Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
复制标题
DOI：
10.1172/jci69589
复制
发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Gattinoni, Luca
中科院分区：
文献类型：
--
作者：
Sukumar, Madhusudhanan;Liu, Jie;Gattinoni, Luca
初始CD 8（+）T细胞依赖于脂肪酸的氧化作为主要的能量来源。在遇到抗原后，T细胞转变为糖酵解代谢以维持效应子功能。然而，目前还不清楚葡萄糖代谢的变化是否最终影响激活的能力。T细胞成为长寿的记忆细胞。我们使用荧光葡萄糖类似物2-NBDG来定量活化的CD 8（+）T细胞中的葡萄糖摄取。我们发现，与摄取大量葡萄糖的细胞相比，表现出有限葡萄糖掺入的细胞具有记忆前体细胞的分子特征，并且进入记忆池的能力增加。因此，通过过度表达糖酵解酶磷酸甘油酸酯β-1来加强糖酵解代谢，严重损害了CD 8（+）T细胞形成长期记忆的能力。相反，在糖酵解抑制剂2-脱氧葡萄糖存在的情况下，CD 8（+）T细胞的激活增强了记忆细胞的产生和抗肿瘤功能。我们的数据表明，增加糖酵解通量驱动CD 8（+）T细胞向终末分化状态，而其抑制则保留了长寿命记忆CD 8（+）T细胞的形成。这些结果对于提高基于T细胞的疗法对慢性感染性疾病和癌症的疗效具有重要意义。
Naive CD8(+) T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated. T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8(+) T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8(+) T cells to form long-term memory. Conversely, activation of CD8(+) T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8(+) T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8(+) T cells. These results have important implications for improving the efficacy of T cell-based therapies against chronic infectious diseases and cancer.