Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment
Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment
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DOI：
10.1128/jvi.77.8.4911-4927.2003
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发表时间：
2003-04-01
影响因子：
5.4
通讯作者：
Ahmed, R
中科院分区：
文献类型：
--
作者：
Wherry, EJ;Blattman, JN;Ahmed, R
由于病毒特异性T细胞的功能衰竭或物理缺失，慢性病毒感染经常导致无效的CD8 T细胞反应。然而，持续病毒如何影响各种CD8 t细胞效应功能，以及如何影响CD8 t细胞动力学的其他方面，如免疫优势和组织分布，在很大程度上仍然未知。使用不同的淋巴细胞性脉络丛脑膜炎病毒（LCMV）菌株，我们比较了急性或慢性感染期间对相同CD8 t细胞表位的反应。持续感染导致急性感染后CD8 T细胞反应的正常免疫优势等级被破坏，并显著改变lcmv特异性CD8 T细胞在淋巴组织和非淋巴组织中的组织分布。最重要的是，CD8 t细胞功能损伤在慢性感染小鼠中以分层方式发生。白细胞介素2的产生和体外裂解靶细胞的能力是第一个功能受损的，其次是产生肿瘤坏死因子α的能力，而γ干扰素的产生对功能衰竭的抵抗力最强。抗原似乎是这种功能丧失的驱动力，因为病毒载量和疲劳水平之间存在很强的相关性。此外，体内较高水平的表位导致物理缺失，而较低水平的表位则导致功能衰竭。提出了一种模型，其中抗原水平驱动慢性感染期间不同CD8 T细胞效应功能的分层丧失，导致不同阶段的功能损伤，并最终导致病毒特异性T细胞的物理缺失。这些结果对人类慢性感染的研究具有启示意义，在那里已经观察到类似的t细胞缺失和功能失调。
Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and non-lymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.