National Research Council of Canada, Institute for Biological Sciences, Ottawa, Ontario K1A 0R6, Canada.
J Immunol. 2013 Feb 1;190(3):1066-75. doi: 10.4049/jimmunol.1200639. Epub 2012 Dec 31.
CD8(+) T cells undergo rapid expansion during infection with intracellular pathogens, which is followed by swift and massive culling of primed CD8(+) T cells. The mechanisms that govern the massive contraction and maintenance of primed CD8(+) T cells are not clear. We show in this study that the transcription factor, FoxO3a, does not influence Ag presentation and the consequent expansion of CD8(+) T cell response during Listeria monocytogenes infection, but plays a key role in the maintenance of memory CD8(+) T cells. The effector function of primed CD8(+) T cells as revealed by cytokine secretion and CD107a degranulation was not influenced by inactivation of FoxO3a. Interestingly, FoxO3a-deficient CD8(+) T cells displayed reduced expression of proapoptotic molecules BIM and PUMA during the various phases of response, and underwent reduced apoptosis in comparison with wild-type cells. A higher number of memory precursor effector cells and memory subsets was detectable in FoxO3a-deficient mice compared with wild-type mice. Furthermore, FoxO3a-deficient memory CD8(+) T cells upon transfer into normal or RAG1-deficient mice displayed enhanced survival. These results suggest that FoxO3a acts in a cell-intrinsic manner to regulate the survival of primed CD8(+) T cells.
CD8(+) T 细胞在感染细胞内病原体时会经历快速扩增，随后是被激活的 CD8(+) T 细胞的迅速大量清除。调控被激活的 CD8(+) T 细胞大量收缩和维持的机制尚不清楚。在本研究中我们表明，转录因子 FoxO3a 并不影响抗原呈递以及李斯特菌感染过程中 CD8(+) T 细胞反应的随后扩增，但在记忆 CD8(+) T 细胞的维持中发挥关键作用。细胞因子分泌和 CD107a 脱颗粒所揭示的被激活的 CD8(+) T 细胞的效应功能不受 FoxO3a 失活的影响。有趣的是，与野生型细胞相比，FoxO3a 缺陷型 CD8(+) T 细胞在反应的各个阶段表现出较低水平的促凋亡分子 BIM 和 PUMA 的表达，并发生较低水平的细胞凋亡。与野生型小鼠相比，FoxO3a 缺陷型小鼠中可检测到更多的记忆前体细胞效应细胞和记忆细胞亚群。此外，FoxO3a 缺陷型记忆 CD8(+) T 细胞在转移到正常或 Rag1 缺陷型小鼠中时表现出增强的存活。这些结果表明，FoxO3a 以细胞内在的方式作用于调控被激活的 CD8(+) T 细胞的存活。
