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

被引:27
作者
Dinney, Colin M. [1 ]
Zhao, Lu-Dong [2 ]
Conrad, Charles D. [1 ]
Duker, Jay M. [1 ]
Karas, Richard O. [1 ]
Hu, Zhibin [1 ]
Hamilton, Michele A. [3 ]
Gillis, Thomas R. [3 ]
Parker, Thomas M. [4 ]
Fan, Bing [4 ]
Advani, Andrew H. [4 ]
Poordad, Fred B. [5 ]
Fauceglia, Paulette L. [5 ]
Kirsch, Kathrin M. [5 ]
Munk, Peter T. [6 ]
Ladanyi, Marc P. [6 ]
Bochner, Bernard A. [6 ]
Bekelman, Justin A. [6 ]
Grandori, Carla M. [4 ]
Olson, James C. [5 ]
Lechan, Ronald D. [6 ]
Abou, Ghassan M. A. [3 ]
Goodarzi, Mark A. [3 ]
机构
[1] Wayne State Univ, Med Ctr, Detroit, MI 48201 USA
[2] Linyi Peoples Hosp, Dept Hepatobilialy Surg, Shandong 276000, Peoples R China
[3] Univ Maryland, Medscientist Grp, Baltimore, MD 21201 USA
[4] Tufts Univ, Boston, MA 02111 USA
[5] Univ British Columbia, Vancouver, BC V6T 2B5, Canada
[6] Georgetown Univ, Washington, DC 20057 USA
关键词
Tim-3; PD-1; HBV; HCC; HEPATITIS-B-VIRUS; TIM-3; EXPRESSION; HEPATOCELLULAR-CARCINOMA; PD-1; PATHWAY; IDENTIFICATION; DYSFUNCTION; IMMUNITY;
D O I
10.1007/s12275-015-5314-y
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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-gamma), tumor necrosis factor alpha (TNF-alpha), 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.
引用
收藏
页码:718 / 724
页数:7
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