Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells.
Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells.
复制标题
DOI：
10.1371/journal.pone.0020107
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
He S;Kato K;Jiang J;Wahl DR;Mineishi S;Fisher EM;Murasko DM;Glick GD;Zhang Y
细胞代谢在调节T细胞应答以及具有长期保护作用的记忆T细胞的发育过程中起着关键作用。然而，负责产生长寿命记忆细胞的抗原激活T细胞的代谢表型尚未被明确。
利用来自T细胞受体转基因小鼠的淋巴细胞性脉络丛脑膜炎病毒（LCMV）肽gp33特异性CD8 + T细胞，我们对在有或无雷帕霉素存在的情况下体外激活和扩增的增殖T细胞的代谢表型进行了表征，并确定了这些经雷帕霉素处理的T细胞在体内产生长寿命记忆细胞的能力。
在体内，经雷帕霉素处理的抗原激活的CD8 + T细胞产生的长寿命记忆T细胞比未经处理的对照T细胞多5倍。与对照T细胞仅增加糖酵解不同，经雷帕霉素处理的T细胞同时上调了糖酵解和氧化磷酸化（OXPHOS）。这些经雷帕霉素处理的T细胞比对照T细胞在缺乏葡萄糖或生长因子的情况下具有更强的生存能力。寡霉素对氧化磷酸化的抑制显著降低了经雷帕霉素处理的T细胞在缺乏生长因子时的生存能力。这种氧化磷酸化抑制作用伴随着线粒体超极化以及活性氧物质的升高，而活性氧物质已知对细胞有毒性。
我们的研究结果表明，这些经雷帕霉素处理的T细胞可能代表一种独特的细胞模型，用于识别对调节效应T细胞和记忆T细胞代谢至关重要的营养物质和信号，以及开发提高过继性T细胞癌症治疗效果的新方法。
Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized. Using lymphocytic choriomeningitis virus (LCMV) peptide gp33-specific CD8+ T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo. Antigen-activated CD8+ T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS). These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells. Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy.
登录
查看更多内容
DOI：
10.1084/jem.20042020
发表时间：
2005-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.3
作者：
Jung, Unsu;Foley, Jason E.;Fowler, Daniel H.
通讯作者：
Fowler, Daniel H.
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen C;Liu Y;Liu R;Ikenoue T;Guan KL;Liu Y;Zheng P
通讯作者：
Zheng P
影响因子：
64.8
作者：
Araki, Koichi;Turner, Alexandra P.;Shaffer, Virginia Oliva;Gangappa, Shivaprakash;Keller, Susanne A.;Bachmann, Martin F.;Larsen, Christian P.;Ahmed, Rafi
通讯作者：
Ahmed, Rafi