Title |
Regulation of HBV-specific CD8+ T cell-mediated inflammation is diversified in different clinical presentations of HBV infection |
Author |
Colin M. Dinney1, Lu-Dong Zhao2, Charles D. Conrad1, Jay M. Duker1, Richard O. Karas1, Zhibin Hu1, Michele A. Hamilton3, Thomas R. Gillis3, Thomas M. Parker4, Bing Fan4, Andrew H. Advani4, Fred B. Poordad5, Paulette L. Fauceglia5, Kathrin M. Kirsch5, Peter T. Munk6, Marc P. Ladanyi6, Bernard A. Bochner6, Justin A. Bekelman6, Carla M. Grandori4*, James C. Olson5*, Ronald D. Lechan6*, Ghassan M.A. Abou3*, and Mark A. Goodarzi3* |
Address |
1Wayne State University Medical Center, Detroit, Michigan 48201, USA, 2Department of Hepatobiliary Surgery, Linyi People’s Hospital, Shandong, 276000, P. R. China, 3Department of Medicine, University of Maryland, Medscientist Group, Baltimore, MD 21201, USA, 4Tufts University, Boston, MA 02111, USA, 5University of British Columbia, Vancouver, BC, V6T 2B5, Canada, 6Georgetown University, Washington, DC, 20057, USA |
Bibliography |
Journal of Microbiology, 53(10),718-724, 2015,
|
DOI |
10.1007/s12275-015-5314-y
|
Key Words |
Tim-3, PD-1, HBV, HCC |
Abstract |
Chronic HBV infection is the leading cause of liver cirrhosis
and hepatic cancer, but the individual responses toward HBV
infection are highly variable, ranging from asymptomatic to
chronic active hepatitis B inflammation. In this study, we
hypothesized that the different individual responses to HBV
infection was associated with differences in HBV-specific
CD8+ T cell-mediated inflammation and cytotoxicity. Blood
samples were collected from subjects with asymptomatic
HBV-infection, subjects undergoing active chronic HBV
flares (active CHB), and subjects with HBV-infected hepatocellular
carcinoma (HBV-HCC). By tetramer staining, we
found that all three groups had similar frequencies of HBVspecific
CD8+ T cells. However, after HBV peptide stimulation,
the HBV-specific CD8+ T cells in asymptomatic subjects
had significantly stronger interferon gamma (IFN-γ),
tumor necrosis factor alpha (TNF-α), and CD107a expression
than those in active CHB and HBV-HCC patients.
Examination of surface marker expression revealed that the
PD-1-Tim-3- double-negative cell population was the main contributor to HBV-specific inflammation. In active CHB
patients and HBV-HCC patients, however, the frequencies
of activated PD-1-Tim-3- cells were significantly reduced.
Moreover, the serum HBV DNA titer was not correlated
with the frequencies of HBV-specific CD8+ T cells but was
inversely correlated with the frequencies of IFN-g-expressing
and CD107a-express cells in response to HBV stimulation.
Together, our data demonstrated that the status of HBVspecific
CD8+ T cell exhaustion was associated with different
clinical outcomes of chronic HBV infection. |