Regulation of glucose metabolism in T cells: new insight into the role of Phosphoinositide 3-kinases

Abstract

Naïve T cells are relatively quiescent cells that only require energy to prevent atrophy and for survival and migration. However, in response to developmental or extrinsic cues T cells can engage in rapid growth and robust proliferation, produce of a range of effector molecules and migrate through peripheral tissues. To meet the significantly increased metabolic demands of these activities, T cells switch from primarily metabolizing glucose to carbon dioxide through oxidative phosphorylation to utilizing glycolysis to convert glucose to lactate (termed aerobic glycolysis). This metabolic switch allows glucose to be used as a source of carbon to generate biosynthetic precursors for the production of protein, DNA, and phospholipids, and is crucial for T cells to meet metabolic demands. Phosphoinositide 3-kinases (PI3K) are a family of inositol lipid kinases linked with a broad range of cellular functions in T lymphocytes that include cell growth, proliferation, metabolism, differentiation, survival, and migration. Initial research described a critical role for PI3K signaling through Akt (also called protein kinase B) for the increased glucose uptake and glycolysis that accompanies T cell activation. This review article relates this original research with more recent data and discusses the evidence for and against a role for PI3K in regulating the metabolic switch to aerobic glycolysis in T cells.

Keywords: Akt; Glucose metabolism; PDK1; PI3K; T lymphocyte; aerobic glycolysis; c-Myc.

FIGURE 1

Pl3K and Akt signaling. (A) PI(4,5)P₂ is phosphorylated by Class 1 PI3K isoforms generating the second messenger molecule PI(3,4,5)P₃. Levels of PI(3,4,5)P₃ are negatively regulated by the lipid phosphatases PTEN and SHIP. Binding of the PH domain of Akt to PI(3,4,5)P₃ in the membrane results in a conformational change that allows for the phosphorylation of Akt on key residues(T308 and S473) by PDK1 and mTORC2. The recruitment of PDK1, via its PH domain, to the site of PI(3,4,5)P₃ is required for efficient Akt activation. (B) Active Akt phosphorylates Foxo transcription factors on multiple sites resulting in their translocation to the cytoplasm where they are retained in complex with 14-3-3 proteins. mTORC1 can be activated downstream of Akt, though this does not occur in all T cell types. (C) PDK1 also phosphorylates and activates a number of other members of the AGC kinase family in a PI3K independent manner.

FIGURE 2

PI3K controls the metabolic switch to aerobic glycolysis in thymocytes but not in mature T cells. Naïve T cells take up small amounts of glucose which is for the most part metabolized to CO₂ via mitochondrial oxidative phosphorylation (OxPhos) for the efficient generation of ATP. Activated T cells and certain thymocyte subsets increase the expression of the GLUT1 glucose transporter and thus glucose uptake, and increase glycolytic flux, primarily converting glucose to lactate. This metabolic switch increases the biosynthetic capacity of the T cells and is stimulated by antigen receptor signaling (PreTCR, TCR) and maintained by certain cytokines (IL2). PI3K signaling is required for this metabolic switch during thymopoiesis but not in peripheral activated T cells.