The role of metabolic reprogramming in T cell fate and function

Abstract

T lymphocytes undergo extensive changes in their metabolic properties during their transition through various differentiation states, from naïve to effector to memory or regulatory roles. The cause and effect relationship between metabolism and differentiation is a field of intense investigation. Many recent studies demonstrate the dependency of T cell functional outcomes on metabolic pathways and the possibility of metabolic intervention to modify these functions. In this review, we describe the basic metabolic features of T cells and new findings on how these correlate with various differentiation fates and functions. We also highlight the latest information regarding the main factors that affect T cell metabolic reprogramming.

Keywords: T lymphocytes; differentiation fate and function; metabolism.

Figure 1. Basic metabolic features of T cells

In order for the TCA cycle to function properly, it must be supplied with intermediate metabolites to ensure continuation of its reactions, a process known as anaplerosis. Both, excess of oxaloacetate and acetyl-coA are required for the TCA cycle to continue. Glycolysis can fulfill this requirement by supplying TCA with oxaloacetate and acetyl-coA derived from pyruvate. Moreover, acetyl-coA derived from FAO and ketogenic amino acids can supply the TCA cycle in parallel with pyruvate coming from glycolysis or α-ketoglutarate derived from glutamine. Glycolysis and TCA cycle generate ATP and biosynthetic intermediates. Glucose is necessary not only for glycolysis, but also for the pentose phosphate pathway, which generates intermediates for nucleic acid synthesis and glycolysis and also NADPH. NADPH is a critical co-factor for anabolic reactions such as FA synthesis and also for antioxidant enzymes such as glutathione reductase, and thus important for the maintenance of cellular redox homeostasis. Naïve, resting, Tm and Treg T cells (panel A) depend mainly on OXPHOS, FAO and on either glucose or glutamine to support anaplerosis of the TCA cycle. Tm cells have high spare respiratory capacity and thus are immediately ready for maximal activation upon antigen encounter. In contrast, Teff cells Th1, Th2 and Th17 cells (panel B) depend on high rate of glycolysis and to a lower degree on OXPHOS for maximum energy production and biosynthesis. TG: triglycerides, FAs: fatty acids, FAO: fatty acid oxidation, FAS: fatty acid synthesis, A-CoA: acetyl-coenzyme A, TCA cycle: tricarboxylic acid cycle, PPP: pentose phosphate pathway, OXPHOS: oxidative phosphorylation.