Celluar metabolism of Treg in the control of chronic inflammatory diseases

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Cellular metabolism is becoming an emerging field of investigation in Immunology. For instance, it has been recently shown that a switch from oxidative phosphorylation to aerobic glycolysis in conventional T cells is a prerequisite for their proper activation. CD4+Foxp3+ regulatory T cells (Tregs) play a major role in the control of autoimmune and chronic inflammatory diseases. Current knowledge concerning the cellular metabolic characteristics of Tregs is limited and published studies are controversial. In this project, we will study the role of glucose and lipid metabolism in Treg homeostasis and function. First, we will compare the metabolic features of resting versus effector Tregs, and of Tregs from lymphoid versus non-lymphoid tissues. We will also analyze the effect of different types of chronic inflammation (such as high fat diet, cancer, autoimmunity or chronic infection) on Treg metabolism in specific tissues. Together, these data will allow us to obtain an integrative view of the metabolic features of Treg subsets according to their origin, activation state, tissue localization and inflammatory environment. We hypothesize that Tregs modify their metabolism depending on external cues and environment, providing an explanation for the existing controversies in the literature. Furthermore, we will use novel and unique models of conditional knock-out mice for genes that control critical hubs of glucose and lipid metabolism, to better understand how different aspects of glucose and lipid metabolism specifically in Tregs affect their biology in different tissues and thus their capacity to control inflammation. We will evaluate the influence of critical metabolic checkpoints for the development of spontaneous autoimmunity and other chronic inflammatory processes. Finally, in the last part of the project, we will make use of our conditional knock-out mice to narrow down the mechanism of action of metformin, a drug widely used in type 2 diabetic patients to regulate cellular metabolism. Because the drug has also an immuno-regulatory effect, we will assess whether part of its therapeutic action is due to a direct effect on Tregs. All in all, this project should increase our basic knowledge on the metabolism of Tregs, its impact on Treg homeostasis and function depending on environmental cues and last but not least, improve our understanding of the pathophysiology of major chronic immune-mediated diseases that are controlled by Tregs.