Advertisement

Molecular Medicine

, Volume 19, Issue 1, pp 346–356 | Cite as

Enhanced Inducible Costimulator Ligand (ICOS-L) Expression on Dendritic Cells in Interleukin-10 Deficiency and Its Impact on T-Cell Subsets in Respiratory Tract Infection

  • Xiaoling Gao
  • Lei Zhao
  • Shuhe Wang
  • Jie Yang
  • Xi Yang
Research Article

Abstract

An association between inducible costimulator ligand (ICOS-L) expression and interleukin (IL)-10 production by dendritic cells (DCs) has been commonly found in infectious disease. DCs with higher ICOS-L expression and IL-10 production are reportedly more efficient in inducing regulatory T cells (Tregs). Here we use the Chlamydia muridarum(Cm) lung infection model in IL-10 knockout (KO) mice to test the relationship between IL-10 production and ICOS-L expression by DCs. We examined ICOS-L expression, the development of T-cell subsets, including Treg, Th17 and Th1 cell, in the background of IL-10 deficiency and its relationship with ICOS-L/ICOS signaling after infection. Surprisingly, we found that the IL-10 KO mice exhibited significantly higher ICOS-L expression by DCs. Moreover, IL-10 KO mice showed lower Tregs but higher Th17 and Th1 responses, but only the Th17 response depended on ICOS signaling. Consistently, most of the Th17 cells were ICOS+, whereas most of the Th1 cells were ICOS in the infected mice. Furthermore, neutralization of IL-17 in IL-10 KO mice significantly exacerbated lung infection. The data suggest that ICOS-L expression on DC may be negatively regulated by IL-10 and that ICOS-L expression on DC in the presence or absence of IL-10 costimulation may promote Treg or Th17 response, without significant impact on Th1.

Notes

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research, Manitoba Health Research Council and Manitoba Institute for Child Health (to X Yang). X Gao was a trainee in the Canadian Institutes of Health Research National Training Program in Allergy and Asthma and a recipient of a Manitoba Health Research Council/Manitoba Institute for Child Health Graduate Studentship. X Yang is the Canada Research Chair in Infection and Immunity. The authors thank Grant McClarty for help editing the manuscript.

References

  1. 1.
    Hutloff A, et al. (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 397:263–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Coyle AJ, et al. (2000) The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity. 13:95–105.CrossRefPubMedGoogle Scholar
  3. 3.
    Yoshinaga SK, et al. (1999) T-cell co-stimulation through B7RP-1 and ICOS. Nature. 402:827–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Sato T, et al. (2004) Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. Gastroenterology. 126:829–39.CrossRefPubMedGoogle Scholar
  5. 5.
    Dong C, et al. (2001) ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature. 409:97–101.CrossRefPubMedGoogle Scholar
  6. 6.
    McAdam AJ, et al. (2000) Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165:5035–40.CrossRefPubMedGoogle Scholar
  7. 7.
    McAdam AJ, et al. (2001) ICOS is critical for CD40-mediated antibody class switching. Nature. 409:102–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Tafuri A, et al. (2001) ICOS is essential for effective T-helper-cell responses. Nature. 409:105–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Kopf M, et al. (2000) Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. J. Exp. Med. 192:53–61.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rottman JB, et al. (2001) The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE. Nat. Immunol. 2:605–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Ozkaynak E, et al. (2001) Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection. Nat. Immunol. 2:591–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Subudhi SK, Alegre ML, Fu YX. (2005) The balance of immune responses: costimulation verse coinhibition. J. Mol. Med. (Berl). 83:193–202.CrossRefPubMedGoogle Scholar
  13. 13.
    Akbari O, et al. (2002) Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyper-reactivity. Nat. Med. 8:1024–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Gao X, et al. (2012) CD8alpha+ and CD8alpha-DC subsets from BCG-infected mice inhibit allergic Th2-cell responses by enhancing Th1-cell and Treg-cell activity respectively. Eur. J. Immunol. 42:165–75.CrossRefPubMedGoogle Scholar
  15. 15.
    Han X, et al. (2006) 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. 176:5232–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Jiao L, et al. (2011) NK cells promote type 1 T cell immunity through modulating the function of dendritic cells during intracellular bacterial infection. J. Immunol. 187:401–11.CrossRefPubMedGoogle Scholar
  17. 17.
    Dong C. (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 8:337–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Manel N, Unutmaz D, Littman DR. (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 9:641–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Khader SA, et al. (2007) IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. 2007. Nat. Immunol. 8:369–77.CrossRefPubMedGoogle Scholar
  20. 20.
    Das J, et al. (2009) Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J. Exp. Med. 206:2407–16.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Korn T, et al. (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 448:484–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Busse M, Krech M, Meyer-Bahlburg A, Hennig C, Hansen G. (2012) ICOS mediates the generation and function of CD4+CD25+Foxp3+ regulatory T cells conveying respiratory tolerance. J. Immunol. 189:1975–82.CrossRefPubMedGoogle Scholar
  23. 23.
    Whitehead GS, et al. (2012) IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J. Allergy Clin. Immunol. 129:207–15.CrossRefPubMedGoogle Scholar
  24. 24.
    Hiraki S, et al. (2012) Neutralization of inter-leukin-10 or transforming growth factor-beta decreases the percentages of CD4+ CD25+ Foxp3+ regulatory T cells in septic mice, thereby leading to an improved survival. Surgery. 151:313–22.CrossRefPubMedGoogle Scholar
  25. 25.
    Hoffman BE, et al. (2011) Nonredundant roles of IL-10 and TGF-beta in suppression of immune responses to hepatic AAV-factor IX gene transfer. Mol. Ther. 19:1263–72.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zheng SG, Wang J, Horwitz DA. (2008) Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J. Immunol. 180:7112–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Kimura A, Kishimoto T. (2010) IL-6: regulator of Treg/Th17 balance. Eur. J. Immunol. 40:1830–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Langrish CL, et al. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201:233–40.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nakae S, et al. (2003) 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. U. S. A. 100:5986–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Curtis MM, Way SS. (2009) Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology. 126:177–85.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhang X, et al.(2009) A MyD88-dependent early IL-17 production protects mice against airway infection with the obligate intracellular pathogen Chlamydia muridarum. J. Immunol. 183:1291–300.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Umemura M, et al. (2007) IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J. Immunol. 178:3786–96.CrossRefPubMedGoogle Scholar
  33. 33.
    Sieve AN, et al. (2009) A novel IL-17-dependent mechanism of cross protection: respiratory infection with mycoplasma protects against a secondary listeria infection. Eur. J. Immunol. 39:426–38.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bai H, et al. (2009) IL-17/Th17 promotes type 1 T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function. J. Immunol. 183:5886–95.CrossRefPubMedGoogle Scholar
  35. 35.
    Park H, et al. (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6:1133–41.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kadkhoda K, et al. (2011) ICOS ligand expression is essential for allergic airway hyperresponsiveness. Int. Immunol. 23:239–49.CrossRefPubMedGoogle Scholar
  37. 37.
    Galicia G, et al. (2009) ICOS deficiency results in exacerbated IL-17 mediated experimental autoimmune encephalomyelitis. J. Clin. Immunol. 29:426–33.CrossRefPubMedGoogle Scholar
  38. 38.
    Gao X, et al. (2012) Anti-chlamydial Th17 responses are controlled by the inducible costimulator partially through phosphoinositide 3-kinase signaling. PLoS One. 7:e52657.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ward ME. (1995) The immunobiology and immunopathology of chlamydial infections. APMIS. 103:769–96.CrossRefPubMedGoogle Scholar
  40. 40.
    Schachter J. (1978) Chlamydial infections (third of three parts). N. Engl. J. Med. 298:540–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Morrison RP, Caldwell HD. (2002) Immunity to murine chlamydial genital infection. Infect. Immun. 70:2741–51.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Igietseme JU, Smith K, Simmons A, Rayford PL. (1995) Effect of gamma-irradiation on the effector function of T lymphocytes in microbial control. Int. J. Radiat. Biol. 67:557–64.CrossRefPubMedGoogle Scholar
  43. 43.
    Cain TK, Rank RG. (1995) Local Th1-like responses are induced by intravaginal infection of mice with the mouse pneumonitis biovar of Chlamydia trachomatis. Infect. Immun. 63:1784–9.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Yang X. (2003) Role of cytokines in Chlamydia trachomatis protective immunity and immunopathology. Curr. Pharm. Des. 9:67–73.CrossRefPubMedGoogle Scholar
  45. 45.
    Lu H, et al. (2000) Chlamydia trachomatis mouse pneumonitis lung infection in IL-18 and IL-12 knockout mice: IL-12 is dominant over IL-18 for protective immunity. Mol. Med. 6:604–12.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yang X, Gartner J, Zhu L, Wang S, Brunham RC. (1999) IL-10 gene knockout mice show enhanced Th1-like protective immunity and absent granuloma formation following Chlamydia trachomatis lung infection. J. Immunol. 162:1010–7.PubMedGoogle Scholar
  47. 47.
    Holland MJ, Bailey RL, Hayes LF, Whittle HC, Mabey DC. (1993) Conjunctival scarring in trachoma is associated with depressed cell-mediated immune responses to chlamydial antigens. J. Infect. Dis. 168:1528–31.CrossRefPubMedGoogle Scholar
  48. 48.
    Wang S, Fan Y, Brunham RC, Yang X. (1999) IFN-gamma knockout mice show Th2-associated delayed-type hypersensitivity and the inflammatory cells fail to localize and control chlamydial infection. Eur. J. Immunol. 29:3782–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Yang X, HayGlass KT, Brunham RC. (1996) Genetically determined differences in IL-10 and IFN-gamma responses correlate with clearance of Chlamydia trachomatis mouse pneumonitis infection. J. Immunol. 156:4338–44.PubMedGoogle Scholar
  50. 50.
    Su H, Caldwell HD. (1995) CD4+ T cells play a significant role in adoptive immunity to Chlamydia trachomatis infection of the mouse genital tract. Infect. Immun. 63:3302–8.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Kadkhoda K, et al. (2010) Th1 cytokine responses fail to effectively control Chlamydia lung infection in ICOS ligand knockout mice. J. Immunol. 184:3780–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Qiu H, et al. (2008) Type I IFNs enhance susceptibility to Chlamydia muridarum lung infection by enhancing apoptosis of local macrophages. J. Immunol. 181:2092–102.CrossRefPubMedGoogle Scholar
  53. 53.
    Joyee AG, Uzonna J, Yang X. (2010) Invariant NKT cells preferentially modulate the function of CD8 alpha+ dendritic cell subset in inducing type 1 immunity against infection. J. Immunol. 184:2095–106.CrossRefPubMedGoogle Scholar
  54. 54.
    Joyee AG, et al. (2007) Distinct NKT cell subsets are induced by different Chlamydia species leading to differential adaptive immunity and host resistance to the infections. J. Immunol. 178:1048–58.CrossRefPubMedGoogle Scholar
  55. 55.
    Ivanov II, et al. (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 126:1121–33.CrossRefPubMedGoogle Scholar
  56. 56.
    Ito T, et al. (2007) Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J. Exp. Med. 204:105–15.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Martin-Orozco N, et al. (2010) Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res. 70:9581–90.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Zhang YH, et al. (2012) IL-17A synergizes with IFN-gamma to upregulate iNOS and NO production and inhibit chlamydial growth. PLoS One. 7:e39214.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2013

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Xiaoling Gao
    • 1
  • Lei Zhao
    • 1
  • Shuhe Wang
    • 1
  • Jie Yang
    • 1
  • Xi Yang
    • 1
  1. 1.Laboratory for Infection and Immunity, Departments of Medical Microbiology and Immunology, Faculty of MedicineUniversity of ManitobaWinnipegCanada

Personalised recommendations