DC Metabolism · Metabolic Regulation of Conventional Dendritic Cell Development and Function

Metabolic Regulation of Conventional Dendritic Cell Development and Function

Dendritic cells (DCs) are key sentinel immune cells that alert the body to the presence of damage or infection, and arm T-lymphocytes to expand and eliminate aberrant or infected cells. Despite their importance in immunity, the mechanisms that govern their development and specific functions are not fully understood. Conventional DCs can be subdivided into type 1 (cDC1) and 2 (cDC2) subsets, which both descend from a common precursor under the shared influence of the growth factor cytokine Flt3L. The signals that differentiate cDC1 from cDC2 during development remain unknown. Apart from development, cDC1 and cDC2 also have specialized roles in immune responses. cDC1 are important for arming CD8+ T cells by processing and presenting proteins derived from cancer or infected cells through a process termed cross-presentation, whereas cDC2 help mediate immunity to parasites and extracellular bacteria. The importance of cDC1 in controlling immune responses against cancer is established by numerous studies demonstrating that a lack of cDC1 in mice impairs their rejection of tumours and responses to immune checkpoint blockade and adoptive T cell therapies. However, the precise mechanisms underlying the ability of cDC1 to cross-present are unclear. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only serve to provide energy and breakdown or produce nutrients for growth and survival, but also to instruct their development and function. For example, failure to engage specific metabolic pathways has been found to impair the development of memory T cells and the activation of macrophages, another type of sentinel immune cell. This project aims at delineating the role and importance of metabolic regulation in DC basic biology by answering two main questions: do distinct metabolic programs dictate cDC1 versus cDC2 specification, and what are the metabolic pathways or nutrients required for cDC1-dependent cross-presentation? Understanding the role metabolism plays in directing DC physiology will identify novel mechanisms of immune cell control with implications for antiviral and anticancer immunity. The conclusions of the action are thus far: the metabolic profiles of cDC1 and cDC2 were assessed and a specific isoform of hexokinase, a protein essential to the metabolism of sugar, was found to be expressed primarily by cDC1. Preliminary data using novel reagents suggests that this isoform may be critical to cDC1 differentiation and survival.

Data: CORDIS, © European Union