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Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2018-01-02 , DOI: 10.1084/jem.20161066
Mark Y. Jeng 1, 2 , Philip A. Hull 1, 3 , Mingjian Fei 1, 2 , Hye-Sook Kwon 1, 2 , Chia-Lin Tsou 1 , Herb Kasler 1, 4 , Che-Ping Ng 1, 4 , David E. Gordon 1, 5 , Jeffrey Johnson 1, 5 , Nevan Krogan 1, 5 , Eric Verdin 1, 4 , Melanie Ott 1, 2
Affiliation  

The expansion of CD8+CD28 T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28 T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28 T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28 T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28 T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28 T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.



中文翻译:

通过丢失SIRT1对人CD8 +记忆T细胞进行代谢重编程

CD8 + CD28 - T细胞(一种最终分化的记忆T细胞)的扩增是人类衰老过程中最一致的免疫学变化之一。CD8 + CD28 T细胞具有高度细胞毒性,其频率与许多与年龄有关的疾病有关。由于它们没有在小鼠体内积累,因此调节其命运和功能的许多分子机制仍不清楚。在本文中,我们发现人CD8 + CD28 - T细胞在静止条件下具有增强的糖酵解能力,这种功能与NAD +的表达降低有关。依赖性蛋白脱乙酰基酶SIRT1。全球基因表达谱鉴定为转录因子FoxO1为SIRT1靶标,参与CD8 + CD28 T细胞的转录重编程。FoxO1的是proteasomally降解在SIRT1缺陷型CD8 + CD28 - T细胞,并在休息CD8抑制其活性+ CD28 +增强糖酵解能力和粒酶B的生产如在CD8 T细胞+ CD28 - T细胞。这些数据确定了进化上保守的SIRT1-FoxO1轴是调节人体内CD8 +记忆T细胞代谢和活性的调节剂。

更新日期:2018-01-02
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