Is PFKFB4 a metabolic checkpoint controlling 1,25(OH)2D3-modulated dendritic cell (DC) tolerogenicity?

There is growing awareness of metabolic regulation of immune cell fate and function. While inflammatory cells like M1 macrophages and activated dendritic cells (DCs) mainly use glucose for ATP synthesis and survival, regulatory cells like M2 macrophages and regulatory T cells favour oxidative phosphorylation (OXHOS) to sustain functionality. Metabolites are thus important not just as energy sources, but also as actual signals defining the immune cell phenotype. How tolerogenic DCs (tolDCs) are generated and the mechanisms by which active vitamin D3, 1,25(OH)2D3, can modulate their differentiation, maturation, and function are key questions in DC biology. In this proposal, we want study the intricate interface between tolDC immunology and metabolism. We have strong arguments that 1,25(OH)2D3 reprograms the metabolism of differentiating monocytes during tolDC development and makes them depend on glycolysis rather than OXPHOS. We also identified in these cells several molecules of the glycolytic pathway that are strongly regulated by 1,25(OH)2D3. Among these molecules was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4). We will study whether PFKFB4 is crucial for the metabolic phenotype of 1,25(OH)2D3-modulated tolDCs and essential for DC tolerogenicity. A better understanding of the metabolic processes implicated in tolDC generation may accelerate clinical translation and will be key to developing new techniques that target metabolism for immunotherapy.