Table_1_Naïve CD8+ T-Cells Engage a Versatile Metabolic Program Upon Activation in Humans and Differ Energetically From Memory CD8+ T-Cells.xlsx

Background: Characterization of the intracellular biochemical processes that regulate the generation and maintenance of effector and memory CD8+ T-cells from naïve precursors is essential for our understanding of adaptive immune responses and the development of immunotherapies. However, the metabolic determinants of antigen-driven activation and differentiation remain poorly defined, especially in humans.
Methods: We used a variety of different approaches, including gene expression profiling and measurements of nutrient flux, to characterize the basal and activation-induced energetic requirements of naïve and phenotypically-defined subsets of human memory CD8+ T-cells.
Findings: Profound metabolic differences were apparent as a function of differentiation status, both at rest and in response to stimulation via the T cell receptor (TCR). Of particular note, resting naïve CD8+ T cells were largely quiescent, but rapidly upregulated diverse energetic pathways after ligation of surface-expressed TCRs. Moreover, autophagy and the mechanistic target of rapamycin (mTOR)-dependent glycolytic pathway were identified as critical mediators of antigen-driven priming in the naïve CD8+ T cell pool, the efficiency of which was dampened by the presence of neutral lipids and fatty acids.
Interpretation: These observations provide a metabolic roadmap of the CD8+ T-cell compartment in humans and reveal potentially selective targets for novel immunotherapies.

背景：解析调控初始前体向效应性及记忆性CD8+ T细胞生成与维持的细胞内生化过程，对于阐明适应性免疫应答机制、开发免疫治疗手段均具有重要意义。然而，抗原驱动的活化与分化的代谢决定因素仍未得到充分阐释，尤其是在人类样本中。
方法：本研究采用多种实验策略，包括基因表达谱分析与营养通量检测，对人类初始CD8+ T细胞及表型定义的记忆性CD8+ T细胞亚群的基础代谢需求与活化诱导的能量需求开展了特征解析。
结果：无论静息状态还是经T细胞受体（T cell receptor, TCR）刺激后，代谢差异均随分化状态呈现显著差异。尤为值得关注的是，静息初始CD8+ T细胞整体处于静息状态，但在表面TCR交联结合后会快速上调多条能量代谢通路。此外，自噬与雷帕霉素靶蛋白（mTOR）依赖的糖酵解通路被证实是初始CD8+ T细胞群中抗原驱动初始活化的关键介导因子，其活化效率会因中性脂质与脂肪酸的存在而受到抑制。
解释：本研究结果揭示了人类CD8+ T细胞区室的代谢调控蓝图，并为新型免疫治疗手段提供了潜在的特异性靶点。