Cell intrinsic regulation of central carbon metabolism in effector T cells

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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.