Factors That Determine the Antiviral Efficacy of HCV-Specific CD8+ T Cells Ex Vivo
Factors That Determine the Antiviral Efficacy of HCV-Specific CD8+ T Cells Ex Vivo
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DOI：
10.1053/j.gastro.2012.10.047
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发表时间：
2013-02-01
期刊：
影响因子：
29.4
通讯作者：
Thimme, Robert
中科院分区：
文献类型：
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作者：
Seigel, Bianca;Bengsch, Bertram;Thimme, Robert
背景与目的：功能失调的CD8(+) T细胞被认为有助于丙型肝炎病毒（HCV）逃避免疫应答的能力。大多数研究集中在hcv特异性CD8(+) T细胞的效应功能或其表面表达的抑制受体。目前还没有关于hcv特异性CD8(+) T细胞体外抑制病毒复制能力（抗病毒功效）的信息。方法：为了分析病毒特异性CD8(+) T细胞的体外抗病毒效果，我们使用了一种基于表达HLA-A*02并含有稳定复制的HCV报告复制子的细胞系的免疫模型。我们从18例HLA-A*02阳性的慢性HCV感染患者和15例已治愈的HCV感染患者（7例自发，8例治疗后）中分离出HCV特异性CD8(+) T细胞。用病毒特异性肽标记复制子细胞；在与病毒特异性CD8(+) T细胞共培养72小时后，通过测量荧光素酶活性来确定HCV复制的抑制作用。结果：来自慢性HCV感染患者的HCV特异性CD8(+) T细胞的抗病毒效果明显低于流感病毒、eb病毒和巨细胞病毒特异性CD8(+) T细胞。抗病毒效果与病毒特异性CD8(+) T细胞分泌干扰素γ的能力有关。hcv特异性CD8(+) T细胞的抗病毒效果与CD127和PD-1的表面表达有关。细胞因子白介素-2、白介素-7和白介素-15增加了cd127阳性、hcv特异性CD8(+) T细胞的抗病毒效果，但对cd127阴性的hcv特异性CD8(+) T细胞没有作用。自发而非抗病毒治疗诱导的病毒清除与抗病毒疗效的增加有关。结论：CD8(+) T细胞体外抑制HCV复制的能力与其分泌干扰素γ的能力及其表面CD127和PD-1的表达有关。
BACKGROUND & AIMS: Dysfunctional CD8(+) T cells are believed to contribute to the ability of hepatitis C virus (HCV) to evade the immune response. Most studies have focused on the effector functions of HCV-specific CD8(+) T cells or their surface expression of inhibitory receptors. There is currently no information available about the ex vivo ability of HCV-specific CD8(+) T cells to inhibit viral replication (antiviral efficacy). METHODS: To analyze the antiviral efficacy of virus-specific CD8(+) T cells ex vivo, we used an immunologic model based on a cell line that expresses HLA-A*02 and contains a stably replicating HCV reporter replicon. We isolated HCV-specific CD8(+) T cells from 18 HLA-A*02-positive patients with chronic HCV infection and 15 subjects with resolved HCV infection (7 spontaneous, 8 after therapy). Replicon cells were labeled with virus-specific peptides; inhibition of HCV replication was determined by measuring luciferase activity after 72 hours of coculture with virus-specific CD8(+) T cells. RESULTS: HCV-specific CD8(+) T cells from patients with chronic HCV infection had a significantly lower antiviral efficacy than influenza-, Epstein-Barr virus-, and cytomegalovirus-specific CD8(+) T cells. Antiviral efficacy was associated with the ability of virus-specific CD8(+) T cells to secrete interferon gamma. The antiviral efficacy of HCV-specific CD8(+) T cells was linked to surface expression of CD127 and PD-1. The cytokines interleukin-2, interleukin-7, and interleukin-15 increased the antiviral efficacy of CD127-positive but not of CD127-negative, HCV-specific CD8(+) T cells. Spontaneous, but not antiviral therapy-induced, viral clearance was associated with increased antiviral efficacy. CONCLUSIONS: The ability of CD8(+) T cells to inhibit HCV replication ex vivo is associated with their ability to secrete interferon gamma and their surface expression of CD127 and PD-1.