Metabolic pathways in immune cell activation and quiescence

Abstract

Studies of immune system metabolism ("immunometabolism") segregate along two paths. The first investigates the effects of immune cells on organs that regulate whole-body metabolism, such as adipose tissue and liver. The second explores the role of metabolic pathways within immune cells and how this regulates immune response outcome. Distinct metabolic pathways diverge and converge at many levels, and, therefore, cells face choices as to how to achieve their metabolic goals. There is interest in fully understanding how and why immune cells commit to particular metabolic fates and in elucidating the immunologic consequences of reaching a metabolic endpoint by one pathway versus another. This is particularly intriguing, given that metabolic commitment is influenced not only by substrate availability but also by signaling pathways elicited by metabolites. Thus, metabolic choices in cells enforce fate and function, and this area will be the subject of this review.

Figure 1. Cell fate and function in the immune system is supported by engagement of metabolic pathways

In this diagram colored arrows represent pathways that have been shown to be used in the cell types indicated, grey arrows indicate pathways that might be used, but have yet to be clearly defined, and dashed arrows indicate multiple steps shown in a single arrow. A. In activated neutrophils, M1 macrophages and iNOS expressing DCs stimulated with TLR agonists, Warburg metabolism dominates. ATP production and cellular survival are dependent on glycolysis, with the majority of pyruvate being converted to lactate. In this pro-glycolytic state, the PPP is active and provides NADPH for key microbicidal pathways regulated by NADPH oxidase. Under these conditions, there is little evidence for OXPHOS, but maintenance of mitochondrial potential and integrity are needed to maintain cell survival. B. Activated T cells engage OXPHOS and glycolysis. Most pyruvate is excreted as lactate, but some also enters the TCA cycle. Glutaminolysis is an important pathway in these cells as glutamine replenishes TCA cycle intermediates as they are withdrawn for biosynthesis. Metabolizing glucose in the PPP can yield both nucleotides and NADPH for lipid synthesis. C. Memory T cells, Treg cells, and alternatively activated macrophages use FAO for survival and to support function. Other pathways are depicted in grey as the extent to which they are used in these cells, if at all, has not been established. D. Overview of the TCA cycle.

Figure 2. Model for competition for substrates and production of regulatory metabolites at sites of infection or within tumors

In the lymph nodes and blood, nutrients and other supportive signals are abundant, and T cells are able to engage Warburg metabolism and attain full effector status. However, conflicting metabolic signals may inhibit T cell function and fate within diseased tissues. T cells may face metabolic restrictions such as reduced local glucose and/or oxygen concentrations due to rapid tumor and/or pathogen growth, and reduced vascular perfusion. Additionally, tumors and sites of infection can be infiltrated by suppressive myeloid cells, which aggressively deplete important substrates such as tryptophan and arginine, and further produce toxic gases (such as NO) that can inhibit OXPHOS.