Metabolic Regulation of Conventional Dendritic Cell Development and Function

ended

Dendritic cells (DCs) play critical roles in directing innate and adaptive immune responses against infections and cancer. Understanding the mechanisms that control DC development and function may reveal new ways to alter the course of complex human diseases such as cancer. Despite their importance in immunity, some open questions remain in regards to DC basic biology. Two of these questions, in particular, are the subject of this application: 1) DCs are a heterogenous population, which can be subdivided into conventional DC type 1 (cDC1) and 2 (cDC2) subsets. Although their development depends on distinct transcriptional programs, cDC1 and cDC2 descend from a common precursor under the influence of the same growth factor cytokine. What determines cDC1/2 differentiation? 2) Various loss-of-function studies demonstrate that cDC1 are key antigen-presenting cells for initiating CD8+ T cell responses to tumours and some viruses. This primarily relies on a process termed cross-presentation. How is cross-presentation regulated in cDC1? Recent studies indicate that profound changes in cellular metabolism are coupled to immune cell function and may fundamentally underpin cell-fate decisions. Based on previous observations and our own preliminary data, we hypothesise that glycolysis programs cDC1 development and activation, whereas fatty acid metabolism controls the ability of the same cells to cross-present antigens to CD8+ T cells. We propose to define the metabolic programs that drive DC formation and that underlie cDC1 and cDC2 identity and complement this approach with loss and gain-of-function experiments that will allow specific testing of our hypotheses. Globally, these studies will identify novel mechanisms of immune cell control with implications for antiviral and anticancer immunity.