Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2012;7(3):e32576. doi: 10.1371/journal.pone.0032576. Epub 2012 Mar 2.
No unique transcription factor or biomarker has been identified to reliably distinguish effector from memory T cells. Instead a set of surface markers including IL-7Rα and KLRG1 is commonly used to predict the potential of CD8 effector T cells to differentiate into memory cells. Similarly, these surface markers together with the tumor necrosis factor family member CD27 are frequently used to predict a memory T cell's ability to mount a recall response. Expression of these markers changes every time a memory cell is stimulated and repeated stimulation can lead to T cell senescence and loss of memory T cell responsiveness. This is a concern for prime-boost vaccine strategies which repeatedly stimulate T cells with the aim of increasing memory T cell frequency. The molecular cues that cause senescence are still unknown, but cell division history is likely to play a major role. We sought to dissect the roles of inflammation and cell division history in developing T cell senescence and their impact on the expression pattern of commonly used markers of senescence. We developed a system that allows priming of CD8 T cells with minimal inflammation and without acquisition of maximal effector function, such as granzyme expression, but a cell division history similar to priming with systemic inflammation. Memory cells derived from minimal effector T cells are fully functional upon rechallenge, have full access to non-lymphoid tissue and appear to be less senescent by phenotype upon rechallenge. However, we report here that these currently used biomarkers to measure senescence do not predict proliferative potential or protective ability, but merely reflect initial priming conditions.
尚未发现独特的转录因子或生物标志物，能够可靠地区分效应 T 细胞和记忆 T 细胞。相反，一组表面标志物，包括 IL-7Rα 和 KLRG1，通常用于预测 CD8 效应 T 细胞分化为记忆细胞的潜力。同样，这些表面标志物与肿瘤坏死因子家族成员 CD27 一起，常用于预测记忆 T 细胞引发回忆反应的能力。这些标志物的表达每次记忆细胞受到刺激都会发生变化，反复刺激会导致 T 细胞衰老和记忆 T 细胞反应性丧失。这是一个主要关注的问题，因为引发疫苗策略会反复刺激 T 细胞，目的是增加记忆 T 细胞的频率。导致衰老的分子线索尚不清楚，但细胞分裂史可能起主要作用。我们试图剖析炎症和细胞分裂史在发展 T 细胞衰老中的作用，以及它们对常用衰老标志物表达模式的影响。我们开发了一种系统，允许在最小炎症和不获得最大效应功能（如颗粒酶表达）的情况下对 CD8 T 细胞进行初始激活，但具有与全身性炎症初始激活相似的细胞分裂史。从最小效应 T 细胞衍生的记忆细胞在再次受到挑战时完全发挥功能，完全可以进入非淋巴组织，并且在再次受到挑战时表型上似乎衰老程度较低。然而，我们在这里报告称，这些目前用于测量衰老的生物标志物不能预测增殖潜力或保护能力，而仅仅反映初始初始激活条件。
