Cell intrinsic regulation of central carbon metabolism in effector T cells

层级摘要 新陈代谢是指在维持生命的生物体内发生的所有化学过程。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使细胞分裂至关重要。 在快速分裂的免疫细胞，如CD8+T细胞中，这一点尤其苛刻。为了产生足够的能量和积木，CD8+T细胞使用所谓的华宝新陈代谢。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基础的生化途径。尽管这一途径的各个组成部分已经知道了近一个世纪，但我们仍然缺乏对这一途径在T细胞中使用的精确调控的全面了解。CD8+T细胞的功能是通过产生效应分子来衡量的。我们所理解的是，当糖不再被用于能量，而是被用于其他途径来驱动构建块的生成时，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，我们发现在CD8+细胞中葡萄糖的使用可以迅速改变。当我们暂时将葡萄糖从这些细胞的环境中移除时，细胞中的变化支持了当葡萄糖重新加入时对其使用的改变。我们发现，细胞不再使用葡萄糖进行Warburg代谢，但表现出增强的功能。这突出表明，除了利用葡萄糖进行Warburg代谢外，CD8+T细胞还可以使用其他生化途径来支持效应器分子的产生。这表明CD8+T细胞有能力选择使用葡萄糖来做什么，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的组成部分在表达上没有差异，我们认为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计划，研究控制免疫细胞新陈代谢的细胞内在调节信号，并绘制改变葡萄糖等代谢物使用的代谢途径酶的活性变化图。为了实现这一点，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动变化期间葡萄糖和其他代谢物的使用。最初的重点是在细胞内信号通路的控制下，葡萄糖用于能量生产和生物分子的产生之间的平衡，以支持CD8+T细胞的功能。这项研究为我们进一步了解通过细胞内在途径来控制代谢产物的分配以确保细胞功能来调节代谢途径的活动奠定了基础。

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.