Metabolic Regulation of T Lymphocytes

Abstract

T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

“…These results indicate that Tsc1 promotes memory T-cell responses, in part, by impinging upon the transcriptional programs required for memory precursor differentiation. The metabolic programs are dynamically regulated to match the differentiation and function of T cells (4)(5)(6). For the fate decisions between effector and memory CD8 + T cells, the glycolytic and lipid synthetic metabolism promotes effector T-cell generation (7,11), whereas oxidative phosphorylation and mitochondrial activity facilitate memory development (12,13).…”

“…T cells dynamically reprogram cellular metabolism to fulfill the bioenergetics and biosynthetic requirements for their survival, proliferation, and differentiation (4)(5)(6). Naïve and memory T cells use catabolic metabolism via oxidative phosphorylation, especially fatty acid oxidation, to produce ATP for their survival.…”

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

“…15 Thus, in the absence of Bim, the enormous numbers of KLRG1 hi CD127 lo cells act as a sink for IL-15 and likely other nutrients (glucose, amino acids) that prevent engagement of other BH3-only proteins. 35 Although Bcl-2 antagonizes Puma, Bcl-2 has an extremely low affinity for Noxa. 36,37 Instead, both Mcl-1 and A1 have a higher affinity for Noxa.…”

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

“…This involves a switch from oxidative phosphorylation to glycolysis to provide fuel and metabolites for nucleic acid, protein, and lipid biosynthesis. T-cell metabolism is controlled by thymoma viral proto-oncogene (Akt), mammalian target of rapamycin (mTOR), and ERK signaling pathways as well as by the transcription factors myelocytomatosis oncogene (c-Myc), hypoxia-inducible factor-1 alpha (HIF-1α), and estrogenrelated receptor alpha (ERR) (1)(2)(3). Induction of c-Myc by TCR and cytokine signals is particularly critical for the metabolic reprogramming and the proliferation of naive T cells (4,5).…”