Dissecting the role of fatty acid oxidation in dendritic cell function and regulation of immune responses.

Objective

Conventional dendritic cells (cDCs) are pivotal regulators of the immune system capable of tilting immune responses towards effective immunity or tolerance. Over the last 15 years, an increasing body of work has highlighted how changes in the metabolic state of immune cells influence their functions. It has been shown that melanomas can promote cDC tolerogenic functions by augmenting mitochondrial fatty acid oxidation (FAO) via the β-catenin signalling pathway. Intriguingly, recent unpublished results in the host group suggest that boosting oxidative phosphorylation, a metabolic process closely related to FAO, increases cDC immunogenicity. Therefore, further work is required to delineate the relationship between mitchondrial metabolic adpatations and cDC tolerogenic and immunogenic functions. This action aims to further dissect the interconnection between FAO and cDC functions across different tissues both in steady-state and disease. To this end, I will use novel murine lines that allow for the modulation of FAO in cDCs and will combine classical immunology and biochemial assays to characterise cDCs both functionally and metabolically. This interdisciplinary approach will help us understand the relationship between metabolism and function in cDCs and how this affects the initiation of immune responses across tissues.