Inaba M, Kurasawa K, Mamura M, Kumano K, Saito Y, Iwamoto I
Department of Internal Medicine II, Chiba University School of Medicine, Japan.
J Immunol. 1999 Aug 1;163(3):1315-20.
Memory T cells respond in several functionally different ways from naive T cells and thus function as efficient effector cells. In this study we showed that primed T cells were more resistant to Fas-mediated activation-induced cell death (AICD) than naive T cells using OVA-specific TCR transgenic DO10 mice and Fas-deficient DO10 lpr/lpr mice. We found that apoptosis was efficiently induced in activated naive T cells at 48 and 72 h after Ag restimulation (OVA peptide; 0.3 and 3 microM), whereas apoptosis was not significantly increased in activated primed T cells at 24-72 h after Ag restimulation. We further showed that the resistance to AICD in primed T cells was due to the decreased sensitivity to apoptosis induced by Fas-mediated signals, but TCR-mediated signaling equally activated both naive and primed T cells to induce Fas and Fas ligand expressions. Furthermore, we demonstrated that primed T cells expressed higher levels of Fas-associated death domain-like IL-1beta-converting enzyme inhibitory protein (FLIP), an inhibitor of Fas-mediated apoptosis, at 24-48 h after Ag restimulation than naive T cells. In addition, Bcl-2 expression was equally observed between activated naive and primed T cells after Ag restimulation. Thus, these results indicate that naive T cells are sensitive to Fas-mediated AICD and are easily deleted by Ag restimulation, while primed/memory T cells express higher levels of FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus function as efficient effector cells for a longer period.
记忆性T细胞的反应方式在功能上与初始T细胞不同，因此可作为高效的效应细胞发挥作用。在本研究中，我们使用卵清蛋白（OVA）特异性TCR转基因DO10小鼠和Fas缺陷型DO10 lpr/lpr小鼠，发现致敏T细胞比初始T细胞对Fas介导的活化诱导细胞死亡（AICD）更具抗性。我们发现，在抗原再刺激（OVA肽；0.3和3 microM）后48小时和72小时，活化的初始T细胞能有效诱导凋亡，而在抗原再刺激后24 - 72小时，活化的致敏T细胞凋亡并未显著增加。我们进一步表明，致敏T细胞对AICD的抗性是由于对Fas介导信号诱导的凋亡敏感性降低，但TCR介导的信号同样能激活初始T细胞和致敏T细胞，诱导Fas和Fas配体表达。此外，我们证明，在抗原再刺激后24 - 48小时，致敏T细胞比初始T细胞表达更高水平的Fas相关死亡结构域样白细胞介素-1β转换酶抑制蛋白（FLIP），它是Fas介导凋亡的抑制剂。另外，在抗原再刺激后，活化的初始T细胞和致敏T细胞中均能观察到同等水平的Bcl-2表达。因此，这些结果表明，初始T细胞对Fas介导的AICD敏感，容易因抗原再刺激而被清除，而致敏/记忆性T细胞在抗原再刺激后表达更高水平的FLIP，对Fas介导的AICD具有抗性，从而能在更长时间内作为高效的效应细胞发挥作用。
