Hepatitis B Virus-Specific and Global T-Cell Dysfunction in Chronic Hepatitis B

Jang June Park, David K. Wong, Abdus S. Wahed, William M. Lee, Jordan J. Feld, Norah Terrault, Mandana Khalili, Richard K. Sterling, Kris V. Kowdley, Natalie Bzowej, Daryl T. Lau, W. Ray Kim, Coleman Smith, Robert L. Carithers, Keith W. Torrey, James W. Keith, Danielle L. Levine, Daniel Traum, Suzanne Ho, Mary E. ValigaGeoffrey S. Johnson, Edward Doo, Anna S F Lok, Kyong Mi Chang

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3+CD127- regulatory T cells and CD4+ T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)+ than HBeAg- patients (percent responders: 3% vs 23%; P =.00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg- patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Original languageEnglish (US)
Pages (from-to)684-695e5
JournalGastroenterology
Volume150
Issue number3
DOIs
StatePublished - Mar 1 2016

Keywords

  • HBRN
  • IFN
  • IL10
  • LPS

ASJC Scopus subject areas

  • Gastroenterology

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    Park, J. J., Wong, D. K., Wahed, A. S., Lee, W. M., Feld, J. J., Terrault, N., Khalili, M., Sterling, R. K., Kowdley, K. V., Bzowej, N., Lau, D. T., Kim, W. R., Smith, C., Carithers, R. L., Torrey, K. W., Keith, J. W., Levine, D. L., Traum, D., Ho, S., ... Chang, K. M. (2016). Hepatitis B Virus-Specific and Global T-Cell Dysfunction in Chronic Hepatitis B. Gastroenterology, 150(3), 684-695e5. https://doi.org/10.1053/j.gastro.2015.11.050