Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection
Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection
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DOI：
10.1128/jvi.01075-08
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发表时间：
2008-10-01
影响因子：
5.4
通讯作者：
Grakoui, Arash
中科院分区：
文献类型：
--
作者：
Radziewicz, Henry;Ibegbu, Chris C.;Grakoui, Arash
大多数感染丙型肝炎病毒（HCV）的患者不能维持有效的T细胞应答，病毒血症持续存在。导致慢性感染患者HCV特异性CD 8（+）T细胞应答失败的机制尚不清楚。我们研究了HCV感染急性和慢性阶段特异性CD 8（+）T细胞的凋亡易感性。尽管在感染的急性期血液中和慢性期肝脏中的HCV特异性CD 8（+）T细胞高度活化并表达效应表型，但大多数正在经历凋亡。相反，慢性期外周血HCV特异性CD 8（+）T细胞表达静息记忆表型。HCV特异性CD 8（+）T细胞的凋亡易感性与非常高水平的程序性死亡-1（PD-1）和低水平的CD 127表达以及显著的功能性T细胞缺陷相关。对急性HCV感染期间HCV特异性CD 8（+）T细胞的“死亡期”的进一步评估表明，大多数细胞通过激活的caspase 9介导的细胞因子撤退过程死亡。尽管病毒持续存在，但急性期的收缩通过这一过程迅速发生。值得注意的是，在丙型肝炎病毒感染的慢性期，在肝脏感染部位，也存在大量由半胱天冬酶9介导的T细胞死亡。这项研究强调了细胞因子缺乏介导的细胞凋亡的重要性，从而下调了急性和慢性感染期间对HCV的免疫反应。
A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8(+) T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8(+) T cells during the acute and chronic stages of infection. Although HCV-specific CD8(+) T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8(+) T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8(+) T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCV-specific CD8(+) T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.