Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection
Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection
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DOI：
10.1128/jvi.00889-12
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
Wherry, E. John
中科院分区：
文献类型：
--
作者：
Angelosanto, Jill M.;Blackburn, Shawn D.;Wherry, E. John
在许多慢性病毒感染和癌症中，T细胞耗尽和记忆力丧失发生。我们研究了慢性病毒感染期间病毒特异性CD8 T细胞的何时失去形成记忆的潜力。如果从感染中去除，已建立的慢性感染的病毒特异性CD8 T细胞将无法成为记忆CD8 T细胞。但是，在慢性感染的早期阶段，这些病毒特异性的CD8 T细胞保留了转移到无感染小鼠后部分或完全恢复为记忆分化程序的潜力。相反，如果转移到慢性感染中，则在急性感染期间启动的效应CD8 T细胞不受疲劳的保护。我们还测试了记忆和耗尽的CD8 T细胞是否来自效应CD8 T细胞的不同亚群，发现只有KLRG1（LO）记忆前体子集为耗尽的CD8 T细胞而产生。总之，这些研究表明，CD8 T细胞耗尽是一个渐进的发育过程。在慢性感染期间的早期，病毒特异性CD8 T细胞的命运仍然是塑性的，而后来，精疲力竭的CD8 T细胞固定在其分化状态下。此外，耗尽的CD8 T细胞是由记忆前体产生的，而不是终端分化的效应CD8 T细胞的子集。这些研究对我们对衰老与精疲力尽的理解以及在慢性感染过程中的治疗干预具有影响。
T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection. However, at earlier stages of chronic infection, these virus-specific CD8 T cells retained the potential to partially or fully revert to a memory differentiation program after transfer to infection-free mice. Conversely, effector CD8 T cells primed during acute infection were not protected from exhaustion if transferred to a chronic infection. We also tested whether memory and exhausted CD8 T cells arose from different subpopulations of effector CD8 T cells and found that only the KLRG1(lo) memory precursor subset gave rise to exhausted CD8 T cells. Together, these studies demonstrate that CD8 T cell exhaustion is a progressive developmental process. Early during chronic infection, the fate of virus-specific CD8 T cells remains plastic, while later, exhausted CD8 T cells become fixed in their differentiation state. Moreover, exhausted CD8 T cells arise from the memory precursor and not the terminally differentiated subset of effector CD8 T cells. These studies have implications for our understanding of senescence versus exhaustion and for therapeutic interventions during chronic infection.