Metabolism along the life journey of T cells

Abstract

T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation, which serves as an excellent example to dissect the metabolic basis of cell fate decisions. During the last decade, there has been an explosion of research into the metabolic control of T-cell responses. The roles of common metabolic pathways, including glycolysis, lipid metabolism, and mitochondrial oxidative phosphorylation, in T-cell responses have been well characterized, and their mechanisms of action are starting to emerge. In this review, we present several considerations for T-cell metabolism-focused research, while providing an overview of the metabolic control of T-cell fate decisions during their life journey. We try to synthesize principles that explain the causal relationship between cellular metabolism and T-cell fate decision. We also discuss key unresolved questions and challenges in targeting T-cell metabolism to treat disease.

Keywords: FAO; OXPHOS; T cells; acetyl-CoA; glycolysis; immunometabolism.

Figure 1

An evolutionary perspective of immunometabolism. Metabolism and immunity are two strong selective forces during natural selection. Inter- and intra-species competition for limited food resource drives optimization of the metabolic network to the highest efficiency of energy usage. Both predator and prey cannot compete with infectious pathogens by conventional flight or fight responses, and thus a robust immune system is the key to survival from infections. The extensive cross-regulation between metabolism and immunity ensures that both systems work efficiently to confer survival advantage during evolution.

Figure 2

Mechanisms of metabolic control of T-cell fate. The interconversions between major nutrients (sugar, protein, and lipid) and intermediate metabolites (pyruvate, amino acid, and fatty acid) during catabolism and anabolism generate energy and building blocks, respectively, for T cells. Certain metabolites, such as ATP, acetyl-CoA, and SAM, function as signaling molecules to modulate the activity of key proteins involved in T-cell fate decision, such as kinases and HATs. This metabolite-signaling model partially explains how metabolism controls T-cell fate. LDHA, lactate dehydrogenase A; OXPHOS, oxidative phosphorylation; ATP, adenosine triphosphate; SAM, S-adenosyl-l-methionine; HAT, histone acetyltransferase.