Cell intrinsic regulation of central carbon metabolism in effector T cells

新陈代谢包括维持生命的所有生物体内发生的化学过程。复杂的代谢途径网络对于能量的产生和新细胞成分的产生至关重要，从而使细胞能够分裂。在快速分裂的免疫细胞中，如CD8+ T细胞，这是特别需要的。为了产生足够的能量和构建块，CD8+ T细胞使用所谓的“Warburg代谢”。这是葡萄糖（糖）转化为产生能量的中间体或RNA、DNA、膜和其他细胞成分的构建块的生化途径。尽管这一途径的各个组成部分已经被发现了近一个世纪，但我们仍然缺乏对T细胞中使用这一途径的精确调控的全面理解。CD8+ T细胞的功能是通过产生效应分子来衡量的。我们所了解的是，当糖不再被用作能量，而是用于其他途径来驱动构建模块的生成时，这可能会对这些细胞的功能产生强烈的影响。在一项初步研究中，我们发现CD8+细胞中葡萄糖的使用可以迅速改变。当我们暂时从这些细胞的环境中去除葡萄糖时，当葡萄糖被添加回来时，细胞的变化支持了葡萄糖的改变使用。我们发现细胞不再使用葡萄糖进行Warburg代谢，但功能增强。这表明除了使用葡萄糖进行Warburg代谢外，CD8+ T细胞还可以使用其他生化途径来支持效应分子的产生。这表明CD8+ T细胞具有“选择”使用葡萄糖的能力，但实现这一目标的机制仍不完全清楚。由于被改变的代谢途径成分的表达没有差异，我们提出这是通过参与不同代谢途径的酶的活性改变来实现的。作为一名新的助理教授（2019年7月），我的长期目标是建立一个研究项目，研究控制免疫细胞代谢的细胞内在调节信号，并绘制代谢途径酶活性的变化，这些酶会改变葡萄糖等代谢物的使用。为了实现这一目标，我们将使用最先进的代谢组学和生化技术来测量代谢途径活性变化过程中葡萄糖和其他代谢物的使用。最初的重点将放在葡萄糖用于能量生产与在细胞内信号通路控制下支持CD8+ T细胞功能的生物分子生成之间的平衡。本研究为进一步了解细胞内在途径调控代谢途径活性，控制代谢物的分配，确保细胞功能奠定了基础。

Lay Summary Metabolism consists of all the chemical processes that occur within a living organism that maintain life. The complex network of metabolic pathways is crucial for the production of energy and the generation of new cellular components to allow cells to divide. In rapidly dividing immune cells, such as the CD8+ T cells this is especially demanding. To allow the generation of sufficient energy and building blocks, CD8+ T cells use so called `Warburg metabolism". This is the biochemical pathway by which glucose (sugar) is converted to intermediates that yield energy, or building blocks for RNA, DNA, membranes and other cellular components. Although the individual components of this pathway have been known for nearly a century, we still lack comprehensive understanding of the precise regulation of the use of this pathway in T cells. The function of CD8+ T cell is measured by the production of effector molecules. What we do understand is that when sugars are no longer being used for energy, but used for other pathways to drive the generation of building blocks as well, this can have a strong impact on the function of these cells. In a preliminary study, we showed that glucose use can be rapidly changed in CD8+ cells. When we temporarily removed glucose from the environment of these cells, changes in the cells supported altered use of glucose when it was added back. We showed that the cells no longer used glucose for Warburg metabolism but showed increased function. This highlights that beside the use of glucose for Warburg metabolism, CD8+ T cells can use other biochemical pathways to support the production of effector molecules. This suggests that CD8+ T cells have the ability to `choose' what to use glucose for, but the mechanism by which this is achieved remains incompletely understood. Since there was no difference in expression of the components of the metabolic pathways that were changed, we proposed that this was achieved by alterations in the activity of enzymes that participate in the different metabolic pathways.  As a new assistant professor (July 2019), my long-term goal is to establish a research program investigating cell-intrinsic regulatory signals that control metabolism in immune cells, and to map changes in the activity of metabolic pathway enzymes that alter the use of metabolites such as glucose. To achieve this, we will use state of the art metabolomic and biochemical techniques to measure the use of glucose and other metabolites during changes in activity of metabolic pathways. The initial focus will be on the balance between glucose use for energy production vs generation of biomolecules in support of CD8+ T cell function under control of intracellular signaling pathways. This research sets the stage to further our understanding of the regulation of metabolic pathway activity by cell intrinsic pathways to control the allocation of metabolites to ensure cellular function.