Kurzfassung

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...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 will 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.» weiterlesen» einklappen