Pronounced virus-dependent activation drives exhaustion but sustains IFN-γ transcript levels.
Pronounced virus-dependent activation drives exhaustion but sustains IFN-γ transcript levels.
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DOI：
10.4049/jimmunol.1000841
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发表时间：
2010-09-15
期刊：
影响因子：
--
通讯作者：
Zajac AJ
中科院分区：
文献类型：
--
作者：
Mackerness KJ;Cox MA;Lilly LM;Weaver CT;Harrington LE;Zajac AJ
在许多慢性感染期间，响应性 CD8 T 细胞会逐渐丧失发挥关键效应功能的能力，从而变得精疲力尽。与原型记忆 CD8 细胞在激活后迅速合成 IFN-γ 不同，严重耗竭的 T 细胞无法产生这种效应分子。然而，耗竭的 CD8 T 细胞的个体发育以及导致其功能失活的潜在机制仍然不明确。我们利用细胞因子报告小鼠（通过 Thy1.1 的表达来标记 IFN-γ mRNA 的转录）来破译慢性感染早期阶段的激活事件如何决定衰竭的发展。我们发现，病毒特异性 CD8 T 细胞在慢性淋巴细胞脉络膜脑膜炎病毒 (LCMV) 感染的早期阶段有明显的反应，并且这种早期 T 细胞反应比最初在急性感染宿主中观察到的反应更明显。因此，耗尽的 CD8 T 细胞似乎是从有效激活的前体细胞群中出现的。与导致响应性 T 细胞大量扩增的急性感染不同，慢性感染期间进一步扩增会迅速减弱。随后在慢性感染宿主体内出现的耗尽的 T 细胞无法产生 IFN-γ 蛋白。令人惊讶的是，高水平的 IFN-γ 转录物仍然存在于耗尽的细胞中，这表明耗尽的细胞产生的 IFN-γ 的消除并不是由于转录沉默。因此，转录后调控机制可能会禁用该效应器模块。
During many chronic infections the responding CD8 T cells become exhausted as they progressively lose their ability to elaborate key effector functions. Unlike prototypic memory CD8 cells, which rapidly synthesize IFN-γ following activation, severely exhausted T cells fail to produce this effector molecule. Nevertheless, the ontogeny of exhausted CD8 T cells as well as the underlying mechanisms that account for their functional inactivation remains ill-defined. We have utilized cytokine reporter mice, which mark the transcription of IFN-γ mRNA by the expression of Thy1.1, to decipher how activation events during the early stages of a chronic infection dictate the development of exhaustion. We show that virus-specific CD8 T cells clearly respond during the early stages of chronic lymphocytic choriomeningitis virus (LCMV) infection, and that this early T cell response is more pronounced than that initially observed in acutely infected hosts. Thus, exhausted CD8 T cells appear to emerge from populations of potently activated precursors. Unlike acute infections, which result in massive expansion of the responding T cells, there is a rapid attenuation of further expansion during chronic infections. The exhausted T cells that subsequently emerge in chronically infected hosts are incapable of producing the IFN-γ protein. Surprisingly, high levels of the IFN-γ transcript are still present in exhausted cells, demonstrating that ablation of IFN-γ production by exhausted cells is not due to transcriptional silencing. Thus, post-transcription regulatory mechanisms likely disable this effector module.
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