Dinney Colin M, Zhao Lu-Dong, Conrad Charles D, Duker Jay M, Karas Richard O, Hu Zhibin, Hamilton Michele A, Gillis Thomas R, Parker Thomas M, Fan Bing, Advani Andrew H, Poordad Fred B, Fauceglia Paulette L, Kirsch Kathrin M, Munk Peter T, Ladanyi Marc P, Bochner Bernard A, Bekelman Justin A, Grandori Carla M, Olson James C, Lechan Ronald D, Abou Ghassan M A, Goodarzi Mark A
Wayne State University Medical Center, Detroit, Michigan, 48201, USA.
Department of Hepatobiliary Surgery, Linyi People's Hospital, Shandong, 276000, P. R. China.
J Microbiol. 2015 Oct;53(10):718-24. doi: 10.1007/s12275-015-5314-y. Epub 2015 Oct 2.
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.
慢性乙肝病毒（HBV）感染是肝硬化和肝癌的主要病因，但个体对HBV感染的反应差异很大，从无症状感染到慢性活动性乙型肝炎炎症不等。在本研究中，我们假设个体对HBV感染的不同反应与HBV特异性CD8(+) T细胞介导的炎症和细胞毒性差异有关。我们采集了无症状HBV感染者、慢性HBV活动期发作患者（慢性活动性乙肝，active CHB）以及HBV感染的肝细胞癌患者（HBV-HCC）的血样。通过四聚体染色，我们发现所有三组中HBV特异性CD8(+) T细胞的频率相似。然而，在HBV肽刺激后，无症状感染者的HBV特异性CD8(+) T细胞产生的干扰素γ（IFN-γ）、肿瘤坏死因子α（TNF-α）和CD107a的表达明显强于慢性活动性乙肝患者和HBV-HCC患者。对表面标志物表达的检测显示，PD-1(-)Tim-3(-)双阴性细胞群体是HBV特异性炎症的主要贡献者。然而，在慢性活动性乙肝患者和HBV-HCC患者中，活化的PD-1(-)Tim-3(-)细胞的频率显著降低。此外，血清HBV DNA滴度与HBV特异性CD8(+) T细胞的频率无关，但与HBV刺激后表达IFN-γ和CD107a的细胞频率呈负相关。总之，我们的数据表明，HBV特异性CD8(+) T细胞耗竭状态与慢性HBV感染的不同临床结局相关。
