Molecular mechanisms of metabolic reprogramming in proliferating cells: implications for T-cell-mediated immunity

Abstract

To engage in proliferation, cells need to increase their biomass and replicate their genome. This process presents a substantial bioenergetic challenge: proliferating cells must increase ATP production and acquire or synthesize raw materials, including lipids, proteins and nucleic acids. To do so, proliferating cells actively reprogramme their intracellular metabolism from catabolic mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis and other anabolic pathways. This metabolic reprogramming, which directs nutrient uptake and metabolism during cell activation and proliferation, is under the control of specific signal transduction pathways. The underlying molecular mechanisms of cell metabolism reprogramming and their relevance to physiology and disease are currently under intense study. Several reports have uncovered the mechanisms of metabolic reprogramming that drive high rates of cell proliferation in cancer. Some recent studies have elucidated the physiological role of metabolic reprogramming during T-cell activation, differentiation and trafficking, which are potentially relevant to inflammatory disorders. This review describes the impact of metabolic reprogramming on the pathogenesis of cancer and the physiology of T-cell-mediated immune responses, with an emphasis on the phosphatidyl inositol 3-kinase-serine/threonine kinase-mammalian target of rapamycin pathway and the recently discovered metabolic processes regulated by nuclear factor-κB. These discoveries will hopefully translate into a better understanding of the role of metabolic reprogramming as a key regulator of T-cell-mediated immune responses and offer novel, immune-based therapeutic approaches.

Figure 1

Tumour cells and activated T cells use the same metabolic pathways to support high rates of proliferation. Downstream of growth factor receptors in tumour cells and T-cell receptor (TCR) in activated T cells phosphatidyl inositol 3-kinase (PI3K) -mediated activation of the serine/threonine kinase Akt promotes glucose uptake – through up-regulation of Glut1 – and glycolysis, while oxidative phosphorylation (OXPHOS) is reduced. The preferential use of glycolysis over OXPHOS enables proliferating cells to produce ATP at a faster rate. Rapid glucose metabolism also enables proliferating cells to spare intermediates of the metabolic pathways for the biosynthesis of nucleotides and lipids. Akt also controls mammalian target of rapamycin (mTOR) activation, which promotes protein synthesis. Increased lipid, nucleotide and protein synthesis supports cell proliferation.

Figure 2

The mammalian target of rapamycin (mTOR) pathway regulates T-cell activation, differentiation and migration. (a) Downstream of T-cell receptor (TCR) and CD28, phosphatidyl inositol 3-kinase (PI3K) leads to activation of the serine/threonine kinase Akt, which subsequently controls mTOR activity. This signalling cascade promotes the glucose metabolism and protein synthesis necessary for T-cell activation, proliferation and differentiation into CD4⁺ T helper type 1 (Th1), Th2 and Th17 subsets. The PI3K–Akt–mTOR axis also promotes down-regulation of secondary lymphoid organ (SLO) homing receptors CD62L, CCR7 and S1P₁. Antigen experienced T cells, therefore, home to their respective non-lymphoid tissues. (b) Inhibition of mTOR via rapamycin or genetic deletion reduces protein synthesis and T-cell proliferation, and promotes differentiation toward anergic, CD4⁺ regulatory T (Treg) cell and CD8⁺ memory cell subsets. Rapamycin-mediated inhibition of mTOR causes T effector cells to re-express CD62L and CCR7 and home to secondary lymphoid organs.