Dicer Regulates the Balance of Short-Lived Effector and Long-Lived Memory CD8 T Cell Lineages.
Dicer Regulates the Balance of Short-Lived Effector and Long-Lived Memory CD8 T Cell Lineages.
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DOI：
10.1371/journal.pone.0162674
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kalia V
中科院分区：
文献类型：
--
作者：
Baumann FM;Yuzefpolskiy Y;Sarkar S;Kalia V
MicroRNAs是控制蛋白质表达的主要转录后机制，并在T细胞发育和功能过程中成为关键的调节因子。最近报道了CD8 T细胞活化和效应分化的增强，以及naïve细胞中Dicer/miRNAs消融后的异常迁移特性，这些都证实了miRNAs在启动过程中的调节作用。在CD8 T细胞扩增和记忆分化的后期阶段，mirna是否继续发挥类似的功能或是否可缺性尚不清楚。在这里，我们报道了Dicer/ mirna在启动后阶段调节长寿命记忆和短寿命末端效应命运平衡中的关键作用，当CD8 T细胞经历克隆扩增以产生大型细胞毒性T淋巴细胞（CTL）池并随后分化为静止记忆状态时。使用独特的dicerfl/fl gzmb-cre小鼠，在颗粒酶B的最佳激活和表达后，对早期效应CD8 T细胞中的Dicer/miRNAs进行条件消融，导致在相同感染环境下，相对于野生型抗原特异性细胞，峰值效应大小显着减小。dicer消融的CD8 T细胞扩增减少与缺乏持续的抗原驱动增殖和短寿命效应细胞积累减少有关。此外，dicer消融的CD8 T细胞在病原体清除后表现出更明显的收缩，并且在记忆池中所占的比例显着降低，尽管在效应峰时CD127Hi记忆前体的比例显着提高。结合之前的报道，当CD8 T细胞从naïve分化到效应和记忆状态时，miRNA表达的动态变化，这些发现支持了miRNA依赖基因调控在CD8 T细胞分化过程中的不同阶段特异性作用。
MicroRNAs constitute a major post-transcriptional mechanism for controlling protein expression, and are emerging as key regulators during T cell development and function. Recent reports of augmented CD8 T cell activation and effector differentiation, and aberrant migratory properties upon ablation of Dicer/miRNAs in naïve cells have established a regulatory role of miRNAs during priming. Whether miRNAs continue to exert similar functions or are dispensable during later stages of CD8 T cell expansion and memory differentiation remains unclear. Here, we report a critical role of Dicer/miRNAs in regulating the balance of long-lived memory and short-lived terminal effector fates during the post-priming stages when CD8 T cells undergo clonal expansion to generate a large cytotoxic T lymphocyte (CTL) pool and subsequently differentiate into a quiescent memory state. Conditional ablation of Dicer/miRNAs in early effector CD8 T cells following optimal activation and expression of granzyme B, using unique dicerfl/fl gzmb-cre mice, led to a strikingly diminished peak effector size relative to wild-type antigen-specific cells in the same infectious milieu. Diminished expansion of Dicer-ablated CD8 T cells was associated with lack of sustained antigen-driven proliferation and reduced accumulation of short-lived effector cells. Additionally, Dicer-ablated CD8 T cells exhibited more pronounced contraction after pathogen clearance and comprised a significantly smaller proportion of the memory pool, despite significantly higher proportions of CD127Hi memory precursors at the effector peak. Combined with previous reports of dynamic changes in miRNA expression as CD8 T cells differentiate from naïve to effector and memory states, these findings support distinct stage-specific roles of miRNA-dependent gene regulation during CD8 T cell differentiation.
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