Quiescence and functional reprogranuning of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection
Quiescence and functional reprogranuning of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection
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DOI：
10.1182/blood-2004-11-4469
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发表时间：
2005-07-15
期刊：
影响因子：
20.3
通讯作者：
Akbar, AN
中科院分区：
文献类型：
--
作者：
Dunne, PJ;Belaramani, L;Akbar, AN
EB病毒（Epstein-Barr virus，EBV）特异性记忆性CD 8（+）T细胞在急性感染后退出细胞周期，其中一部分经历抗原的细胞重新表达CD 45 RA（CD 45主要表达外显子A）。然而，所涉及的信号是未知的。我们研究了白细胞介素15（IL-15）和干扰素-α/β（IFN-I）在这些过程中的作用，因为这些介质在维持CD 8（+）T细胞记忆中具有关键但不确定的作用。我们发现IFN-1（而不是IL-15）允许活化的EBV特异性CD 8（+）T细胞离开细胞周期而不进入凋亡。这与细胞周期蛋白抑制剂p27的上调有关，但与CD 45 RA无关。相反，IL-15（而不是IFN-I）诱导的“稳态”增殖和CD 45 RA再表达这些细胞在体外。因此，不同的信号在活化的EBV特异性CD 8（+）T细胞中诱导静止和CD 45 RA再表达。在T细胞受体（TCR）活化后，新鲜分离的CD 45 RA（+）抗原经历的CD 8（+）T细胞显示出较差的增殖活性，但具有高度细胞毒性并有效地分泌IFN-γ。这表明功能重编程朝向效应子功能，但远离增殖。静止期的诱导和再表达CD 45 RA的增殖非依赖性效应CD 8（+）T细胞的产生可能会使病毒特异性群体中复制性衰老的影响最小化，否则这些影响将在数十年的持续感染中发生。
After acute infection Epstein-Barr virus (EBV)-specific memory CD8(+) T cells exit cell cycle, and a proportion of these antigen-experienced cells reexpress CD45RA (CD45 which predominantly express exon A). However, the signals involved are not known. We investigated the roles of interleukin 15 (IL-15) and interferon-alpha/beta (IFN-I) in these processes, since these mediators have a crucial but undefined role in the maintenance of CD8(+) T-cell memory. We show that IFN-I (but not IL-15) allows activated EBV-specific CD8(+) T cells to leave cell cycle without entering apoptosis. This was associated with up-regulation of the cyclin inhibitor p27, but not of CD45RA. In contrast, IL-15 (but not IFN-I) induced "homeostatic" proliferation and CD45RA reexpression by these cells in vitro. Different signals, therefore, induce quiescence and CD45RA reexpression in activated EBV-specific CD8(+) T cells. After T-cell receptor (TCR) activation freshly isolated CD45RA(+) antigen-experienced CD8(+) T cells show poor proliferative activity but are highly cytotoxic and secrete IFN-gamma efficiently. This suggests functional reprogramming toward effector function but away from proliferation. The induction of quiescence and the generation of proliferation-independent effector CD8(+) T cells that reexpress CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection.