Metabolic regulation of T cell development

Abstract

T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

Keywords: T cell development; T cell metabolism; thymocyte metabolism; thymocytes; thymus.

Figure 1

Overview of metabolic regulators in T cell development. Thymocytes display distinct metabolic profiles depending upon their states of development. DN1 and DN2 T cells are metabolically quiescent and adopt a basal level of nutritional intake, relying on OXPHOS as the primary approach of ATP production. Upon proliferation, T cells from the DN3b stage to early DP stage shift to a state of metabolic activation characterized by incremental nutrient uptake and elevated glycolysis. Then, T cells return to a resting state from the small DP stage to CD4+/CD8+ SP stage. The letters in the yellow box represent glycolysis regulators, and the letters in the blue box represent OXPHOS regulators.

Figure 2

Metabolic programs match expansion demands of thymocytes. Blue cells on the left represent the quiescent thymocytes, and red cells on the right represent proliferative thymocytes. OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation; ROS, reactive oxygen species; ATP, adenosine triphosphate; PPP, pentose phosphate pathway; TCA, the tricarboxylic acid.