Metabolic dynamics instruct CD8+ T-cell differentiation and functions

Abstract

Cytotoxic CD8⁺ T cells are a key element of the adaptative immune system to protect the organism against infections and malignant cells. During their activation and response, T cells undergo different metabolic pathways to support their energetic needs according to their localization and function. However, it has also been recently appreciated that this metabolic reprogramming also directly supports T-cell lineage differentiation. Accordingly, metabolic deficiencies and prolonged stress exposure can impact T-cell differentiation and skew them into an exhausted state. Here, we review how metabolism defines CD8⁺ T-cell differentiation and function. Moreover, we cover the principal metabolic dysregulation that promotes the exhausted phenotype under tumor or chronic virus conditions. Finally, we summarize recent strategies to reprogram impaired metabolic pathways to promote CD8⁺ T-cell effector function and survival.

Keywords: T-cell differentiation; T-cell exhaustion; T cells; infection; metabolism.

Figure 1

Metabolic profiles of CD8⁺ T cells during an immune response. Upon acute infection, the activation of naive CD8⁺ T cells triggers massive expansion and differentiation into effector T cells, which contribute directly to pathogen clearance. TCR signaling stimulates aerobic glycolysis to support the intense cell proliferation. Following the elimination of the antigen, the majority of CD8⁺ T cells undergoes the contraction phase. However, a small percentage of T cells survive and form memory subsets, which can provide long‐term protection. These cells rely on fatty‐acid oxidation and oxidative phosphorylation for their maintenance.

Figure 2

Metabolic reprogramming in CD8⁺ T‐cell activation and memory formation. (A) Metabolic changes in CD8⁺ T cells upon activation. Upon antigen recognition, stimulatory signals T‐cell receptor (TCR) and costimulation CD28 induce the activation of PI3K‐AKT pathway, mTOR, and the calcium release in the cytosol. This pathway result in the upregulation of the transcription factors NFAT and Myc that promote glycolysis and glutaminolysis. (B) Metabolic regulation during memory CD8⁺ T‐cell formation. After antigen clearance, mTORC1 is inhibited which leads to the downregulation of aerobic glycolysis. Fatty acids are used as main substrates for energy production: fatty acids enter the mitochondria through CPT1‐α and are transformed in acetyl‐CoA by fatty‐acid oxidation. Acetyl‐CoA enters then the tricarboxylic acid cycle to support the oxidative phosphorylation and energy production. Mitochondrial fitness is also closely regulated by proteins involved in mitophagy like Nix and also by inner mitochondrial membrane protein Optic atrophy 1 (OPA1) that promotes mitochondrial fusion.

Figure 3

Metabolic deficiency in exhausted CD8⁺ T cells in chronic environment. Upon antigen persistence, T cells form an intermediate progenitor subset that presents memory‐like characteristics like self‐renewal and tcf‐1 expression. This progenitor subset irreversibly gives rise to the short‐lived terminally exhausted subset, which is associated with a glycolytic gene signature as well as mitochondrial damage.

Figure 4

Metabolic reprogramming of terminally exhausted T cells. Different strategies could be used to specifically target the metabolism and the mitochondrial fitness of terminally exhausted T cells. The deletion of mitochondrial regulator REGNASE‐1 can increase mitochondrial quality in a BATF‐dependent manner. Preserving mitochondrial health against the accumulation of mitochondrial ROS by N‐acetylcysteine can also restore T‐cell effector function and memory‐like phenotype. Mitochondrial fusion and biogenesis can be rescued through p38‐MAPK and PGC1‐α activation by 4‐1BB stimulation. Treatment with IL‐10‐Fc fusion protein was able reprogram the metabolism of terminally exhausted TILs by promoting oxidative phosphorylation by the mitochondrial pyruvate carrier MPC.