Skip to main content

Advertisement

SpringerLink
Log in

Regulatory Role of CD4+CD25+Foxp3+ Regulatory T Cells on IL-17-Secreting T Cells in Chronic Hepatitis B Patients

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Both interleukin (IL)-17-secreting CD4+ T (Th17) and CD4+CD25+Foxp3+ T regulatory (Treg) cells have been shown to be associated with disease progression or liver damage in chronic hepatitis B (CHB) patients. However, the relationship between Treg cells and IL-17-secreting T cells in hepatitis B virus (HBV) infections is unclear.

Methods

The frequencies of Treg cells and IL-17-secreting T cells in hepatitis B e antigen (HBeAg)-positive CHB patients and healthy subjects were measured by flow cytometric analysis. The role of Treg cells on the differentiation of Ag-specific IL-17-secreting T cells was determined by removing the Treg cells from peripheral blood mononuclear cells (PBMCs) in HBeAg-positive CHB patients.

Results

The frequencies of both Th17 (1.71 ± 0.58 vs. 1.08 ± 0.36 %; P < 0.01) and Treg cells (8.92 ± 4.11 vs. 6.45 ± 1.56 %; P < 0.01) were increased in the peripheral blood of HBeAg-positive CHB patients compared with healthy controls, but in not the IL-17-secreting CD8+ T (Tc17) cells. The frequency of Treg cells was significantly associated with that of Th17 cells (r = 0.625, P = 0.001) in CHB patients. Spearman analysis showed a positive correlation between the frequency of Treg cells and HBV DNA load (r = 0.508, P = 0.008), as well as between the frequency of Th17 cells and serum alanine aminotransferase level (r = 0.516, P = 0.007). The deletion of Treg cells significantly enhanced both Th17 and Tc17 cell development in PBMCs following recombinant HBV core antigen stimulation.

Conclusions

Our data indicate a clear inverse relationship between Th17 cells and Treg cells and that Treg cells can inhibit Th17 cell development in CHB patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis. 2007;7:804–813.

    Article  CAS  PubMed  Google Scholar 

  2. McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis. 2005;25:3–8.

    Article  PubMed  Google Scholar 

  3. Rehermann B. Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med. 2000;191:1263–1268.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215–229.

    Article  CAS  PubMed  Google Scholar 

  5. Peng G, Li S, Wu W, Sun Z, Chen Y, Chen Z. Circulating CD4+CD25+ regulatory T cells correlate with chronic hepatitis B infection. Immunology. 2008;123:57–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Rowan AG, Fletcher JM, Ryan EJ, et al. Hepatitis C virus-specific TH17 cells are suppressed by virus-induced TGF-beta. J Immunol. 2008;181:4485–4494.

    Article  CAS  PubMed  Google Scholar 

  7. Boissier MC, Assier E, Falgarone G, Bessis N. Shifting the imbalance from Th1/Th2 to Th17/Treg: the changing rheumatoid arthritis paradigm. Joint Bone Spine. 2008;75:373–375.

    Article  CAS  PubMed  Google Scholar 

  8. Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int. 2008;57:121–134.

    Article  CAS  PubMed  Google Scholar 

  9. Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol. 2006;18:670–675.

    Article  CAS  PubMed  Google Scholar 

  10. Wu W, Li J, Chen F, Zhu H, Peng G, Chen Z. Circulating TH17 cells frequency is associated with the disease progression in HBV infected patients. J Gastroenterol Hepatol. 2010;25:750–757.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology. 2010;51:81–91.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang F, Yao S, Yuan J, et al. Elevated IL-6 receptor expression on CD4+ T cells contributes to the increased Th17 responses in patients with chronic hepatitis B. Virol J. 2011;8:270.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Gao L, Wang JF, Xiang M, Fan YC, Zhang ZG, Wang K. Expression of human glucocorticoid receptor in T lymphocytes in acute-on-chronic hepatitis B liver failure. Dig Dis Sci. 2011;56:2605–2612.

    Article  CAS  PubMed  Google Scholar 

  14. Xue-Song L, Cheng-Zhong L, Ying Z, Mo-Bin W. Changes of treg and th17 cells balance in the development of acute and chronic hepatitis B virus infection. BMC Gastroenterol. 2012;12:43.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Li J, Qiu SJ, She WM, et al. Significance of the balance between regulatory T (Treg) and T helper 17 (Th17) cells during hepatitis B virus related liver fibrosis. PLoS One. 2012;7:e39307.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chinese Society of Infectious Diseases and Parasitology and Chinese Society of Hepatology of Chinese Medical Association. Chinese medicine national program for prevention and treatment of viral hepatitis. Chin J Hepatol. 2011;19:13–24.

    Google Scholar 

  17. Li J, Wu W, Peng G, et al. Hbcag induces interleukin-10 production, inhibiting Hbcag-specific th17 responses in chronic hepatitis b patients. Immunol Cell Biol. 2010;88:834–841.

    Article  CAS  PubMed  Google Scholar 

  18. Yang B, Wang Y, Zhao C, et al. Increased Th17 cells and interleukin-17 contribute to immune activation and disease aggravation in patients with chronic hepatitis B virus infection. Immunol Lett. 2013;149:41–49.

    Article  CAS  PubMed  Google Scholar 

  19. Lafdil F, Miller AM, Ki SH, Gao B. Th17 cells and their associated cytokines in liver diseases. Cell Mol Immunol. 2010;7:250–254.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Xu D, Fu J, Jin L, et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 2006;177:739–747.

    Article  CAS  PubMed  Google Scholar 

  21. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6:353–360.

    Article  CAS  PubMed  Google Scholar 

  22. Bouchliou I, Miltiades P, Nakou E, et al. Th17 and Foxp3(+) T regulatory cell dynamics and distribution in myelodysplastic syndromes. Clin Immunol. 2011;139:350–359.

    Article  CAS  PubMed  Google Scholar 

  23. Li N, Bian H, Zhang J, Li X, Ji X, Zhang Y. The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction. Clin Chim Acta. 2010;411:1963–1968.

    Article  CAS  PubMed  Google Scholar 

  24. Li J, Wang L, Wang S, et al. The Treg/Th17 imbalance in patients with idiopathic dilated cardiomyopathy. Scand J Immunol. 2010;71:298–303.

    Article  CAS  PubMed  Google Scholar 

  25. Wang Q, Zheng Y, Huang Z, et al. Activated IL-23/IL-17 pathway closely correlates with increased Foxp3 expression in livers of chronic hepatitis B patients. BMC Immunol. 2011;12:25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Evans HG, Suddason T, Jackson I, Taams LS, Lord GM. Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of toll-like receptor-activated monocytes. Proc Natl Acad Sci USA. 2007;104:17034–17039.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+CD25−Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol. 2007;178:6725–6729.

    Article  CAS  PubMed  Google Scholar 

  28. Weaver CT, Hatton RD. Interplay between the Th17 and Treg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol. 2009;9:883–889.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(h)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453:236–240.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Du J, Huang C, Zhou B, Ziegler SF. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human Foxp3. J Immunol. 2008;180:4785–4792.

    Article  CAS  PubMed  Google Scholar 

  31. Ichiyama K, Yoshida H, Wakabayashi Y, et al. Foxp3 inhibits RORgammat-mediated IL-17a Mrna transcription through direct interaction with RORgammat. J Biol Chem. 2008;283:17003–17008.

    Article  CAS  PubMed  Google Scholar 

  32. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature. 2006;441:235–238.

    Article  CAS  PubMed  Google Scholar 

  33. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–189.

    Article  CAS  PubMed  Google Scholar 

  34. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–240.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133.

    Article  CAS  PubMed  Google Scholar 

  36. Dambacher J, Beigel F, Zitzmann K, et al. The role of interleukin-22 in hepatitis c virus infection. Cytokine. 2008;41:209–216.

    Article  CAS  PubMed  Google Scholar 

  37. Huber M, Heink S, Grothe H, et al. A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity. Eur J Immunol. 2009;39:1716–1725.

    Article  CAS  PubMed  Google Scholar 

  38. Hamada H, de la Luz Garcia-Hernandez M, Reome JB, et al. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J Immunol. 2009;182:3469–3481.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Burrell BE, Csencsits K, Lu G, Grabauskiene S, Bishop DK. Cd8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice. J Immunol. 2008;181:3906–3914.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Tajima M, Wakita D, Noguchi D, et al. Il-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+ T cells. J Exp Med. 2008;205:1019–1027.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Yen HR, Harris TJ, Wada S, et al. Tc17 CD8 T cells: functional plasticity and subset diversity. J Immunol. 2009;183:7161–7168.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by the National Natural Science Fund (No. 81201288), the State S&T Projects of 12th Five Year (No. 2012ZX10002003-004-007) and the Excellent Young Scientist Foundation of Shandong Province (No. 2008BS03014).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Infectious Disease, Shandong Provincial Hospital affiliated to Shandong University, 324 Jingwu Road, Jinan, 250021, Shandong, China

    Jie Li, Jun Shi & Wanhua Ren

  2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China

    Wei Wu & Zhi Chen

Authors
  1. Jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanhua Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jie Li.

Additional information

Jie Li, Jun Shi and Wanhua Ren contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, J., Shi, J., Ren, W. et al. Regulatory Role of CD4+CD25+Foxp3+ Regulatory T Cells on IL-17-Secreting T Cells in Chronic Hepatitis B Patients. Dig Dis Sci 59, 1475–1483 (2014). https://doi.org/10.1007/s10620-013-3022-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-3022-1

Keywords

Search

Navigation