Molecular signature of CD8+ T cell exhaustion during chronic viral infection
Molecular signature of CD8+ T cell exhaustion during chronic viral infection
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DOI：
10.1016/j.immuni.2007.09.006
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发表时间：
2007-10-01
期刊：
影响因子：
32.4
通讯作者：
Ahmed, Rafi
中科院分区：
文献类型：
--
作者：
Wherry, E. John;Ha, Sang-Jun;Ahmed, Rafi
慢性病毒感染常常导致T细胞衰竭。为了确定衰竭的分子特征，我们比较了慢性感染的功能失调淋巴细胞脉络丛脑膜炎病毒（LCMV）特异性CD8(+) T细胞与急性感染后产生的功能性LCMV特异性效应细胞和记忆性CD8(+) T细胞的基因表达谱。这些数据表明，疲惫的CD8+ T细胞：(1)过度表达几种抑制性受体，包括PD-1； (2) T细胞受体和细胞因子信号通路发生重大变化；(3)参与趋化、粘附和迁移的基因表达发生改变；(4)表达一组不同的转录因子；(5)存在严重的代谢和生物能量不足。T细胞耗竭是渐进的，基因表达谱表明T细胞耗竭和能量是不同的过程。因此，功能衰竭可能是由于信号和代谢的主动抑制和被动缺陷。这些结果为设计合理的慢性感染免疫疗法提供了一个框架。
Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cells from chronic infection to functional LCMV-specific effector and memory CD8(+) T cells generated after acute infection. These data showed that exhausted CD8+ T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell exhaustion was progressive, and gene-expression profiling indicated that T cell exhaustion and anergy were distinct processes. Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections.