1 PhD project offered in the IPP winter call 2022
Our immune system works in an orchestrated manner to protect us against pathogens and foreign substances. Failure of this system leads to chronic infection, autoimmune diseases or cancer. In our group “Immunomodulation” at the Paul Klein Center for Immune intervention at the UMC, we investigate how immune cells can be influenced by changes in metabolism and how metabolic pathways can be targeted for therapeutic purposes. Additionally, we study how metabolism influences posttranslational modifications in immune cells and thus influences immune cell function. The focus of our work is the balance between regulatory T cells and inflammatory T cells and their activation by dendritic cells in different infection, cancer and autoimmune disease models. In this context, we have previously demonstrated that the development of Th17 cells depends on de novo fatty acid synthesis (FAS), and that this pathway has therapeutic potential in autoimmune diseases and GvHD. In addition, we showed that activation of the FAS pathway in T cells also has implications during infection, in which excessive protective immune responses can lead to unwanted tissue destruction. Recently, we published new studies on how fatty acid metabolism influences other immune cell subsets such as Tregs or dendritic cells.
PhD Project: Understanding the role of S-palmitoylation in DCs and other immune cells
S-palmitoylation is a metabolism-related protein post-translational modification (PTM) which dynamically modulates several aspects of protein biology. Owing to its unique reversible nature, palmitate attachment onto proteins primarily supports dynamic membrane targeting but also plays a pivotal role in protein stability, trafficking, and biological activity. Within the immune system, S-palmitoylation has been mainly studied in T cells where it is required for the assembling of immunological synapses and transduction of intracellular signals triggered by TCR engagement. In addition, several studies have elucidated the decisive role of S-palmitoylation in a broad array of host-pathogen interactions. However, no comprehensive studies concerning the implications of S-palmitoylation for dendritic cell (DC) function have been conducted so far. Therefore, the main goal of this research project is to unravel the role of S-palmitoylation in DC for immunity against pathogens and tumors. To this aim, we intend to use a range of methods from simple in vitro cultures to more complex in vivo experimental designs involving pathogens (bacterial and viral infection) or sterile inflammation (tumor) models. Hence, we will be able to have a global vision of DC reliance on S-palmitoylation for their interaction with other immune and non-immune cell types. Additionally, we will study the palmitoylome of primary DC upon activation. The composition of the palmitoylated proteome of putative palmitoyl acyltransferase (PAT) knock-out DC will also be dissected, thus allowing for the identification of druggable PAT-substrate pairs. Overall, this project aims to provide the first evidence of the impact of S-palmitoylation on DC activation and function and extend the results to other immune cells.
If you are interested in this project, please select Berod (S-palmitoylation) as your group preference in the IPP application platform.
Publications relevant to this project
Minarrieta L., Ghorbani P., Sparwasser T., and Berod L. (2017). Metabolites: deciphering the molecular language between DCs and their environment. Seminars in immunopathology 39, 177-198. PMID 27921148
Raud B, Roy DG, Divakaruni, AS, Tarasenko TN, Franke R, Ma EH, Samborska B, Hsieh, WY, Wong AH, Stuve P, Arnold-Schrauf C, Guderian M, Lochner M, Rampertaap S, Romito K, Monsale J, Bronstrup M, Bensinge, SJ, Murphy AN, McGuire PJ, Jones RG, Sparwasser T and Berod L (2018) Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab, 28:504-515.e7
Stuve P, Minarrieta L, Erdmann H, Arnold-Schrauf,C, Swallow M, Guderian M, Krull F, Holscher A, Ghorbani P, Behrends J, Abraham WR, Holscher C, Sparwasser T and Berod L (2018) De novo fatty acid synthesis during mycobacterial infection is a prerequisite for the function of highly proliferative T cells, but not for dendritic cells or macrophages. Front Immunol, 9:495
Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller, R, Lochner M and Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med, 20:1327-1333