Immune Cell Metabolism & Cell Fate Decisions

1 PhD project offered in the IPP winter call 2022

Scientific Background

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: Role of short-chain fatty acids and Ffar2 in DC metabolism and function

The interplay among dietary metabolites, the gut commensal microbiota, and the immune system is intimate and complex. Dietary intake of soluble fiber leads to their fermentation by commensal bacteria to short-chain fatty acids (SCFAs) in the gut. SCFAs have multiple effects on the colonic epithelium and are known to be an important energy source. Additionally, SCFAs can promote the differentiation of colonic Treg cells. However, how exactly SCFAs affect the function of other immune cells has yet to be elucidated. SCFAs can act as histone deacetylase inhibitors or bind and signal through G-protein-coupled receptors (GPCRs), such as the Free Fatty Acid Receptor 2 (Ffar2/Gpr43). Yet, due to the lack of appropriate models, the cell-type specific effects of Ffar2 have not been investigated. Thus, the aim of this project is to evaluate the specific contribution of SCFAs on the balance of tolerance versus immunity, particularly focusing on Dendritic cells (DCs). For this, we will use the novel Ffar2 conditional knockout mice to unveil the in vivo effect of SCFAs and discover new potential therapeutic targets.

If you are interested in this project, please select Berod (Ffar2) 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

 

Contact

Univ.-Prof. Dr Luciana Berod
University Medical Centre Mainz
Institute for Molecular Medicine
Email
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