Shaping of Dendritic Cell Function by the Metabolic Micro-Environment

Abstract

Nutrients are required for growth and survival of all cells, but are also crucially involved in cell fate determination of many cell types, including immune cells. There is a growing appreciation that the metabolic micro-environment also plays a major role in shaping the functional properties of dendritic cells (DCs). Under pathological conditions nutrient availability can range from a very restricted supply, such as seen in a tumor micro-environment, to an overabundance of nutrients found in for example obese adipose tissue. In this review we will discuss what is currently known about the metabolic requirements for DC differentiation and immunogenicity and compare that to how function and fate of DCs under pathological conditions can be affected by alterations in environmental levels of carbohydrates, lipids and amino acids as well as by other metabolic cues, including availability of oxygen, redox homeostasis and lactate levels. Many of these insights have been generated using in vitro model systems, which have revealed highly diverse effects of different metabolic cues on DC function. However, they also stress the importance of shifting toward more physiologically relevant experimental settings to be able to fully delineate the role of the metabolic surroundings in its full complexity in shaping the functional properties of DCs in health and disease.

Keywords: dendritic cells; diabetes; metabolism; nutrient availability; tumor micro-environment.

Figure 1

Metabolic demands of conventional DCs during homeostasis. (A) Quiescent DCs in peripheral tissues require, glucose and lipids as fuel for mitochondrial ATP generation and to build up intracellular storage of lipids and glycogen. (B) After TLR ligation uptake of glucose and BCAAs increases and together with glucose derived from glycogen this supports the switch from catabolic to anabolic metabolism, which is required for DC maturation. During this process, lipid bodies support cross-presentation. Glutamine, cysteine, and glutamate promote DC activation via maintaining redox homeostasis and promoting antigen presentation. (C) Glucose also promotes migration via stimulating CCR7 oligomerization and inducing cytoskeletal changes. (D) In the lymph nodes local glucose availability may be reduced due to glucose consumption by T cells, which may allow for more sustained expression of costimulatory markers and thereby more potent T cell priming. Red boxes: nutrients. Blue boxes: Functional consequences. Dotted arrow: presumed mechanism. ER, Endoplasmatic reticulum; Golgi, Golgi apparatus.