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.

Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection

Subjects

Abstract

Hepatitis C virus (HCV) is endemic in many countries due to its high propensity for establishing persistence1. The presence of HCV-specific T cells in subjects repeatedly exposed to HCV who test negative for HCV RNA and antibodies and who do not have any history of HCV infection has been interpreted as T cell–mediated protection2,3,4,5. Here, we show in nonhuman primates that repeated exposure to human plasma with trace amounts of HCV induced HCV-specific T cells without seroconversion and systemic viremia but did not protect upon subsequent HCV challenge. Rather, HCV-specific recall and de novo T cell responses, as well as intrahepatic T cell recruitment and interferon-γ (IFN-γ) production, were suppressed upon HCV challenge, concomitant with quantitative and qualitative changes in regulatory T cells (Treg cells) that occurred after subinfectious HCV exposure and increased after HCV challenge. In vitro Treg cell depletion restored HCV-specific T cell responses. Thus, T cells primed by trace amounts of HCV do not generate effective recall responses upon subsequent HCV infection. Subinfectious HCV exposure predisposes to Treg cell expansion, which suppresses effector T cells during subsequent infection. Strategies to reverse this exposure-induced immune suppression should be examined to aid in the development of T cell−based vaccines against HCV and other endemic pathogens.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Repeated exposure to blood samples from patients positive for antibody to HCV and trace amounts of HCV induces HCV-specific T cell responses.
Figure 2: Repeated exposure to blood samples from patients positive for antibody to HCV and trace amounts of HCV suppresses T cell responses upon HCV challenge.
Figure 3: Repeated exposure to blood samples from patients positive for antibody to HCV and trace amounts of HCV suppresses intrahepatic T cell recruitment and IFN-γ production upon subsequent HCV challenge.
Figure 4: Repeated exposure to trace amounts of HCV predisposes to CD4+CD25+Foxp3+ Treg cell expansion upon subsequent HCV challenge.

References

  1. Rehermann, B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J. Clin. Invest. 119, 1745–1754 (2009).

    CAS  Article  Google Scholar 

  2. Mizukoshi, E. et al. Hepatitis C virus (HCV)-specific immune responses of long-term injection drug users frequently exposed to HCV. J. Infect. Dis. 198, 203–212 (2008).

    CAS  Article  Google Scholar 

  3. Freeman, A.J. et al. Prevalence of production of virus-specific interferon-γ among seronegative hepatitis C-resistant subjects reporting injection drug use. J. Infect. Dis. 190, 1093–1097 (2004).

    CAS  Article  Google Scholar 

  4. Thurairajah, P.H. et al. Hepatitis C virus (HCV)-specific T cell responses in injection drug users with apparent resistance to HCV infection. J. Infect. Dis. 198, 1749–1755 (2008).

    Article  Google Scholar 

  5. Zeremski, M. et al. Hepatitis C virus–specific T-cell immune responses in seronegative injection drug users. J. Viral Hepat. 16, 10–20 (2009).

    CAS  Article  Google Scholar 

  6. Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).

    CAS  Article  Google Scholar 

  7. Thimme, R. et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc. Natl. Acad. Sci. USA 99, 15661–15668 (2002).

    CAS  Article  Google Scholar 

  8. Shoukry, N.H. et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J. Exp. Med. 197, 1645–1655 (2003).

    CAS  Article  Google Scholar 

  9. Grakoui, A. et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 302, 659–662 (2003).

    CAS  Google Scholar 

  10. Al-Sherbiny, M. et al. Exposure to hepatitis C virus induces cellular immune responses without detectable viremia or seroconversion. Am. J. Trop. Med. Hyg. 73, 44–49 (2005).

    Article  Google Scholar 

  11. Scognamiglio, P. et al. Presence of effector CD8+ T cells in hepatitis C virus–exposed healthy seronegative donors. J. Immunol. 162, 6681–6689 (1999).

    CAS  PubMed  Google Scholar 

  12. Veerapu, N.S., Raghuraman, S., Liang, T.J., Heller, T. & Rehermann, B. Sporadic reappearance of minute amounts of hepatitis C virus RNA after successful therapy stimulates cellular immune responses. Gastroenterology 140, 676–685 (2011).

    CAS  Article  Google Scholar 

  13. Bassett, S.E. et al. Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection. Hepatology 33, 1479–1487 (2001).

    CAS  Article  Google Scholar 

  14. Major, M.E. et al. Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge. J. Virol. 76, 6586–6595 (2002).

    CAS  Article  Google Scholar 

  15. Nascimbeni, M. et al. Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees. J. Virol. 77, 4781–4793 (2003).

    CAS  Article  Google Scholar 

  16. Lanford, R.E. et al. Cross-genotype immunity to hepatitis C virus. J. Virol. 78, 1575–1581 (2004).

    CAS  Article  Google Scholar 

  17. Folgori, A. et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat. Med. 12, 190–197 (2006).

    CAS  Article  Google Scholar 

  18. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    CAS  Article  Google Scholar 

  19. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

    CAS  Article  Google Scholar 

  20. Biancotto, A., Dagur, P.K., Fuchs, J.C., Langweiler, M. & McCoy, J.P. Jr. OMIP-004: in-depth characterization of human T regulatory cells. Cytometry A 81, 15–16 (2012).

    Article  Google Scholar 

  21. Kryczek, I. et al. Cutting edge: induction of B7–H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J. Immunol. 177, 40–44 (2006).

    CAS  Article  Google Scholar 

  22. Sica, G.L. et al. B7–H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18, 849–861 (2003).

    CAS  Article  Google Scholar 

  23. Larché, M., Akdis, C.A. & Valenta, R. Immunological mechanisms of allergen-specific immunotherapy. Nat. Rev. Immunol. 6, 761–771 (2006).

    Article  Google Scholar 

  24. Meiler, F. et al. In vivo switch to IL-10–secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 205, 2887–2898 (2008).

    CAS  Article  Google Scholar 

  25. Gottschalk, R.A., Corse, E. & Allison, J.P. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701–1711 (2010).

    CAS  Article  Google Scholar 

  26. Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    CAS  Article  Google Scholar 

  27. Curtsinger, J.M. & Mescher, M.F. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22, 333–340 (2010).

    CAS  Article  Google Scholar 

  28. Ebinuma, H. et al. Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J. Virol. 82, 5043–5053 (2008).

    CAS  Article  Google Scholar 

  29. Li, S. et al. Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection. PLoS Pathog. 5, e1000707 (2009).

    Article  Google Scholar 

  30. Kalia, V. et al. Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32, 91–103 (2010).

    CAS  Article  Google Scholar 

  31. de Göer de Herve, M.G., Jaafoura, S., Vallee, M. & Taoufik, Y. FoxP3+ regulatory CD4 T cells control the generation of functional CD8 memory. Nat. Commun. 3, 986 (2012).

    Article  Google Scholar 

  32. Takaki, A. et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat. Med. 6, 578–582 (2000).

    CAS  Article  Google Scholar 

  33. Heller, T. et al. Occupational exposure to hepatitis C virus: early T-cell responses in the absence of seroconversion in a longitudinal cohort study. J. Infect. Dis. 208, 1020–1025 (2013).

    CAS  Article  Google Scholar 

  34. Osburn, W.O. et al. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology 138, 315–324 (2010).

    CAS  Article  Google Scholar 

  35. Mehta, S.H. et al. Protection against persistence of hepatitis C. Lancet 359, 1478–1483 (2002).

    Article  Google Scholar 

  36. Finney, O.C., Nwakanma, D., Conway, D.J., Walther, M. & Riley, E.M. Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission. Eur. J. Immunol. 39, 1288–1300 (2009).

    CAS  Article  Google Scholar 

  37. Surls, J., Nazarov-Stoica, C., Kehl, M., Casares, S. & Brumeanu, T.D. Differential effect of CD4+Foxp3+ T-regulatory cells on the B and T helper cell responses to influenza virus vaccination. Vaccine 28, 7319–7330 (2010).

    CAS  Article  Google Scholar 

  38. Black, G.F. et al. Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi. J. Infect. Dis. 184, 322–329 (2001).

    CAS  Article  Google Scholar 

  39. Buchbinder, S.P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).

    CAS  Article  Google Scholar 

  40. Shin, E.C. et al. The kinetics of hepatitis C virus–specific CD8 T-cell responses in the blood mirror those in the liver in acute hepatitis C virus infection. J. Virol. 82, 9782–9788 (2008).

    CAS  Article  Google Scholar 

  41. Shin, E.C. et al. Delayed induction, not impaired recruitment, of specific CD8+ T cells causes the late onset of acute hepatitis C. Gastroenterology 141, 686–695 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank T.J. Rowell, J. Fontenot and the staff at New Iberia Research Center for the care of the chimpanzees and technical support and L. Holz (NIDDK) and W. Kastenmüller (NIAID) for discussion and reading of the manuscript. This work was supported by the intramural research program of the NIDDK.

Author information

Authors and Affiliations

Authors

Contributions

S.-H.P., N.S.V. and B.R. designed the study, analyzed the data and wrote the manuscript; S.-H.P., N.S.V. and E.-C.S. processed blood and liver biopsy samples; S.-H.P. and E.-C.S. characterized T cell responses; A.B. and J.P.M. characterized Treg cell subsets by flow cytometry; N.S.V. performed virological assays and some RT-PCR assays and A.F. and S.C. challenged three control chimpanzees and performed virological analyses. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Barbara Rehermann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–2 and Supplementary Methods. (PDF 1668 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Park, SH., Veerapu, N., Shin, EC. et al. Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection. Nat Med 19, 1638–1642 (2013). https://doi.org/10.1038/nm.3408

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3408

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing