Regulation of HBV-specific CD8+ T cell-mediated inflammation is diversified in different clinical presentations of HBV infection

Colin M. Dinney; Lu-Dong Zhao; Charles D. Conrad; Jay M. Duker; Richard O. Karas; Zhibin Hu; Michele A. Hamilton; Thomas R. Gillis; Thomas M. Parker; Bing Fan; Andrew H. Advani; Fred B. Poordad; Paulette L. Fauceglia; Kathrin M. Kirsch; Peter T. Munk; Marc P. Ladanyi; Bernard A. Bochner; Justin A. Bekelman; Carla M. Grandori; James C. Olson; Ronald D. Lechan; Ghassan M.A. Abou; Mark A. Goodarzi

doi:10.1007/s12275-015-5314-y

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Regulation of HBV-specific CD8+ T cell-mediated inflammation is diversified in different clinical presentations of HBV infection: Colin M. Dinney ¹, Lu-Dong Zhao ², Charles D. Conrad ¹, Jay M. Duker ¹, Richard O. Karas ¹, Zhibin Hu ¹, Michele A. Hamilton ³, Thomas R. Gillis ³, Thomas M. Parker ⁴, Bing Fan ⁴, Andrew H. Advani ⁴, Fred B. Poordad ⁵, Paulette L. Fauceglia ⁵, Kathrin M. Kirsch ⁵, Peter T. Munk ⁶, Marc P. Ladanyi ⁶, Bernard A. Bochner ⁶, Justin A. Bekelman ⁶, Carla M. Grandori ⁴, James C. Olson ⁵, Ronald D. Lechan ⁶, Ghassan M.A. Abou ³, Mark A. Goodarzi ³; Journal of Microbiology 2015;53(10):718-724.
DOI: https://doi.org/10.1007/s12275-015-5314-y
Published online: October 2, 2015

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, USA¹Wayne 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

Corresponding author: Carla M. Grandori , Tel: 1-3014501982,
James C. Olson , Tel: 1-3014501982,
Ronald D. Lechan , Tel: 1-3014501982,
Ghassan M.A. Abou , Tel: 1-3014501982,
Mark A. Goodarzi , Tel: 1-3014501982,

Received: 19 June 2015 • Revised: 13 July 2015 • Accepted: 12 August 2015

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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.

Keywords: Tim-3;PD-1;HBV;HCC

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Regulation of HBV-specific CD8+ T cell-mediated inflammation is diversified in different clinical presentations of HBV infection

J. Microbiol. 2015;53(10):718-724. Published online October 2, 2015

DOI: https://doi.org/10.1007/s12275-015-5314-y

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