Allam Atef, Conze Dietrich B, Giardino Torchia Maria Letizia, Munitic Ivana, Yagita Hideo, Sowell Ryan T, Marzo Amanda L, Ashwell Jonathan D
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Blood. 2009 Sep 3;114(10):2121-30. doi: 10.1182/blood-2009-05-220087. Epub 2009 Jul 17.
The ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G(1) to the G(0) cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-gamma production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase-dependent manner. Consistent with these results, maintenance of G(1) in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance.
适应性免疫系统在重复接触抗原时快速且有力地做出反应的能力被称为免疫记忆，并且人们认为记忆性T细胞功能的获得是一个不可逆的分化事件。在本研究中，我们报告称，当抗原特异性CD8记忆性T细胞被剥夺与树突状细胞的接触时，它们的许多表型和功能特征会丧失。在这些情况下，记忆性T细胞从G(1)期恢复到G(0)期细胞周期状态，并像初始T细胞一样对刺激做出反应，这通过增殖、对共刺激的依赖性以及干扰素-γ的产生来评估，同时不会丢失与记忆相关的细胞表面标志物。记忆状态通过肿瘤坏死因子受体超家族成员CD27和4-1BB的信号传导得以维持。Foxo1是一种参与T细胞静止的转录因子，在记忆性细胞中减少，并且通过CD27刺激初始CD8细胞会导致Foxo1磷酸化并以磷脂酰肌醇-3激酶依赖的方式从细胞核中移出。与这些结果一致，在水疱性口炎病毒感染的CD27缺陷小鼠中，抗原特异性记忆性T细胞在体内维持G(1)期的能力受损。因此，维持T记忆性细胞的功能表型需要活跃的信号传导和维持。
