Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection
Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection
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DOI：
10.1002/hep.20856
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发表时间：
2005-10-01
期刊：
影响因子：
13.5
通讯作者：
Thimme, R
中科院分区：
文献类型：
--
作者：
Spangenberg, HC;Viazov, S;Thimme, R
在持续感染期间，肝内丙型肝炎病毒（HCV）特异性CD 8（+）T细胞无法控制病毒的确切机制尚未完全确定。因此，我们研究了27例HILA-A2阳性患者的CD 8（+）T细胞应答，使用了4个以前定义明确的HI-A-A2限制性HCV表位。在一些患者中测定了相应的HCV序列，并与肝内HCV特异性CD 8（+）T细胞反应进行了比较。研究结果表明：（1）慢性HCV感染患者肝内存在HCV特异性CD 8 + T细胞，且与外周血中存在的应答明显重叠。(2)大部分肝内HCV特异性CD 8（+）T细胞分泌干扰素γ（IFN-γ）的能力受损。这种功能障碍对于HCV特异性CD 8（+）T细胞是特异性的，因为肝内流感特异性CD 8（+）T细胞容易分泌这种细胞因子。(3)在某些患者中可能发生了表位变体的T细胞选择。然而，这不是功能性病毒特异性CD 8 + T细胞应答的必然结果，因为几名产生IFN-γ的CD 8（+）T细胞应答的患者携带与原型序列相同或交叉反应的HCV序列。(4)尽管在疾病部位存在病毒特异性CD 4（+）T细胞，但肝内病毒特异性CD 8（+）T细胞无法充分控制病毒。总之，尽管肝内CD 8（+）T细胞在肝脏中持续存在和积累，但不同的机制导致肝内CD 8（+）T细胞无法消除HCV感染。
The precise mechanisms responsible for the failure of intrahepatic hepatitis C virus (HCV)specific CD8(+) T cells to control the virus during persistent infection have not been fully defined. We therefore studied the CD8(+) T-cell response in 27 HILA-A2-positive patients using four previously well-defined HI-A-A2-restricted HCV epitopes. The corresponding HCV sequences were determined in several patients and compared with the intrahepatic HCV-specific CD8(+) T-cell response. The results of the study indicate: (1) intrahepatic HCV-specific CD8+ T cells are present in the majority of patients with chronic HCV infection and overlap significantly with the response present in the peripheral blood. (2) A large fraction of intrahepatic HCV-specific CD8(+) T cells are impaired in their ability to secrete interferon gamma (IFN-gamma). This dysfunction is specific for HCV-specific CD8(+) T cells, since intrahepatic Flu-specific CD8(+) T cells readily secrete this cytokine. (3) T-cell selection of epitope variants may have occurred in some patients. However, it is not an inevitable consequence of a functional virus-specific CD8+ T-cell response, since several patients with IFN-gamma-producing CD8(+) T-cell responses harbored HCV sequences identical or cross-reactive with the prototype sequence. (4) The failure of intrahepatic virus-specific CD8(+) T cells to sufficiently control the virus occurs despite the presence of virus-specific CD4(+) T cells at the site of disease. In conclusion, different mechanisms contribute to the failure of intrahepatic CD8(+) T cells to eliminate HCV infection, despite their persistence and accumulation in the liver.