Hepatitis B virus–specific and global T-cell dysfunction in chronic hepatitis B

JJ Park, DK Wong, AS Wahed, WM Lee, JJ Feld… - Gastroenterology, 2016 - Elsevier
JJ Park, DK Wong, AS Wahed, WM Lee, JJ Feld, N Terrault, M Khalili, RK Sterling
Gastroenterology, 2016Elsevier
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 …
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.
Elsevier