Cell intrinsic regulation of central carbon metabolism in effector T cells

代谢包括所有的化学过程，发生在一个活的有机体，维持生命。代谢途径的复杂网络对于产生能量和产生新的细胞成分以允许细胞分裂至关重要。 在快速分裂的免疫细胞中，如CD8+ T细胞，这是特别苛刻的。为了允许产生足够的能量和结构单元，CD8+ T细胞使用所谓的“瓦尔堡代谢”。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模块的生化途径。虽然这一通路的各个组成部分已经知道了近世纪，但我们仍然缺乏对T细胞中使用这一通路的精确调控的全面了解。CD8+ T细胞的功能通过效应分子的产生来测量。我们所理解的是，当糖不再被用于能量，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，我们发现葡萄糖的使用可以在CD8+细胞中迅速改变。当我们暂时将葡萄糖从这些细胞的环境中移除时，细胞中的变化支持葡萄糖在添加回来时的改变使用。我们发现，细胞不再使用葡萄糖进行瓦尔堡代谢，但功能增强。这突出表明，除了使用葡萄糖进行瓦尔堡代谢外，CD8+ T细胞还可以使用其他生物化学途径来支持效应分子的产生。这表明CD8+ T细胞有能力“选择”使用葡萄糖的用途，但实现这一目标的机制仍不完全清楚。由于改变的代谢途径组分的表达没有差异，我们提出这是通过改变参与不同代谢途径的酶的活性来实现的。 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计划，调查控制免疫细胞代谢的细胞内在调控信号，并绘制代谢途径酶活性的变化，这些酶改变了葡萄糖等代谢产物的使用。为了实现这一目标，我们将使用最先进的代谢组学和生物化学技术来测量代谢途径活性变化期间葡萄糖和其他代谢物的使用。最初的重点将是在葡萄糖用于能量生产与生物分子的产生之间的平衡，以支持CD8+ T细胞功能的细胞内信号传导途径的控制。这项研究为我们进一步了解细胞内在途径对代谢途径活性的调节，以控制代谢物的分配，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.