Zhou Shenghua, Ou Rong, Huang Lei, Moskophidis Demetrius
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
J Virol. 2002 Jan;76(2):829-40. doi: 10.1128/jvi.76.2.829-840.2002.
Viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (LCMV) can be achieved by selective down-regulation of virus-specific T lymphocytes. High viral burden in the onset of infection drives responding cells into functional unresponsiveness (anergy) that can be followed by their physical elimination. In this report, we studied down-regulation of the virus-specific CD8(+)-T-cell response during persistent infection of adult mice with LCMV, with emphasis on the role of perforin-, Fas/FasL-, or tumor necrosis factor receptor 1 (TNFR1)-mediated cytolysis in regulating T-cell homeostasis. The results reveal that the absence of perforin, Fas-ligand, or TNFR1 has no significant effect on the kinetics of proliferation and functional inactivation of virus-specific CD8(+) T cells in the onset of chronic LCMV infection. However, these molecules play a critical role in the homeostatic regulation of T cells, influencing the longevity of the virus-specific CD8(+)-T-cell population once it has become anergic. Thus, CD8(+) T cells specific to the dominant LCMV NP(396-404) epitope persist in an anergic state for at least 70 days in perforin-, FasL-, or TNFR1-deficient mice, but they were eliminated by day 30 in C57BL/6 controls. These effects were additive as shown by a deficit of apoptotic death of NP(396-404) peptide-specific CD8(+) T cells in mice lacking both perforin and TNFR1. This suggests a role for perforin-, FasL-, and TNFR1-mediated pathways in down-regulation of the antiviral T cell response during persistent viral infection by determining the fate of antigen-specific T cells. Moreover, virus-specific anergic CD8(+) T cells in persistently infected C57BL/6 mice contain higher levels of Bcl-2 and Bcl-XL than functionally intact T cells generated during acute LCMV infection. In the case of proapoptotic factors, Bax expression did not differ between T-cell populations and Bad was below the limit of detection in all samples. As expression of the Bcl-2 family members controls susceptibility to apoptosis, this finding may provide a molecular basis for the survival of anergic cells under conditions of prolonged antigen stimulation.
感染侵袭性淋巴细胞性脉络丛脑膜炎病毒（LCMV）后，病毒持续存在可通过选择性下调病毒特异性T淋巴细胞来实现。感染初期的高病毒载量会使反应性细胞进入功能性无反应状态（无反应性），随后这些细胞会被物理清除。在本报告中，我们研究了成年小鼠感染LCMV持续感染期间病毒特异性CD8(+) T细胞反应的下调情况，重点关注穿孔素、Fas/FasL或肿瘤坏死因子受体1（TNFR1）介导的细胞溶解在调节T细胞稳态中的作用。结果显示，在慢性LCMV感染初期，缺乏穿孔素、Fas配体或TNFR1对病毒特异性CD8(+) T细胞的增殖动力学和功能失活没有显著影响。然而，这些分子在T细胞的稳态调节中起关键作用，一旦病毒特异性CD8(+) T细胞群体进入无反应状态，它们会影响其寿命。因此，针对主要LCMV NP(396 - 404)表位的CD8(+) T细胞在穿孔素、FasL或TNFR1缺陷小鼠中以无反应状态持续存在至少70天，但在C57BL/6对照小鼠中到第30天就被清除。如在同时缺乏穿孔素和TNFR1的小鼠中，NP(396 - 404)肽特异性CD8(+) T细胞凋亡死亡不足所示，这些效应是累加的。这表明穿孔素、FasL和TNFR1介导的途径在持续病毒感染期间通过决定抗原特异性T细胞的命运来下调抗病毒T细胞反应中发挥作用。此外，在持续感染的C57BL/6小鼠中，病毒特异性无反应性CD8(+) T细胞比急性LCMV感染期间产生的功能完整T细胞含有更高水平的Bcl-2和Bcl-XL。就促凋亡因子而言，Bax表达在T细胞群体之间没有差异，并且在所有样本中Bad低于检测限。由于Bcl-2家族成员的表达控制对凋亡的敏感性，这一发现可能为无反应性细胞在长期抗原刺激条件下的存活提供分子基础。
