Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion.
Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion.
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DOI：
10.4049/jimmunol.0800997
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发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Katsikis PD
中科院分区：
文献类型：
--
作者：
Bucks CM;Norton JA;Boesteanu AC;Mueller YM;Katsikis PD
CD8+ T细胞对慢性感染应答的失败被称为“衰竭”，并描述了其中CD8+ T细胞表现出降低的分化、增殖和效应子功能的状况。在慢性感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）的鼠模型中已经广泛研究了CD8+ T细胞耗竭。虽然基于LCMV的研究已经产生了许多有趣的发现，但它们并没有考虑到细胞因子和Ag驱动的衰竭之间的作用。我们已经创建了一个系统的慢性Ag刺激使用鼠流感A病毒，导致耗竭和病毒特异性的CD8+ T细胞的功能障碍，在没有高病毒滴度，持续的促炎细胞因子的产生和淋巴细胞感染。我们的研究结果表明，单独的Ag足以驱动CD8+ T细胞损伤，Ag驱动的病毒特异性CD8+ T细胞的损失是TRAIL介导的，并且Ag的去除逆转衰竭。虽然程序性死亡1在慢性Ag刺激的CD8+ T细胞上上调，但它在耗竭中没有作用。这些发现为慢性感染中控制CD8+ T细胞功能衰竭的机制提供了新的见解。
The failure of CD8+ T cells to respond to chronic infection has been termed “exhaustion” and describes the condition in which CD8+ T cells exhibit reduced differentiation, proliferation, and effector function. CD8+ T cell exhaustion has been extensively studied in the murine model of chronic infection, lymphocytic choriomeningitis virus (LCMV). Although LCMV-based studies have yielded many interesting findings, they have not allowed for discrimination between the roles of cytokine- and Ag-driven exhaustion. We have created a system of chronic Ag stimulation using murine influenza A virus that leads to exhaustion and functional disability of virus-specific CD8+ T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection. Our findings show that Ag alone is sufficient to drive CD8+ T cell impairment, that Ag-driven loss of virus-specific CD8+ T cells is TRAIL mediated, and that removal of Ag reverses exhaustion. Although programmed death 1 was up-regulated on chronic Ag-stimulated CD8+ T cells, it played no role in the exhaustion. These findings provide a novel insight into the mechanisms that control functional exhaustion of CD8+ T cells in chronic infection.
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