Mitochondrial Metabolism in T-Cell Exhaustion

Abstract

T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion.

Keywords: T-cell exhaustion; metabolic reprogramming; metabolism; mitochondria; mitochondrial dynamics.

Figure 1

Effect of T cell mitochondrial quality control on immunometabolism. The differentiation and function of immune cells largely depend on specific metabolic programs determined by mitochondria. Mitochondrial metabolism is closely linked to mitochondrial morphology, which is influenced by mitochondrial biogenesis, dynamics, mitophagy, and mitochondrial transfer. Furthermore, mitochondrial biogenesis favors the metabolic reprogramming in T cells, with the crucial regulatory molecule being PGC-1α. PD-1 signaling promotes these metabolic alterations by driving Blimp1-mediated inhibition of PGC-1α. Mitochondrial dynamics, which include fusion and fission, determine T-cell differentiation and fate. Effector T cells possess fissed mitochondria with loosened cristae, whereas memory T cells have fused mitochondria with tighter cristae and expanded space. PD-1 signaling reduces the activity of mitochondrial fission protein Drp1; forcing mitochondrial fusion drives memory T cell differentiation. Mitochondrial autophagy (mitophagy) maintains T cell homeostasis. Mitochondrial transfer can alter the metabolic status of both donor and recipient by affecting mitochondrial mass, thus becoming a target for immunotherapy.