. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun 78: 4714–4722.

  22. Qiu H, Fan Y, Joyee AG, Wang S, Han X, Bai H et al. Type I IFNs enhance susceptibility to Chlamydia muridarum lung infection by enhancing apoptosis of local macrophages. J Immunol 2008; 181: 2092–2102.

    Article  CAS  PubMed  Google Scholar 

  23. Han X, Wang S, Fan Y, Yang J, Jiao L, Qiu H et al. Chlamydia infection induces ICOS ligand-expressing and IL-10-producing dendritic cells that can inhibit airway inflammation and mucus overproduction elicited by allergen challenge in BALB/c mice. J Immunol 2006; 176: 5232–5239.

    Article  CAS  PubMed  Google Scholar 

  24. Joyee AG, Qiu H, Wang S, Fan Y, Bilenki L, Yang X . Distinct NKT cell subsets are induced by different Chlamydia species leading to differential adaptive immunity and host resistance to the infections. J Immunol 2007; 178: 1048–1058.

    Article  CAS  PubMed  Google Scholar 

  25. Nian H, Shao H, Zhang G, Born WK, O'Brien RL, Kaplan HJ et al. Regulatory effect of gammadelta T cells on IL-17+ uveitogenic T cells. Invest Ophthalmol Vis Sci 2010; 51: 4661–4667.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Uezu K, Kawakami K, Miyagi K, Kinjo Y, Kinjo T, Ishikawa H et al. Accumulation of gammadelta T cells in the lungs and their regulatory roles in Th1 response and host defense against pulmonary infection with Cryptococcus neoformans. J Immunol 2004; 172: 7629–7634.

    Article  CAS  PubMed  Google Scholar 

  27. Koenecke C, Chennupati V, Schmitz S, Malissen B, Forster R, Prinz I . in vivo application of mAb directed against the gammadelta TCR does not deplete but generates ‘invisible’ gammadelta T cells. Eur J Immunol 2009; 39: 372–379.

    Article  CAS  PubMed  Google Scholar 

  28. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH . Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31: 331–341.

    Article  CAS  PubMed  Google Scholar 

  29. Cua DJ, Tato CM . Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 2010; 10: 479–489.

    Article  CAS  PubMed  Google Scholar 

  30. Moore TA, Moore BB, Newstead MW, Standiford TJ . Gamma delta-T cells are critical for survival and early proinflammatory cytokine gene expression during murine Klebsiella pneumonia. J Immunol 2000; 165: 2643–2650.

    Article  CAS  PubMed  Google Scholar 

  31. Takano M, Nishimura H, Kimura Y, Mokuno Y, Washizu J, Itohara S et al. Protective roles of gamma delta T cells and interleukin-15 in Escherichia coli infection in mice. Infect Immun 1998; 66: 3270–3278.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. BHiromatsu K, Yoshikai Y, Matsuzaki G, Ohga S, Muramori K, Matsumoto K et al. A protective role of gamma/delta T cells in primary infection with Listeria monocytogenes in mice. J Exp Med 1992; 175: 49–56.

    Article  Google Scholar 

  33. Ladel CH, Blum C, Dreher A, Reifenberg K, Kaufmann SH . Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis. Eur J Immunol 1995; 25: 2877–2881.

    Article  CAS  PubMed  Google Scholar 

  34. King DP, Hyde DM, Jackson KA, Novosad DM, Ellis TN, Putney L et al. Cutting edge: protective response to pulmonary injury requires gamma delta T lymphocytes. J Immunol 1999; 162: 5033–5036.

    CAS  PubMed  Google Scholar 

  35. Jones-Carson J, Vazquez-Torres A, van der Heyde HC, Warner T, Wagner RD, Balish E . Gamma delta T cell-induced nitric oxide production enhances resistance to mucosal candidiasis. Nat Med 1995; 1: 552–557.

    Article  CAS  PubMed  Google Scholar 

  36. Rosat JP, MacDonald HR, Louis JA . A role for gamma delta+T cells during experimental infection of mice with Leishmania major. J Immunol 1993; 150: 550–555.

    CAS  PubMed  Google Scholar 

  37. Hisaeda H, Nagasawa H, Maeda K, Maekawa Y, Ishikawa H, Ito Y et al. Gamma delta T cells play an important role in hsp65 expression and in acquiring protective immune responses against infection with Toxoplasma gondii. J Iimmunol 1995; 155: 244–251.

    CAS  Google Scholar 

  38. O'Brien RL, Yin X, Huber SA, Ikuta K, Born WK . Depletion of a gamma delta T cell subset can increase host resistance to a bacterial infection. J Immunol 2000; 165: 6472–6479.

    Article  CAS  PubMed  Google Scholar 

  39. Emoto M, Nishimura H, Sakai T, Hiromatsu K, Gomi H, Itohara S et al. Mice deficient in gamma delta T cells are resistant to lethal infection with Salmonella choleraesuis. Infect Immun 1995; 63: 3736–3738.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wormley FL Jr., Steele C, Wozniak K, Fujihashi K, McGhee JR, Fidel PL Jr . Resistance of T-cell receptor delta-chain-deficient mice to experimental Candida albicans vaginitis. Infect Immun 2001; 69: 7162–7164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Roberts SJ, Smith AL, West AB, Wen L, Findly RC, Owen MJ et al. T-cell alpha beta+and gamma delta+deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc Natl Acad Sci USA 1996; 93: 11774–11779.

    Article  CAS  PubMed  Google Scholar 

  42. Williams DM, Grubbs BG, Kelly K, Pack E, Rank RG . Role of gamma-delta T cells in murine Chlamydia trachomatis infection. Infect Immun 1996; 64: 3916–3919.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Perry LL, Feilzer K, Caldwell HD . Immunity to Chlamydia trachomatis is mediated by T helper 1 cells through IFN-gamma-dependent and -independent pathways. J Immunol 1997; 158: 3344–3352.

    CAS  PubMed  Google Scholar 

  44. Yang X . Role of cytokines in Chlamydia trachomatis protective immunity and immunopathology. Curr Pharm Des 2003; 9: 67–73.

    Article  CAS  PubMed  Google Scholar 

  45. Yang X, Brunham R . T lymphocyte immunity in host defence against Chlamydia trachomatis and its implication for vaccine development. Can J Infect Dis 1998; 9: 99–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Caccamo N, Sireci G, Meraviglia S, Dieli F, Ivanyi J, Salerno A . gammadelta T cells condition dendritic cells in vivo for priming pulmonary CD8 T cell responses against Mycobacterium tuberculosis. Eur J Immunol 2006; 36: 2681–2690.

    Article  CAS  PubMed  Google Scholar 

  47. Dieli F, Caccamo N, Meraviglia S, Ivanyi J, Sireci G, Bonanno CT et al. Reciprocal stimulation of gammadelta T cells and dendritic cells during the anti-mycobacterial immune response. Eur J Immunol 2004; 34: 3227–3235.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants (to XY) from the Canadian Institutes of Health Research (CIHR), the Manitoba Health Research Council (MHRC) and the Manitoba Institute of Child Health (MICH) and grants (to HB) from the National Natural Science Foundation of China (31070797), the Key Program: 15JCZDJC34900 and 11JCZDJC16200 from Tianjin Municipal Science and Technology Commission (TSTC). XG was a trainee in CIHR National Training Program in Allergy/asthma and a holder of an MICH Studentship. AGJ was a trainee in the CIHR/International Centre for Infectious Diseases (ICID) National Training Program in Infectious Diseases and a holder of an MHRC postdoctoral fellowship. XY was the Canada Research Chair in Infection and Immunity.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xi Yang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bai, H., Gao, X., Zhao, L. et al. Respective IL-17A production by γδ T and Th17 cells and its implication in host defense against chlamydial lung infection. Cell Mol Immunol 14, 850–861 (2017). https://doi.org/10.1038/cmi.2016.53

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2016.53

Keywords

This article is cited by

Search

Quick links