Metabolic reprogramming and metabolic dependency in T cells

Abstract

Summary Upon activation, quiescent naive T cells undergo a growth phase followed by massive clonal expansion and differentiation that are essential for appropriate immune defense and regulation. Accumulation of cell biomass during the initial growth and rapid proliferation during the expansion phase is associated with dramatically increased bioenergetic and biosynthetic demands. This not only requires a metabolic rewiring during the transition between resting and activation, but also ‘addicts’ active T cells to certain metabolic pathways in ways that naive and memory T cells are not. We consider such addiction in terms of the biological effects of deprivation of metabolic substrates or inhibition of specific pathways in T cells. In this review, we illustrate the relevant metabolic pathways revealed by recent metabolic flux analysis and discuss the consequences of metabolic intervention on specific metabolic pathways in T lymphocytes.

Mitochondria Are Gate-keepers of T Cell Function by Producing the ATP That Drives Purinergic Signaling

“…Mitochondria thus occupy a key regulatory position in which they integrate the inside-out (purinergic) and outside-in (Ca 2ϩ ) signaling networks that control T cell activation. This finding is interesting given the fact that glycolysis, and not mitochondrial ATP production, is the predominant mechanism by which activated T cells generate the bulk of their ATP demand (7)(8)(9). The function of mitochondria during T cell activation shifts from ATP production to the production of TCA intermediates that are required for biosynthesis (9,32).…”

“…This finding is interesting given the fact that glycolysis, and not mitochondrial ATP production, is the predominant mechanism by which activated T cells generate the bulk of their ATP demand (7)(8)(9). The function of mitochondria during T cell activation shifts from ATP production to the production of TCA intermediates that are required for biosynthesis (9,32). However, emerging evidence points to a more complex involvement of mitochondria in the T cell activation process (33,34).…”

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 + T cells through IL-12 and TGF-β1

“…Metabolic regulation and cell signaling are tightly and ubiquitously linked with immune responses (53)(54)(55). The effective immune response requires DCs to function in various conditions, including the alteration of extracellular or intracellular metabolic states due to the migration to a nutrient and/or oxygen-deficient environment (tumor microenvironment and inflammatory sites) or an ongoing metabolic reprogramming (resulted from inflammatory stimulation), respectively.…”

Metabolic Reprogramming Supports IFN-γ Production by CD56bright NK Cells

“…Dynamically regulated cellular metabolism is now recognized as an important factor that contributes to a successful immune response (13). Metabolism is important to maintain energy homeostasis and to supply cells with the building blocks for macromolecular synthesis, but cellular metabolism can also directly influence immune cell function and differentiation (14,15). Different immune cell subsets have very different metabolic demands that are accommodated by different types of glucose metabolism.…”