DENDRITIC CELLS · Identification and targeting of metabolic pathways in dendritic cells that regulate their immune polarizing function

Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling activation and polarization of effector T helper cells (Th) and regulatory T cell responses (Treg). Therefore, there is a major focus on developing approaches to manipulate DC function for immunotherapy. It is well known that changes in cellular activation are coupled to changes in cellular metabolism. However, only recently, based on studies with T cells and macrophages, the picture is emerging that manipulation of cellular metabolism can be used to shape immune responses. This field of immunometabolism is rapidly evolving as one of the new frontiers in science. Nonetheless, little is known about the metabolic processes that support DC activation or about the metabolic requirements for DCs to drive Th1, Th2 or Treg responses. My proposal aims to fill this gap and focuses on the novel concept that cellular metabolism regulates the immune-polarizing properties of DCs.Based on my recently published work and preliminary data, I hypothesize (1) that DCs priming Th1 responses are metabolically characterized by a switch to glycolytic metabolism, whereas Th2- or Treg-polarizing DCs, have a catabolic kind of metabolism that is dependent on mitochondrial fatty acid oxidation and oxidative phosphorylation and (2) that these states of metabolism are required for their immune-polarizing capacity.To address this, my project aims (a) to characterize and compare the metabolic profiles of Th1-, Th2- and Treg-polarizing DCs and (b) to determine whether their metabolic programs underpin their T cell-polarizing capacity. (c) Based on these findings I aim to determine whether deliberate modulation of glycolytic or mitochondrial metabolism can alter the immune-polarizing capacity of DCs in such a way that they become either more immunogenic or tolerogenic in vivo. These studies can readily contribute to the development of novel metabolism-based strategies for improving DC-based immunotherapy.