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Gastroenterology ; 150(3): 684-695.e5, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26684441

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.


Subject(s)
Hepatitis B virus/pathogenicity , Hepatitis B, Chronic/virology , Lymphocyte Activation , T-Lymphocytes/virology , Adult , Case-Control Studies , Cell Proliferation , Cells, Cultured , Female , Hepatitis B e Antigens/blood , Hepatitis B virus/immunology , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/immunology , Host-Pathogen Interactions , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/immunology , Interleukin-10/metabolism , Lipopolysaccharides/pharmacology , Lymphocyte Activation/drug effects , Male , Orthomyxoviridae/immunology , Phenotype , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , United States
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