Metabolic pathways in T cell fate and function

Abstract

T cell growth and function must be tightly regulated to provide protection against foreign pathogens, while avoiding autoimmunity and immunodeficiency. It is now apparent that T cell metabolism is highly dynamic and has a tremendous impact on the ability of T cells to grow, activate and differentiate. Specific metabolic pathways provide energy and biosynthetic precursors that must support specific cell functions, as effector, regulatory, memory, and alloreactive T cells have distinct metabolic needs in immunity and inflammation. Here, we review the signaling pathways that control metabolism and how the metabolic phenotypes of T cell subtypes integrate with T cell function. Ultimately, these metabolic differences may provide new opportunities to modulate the immune response and treat inflammatory and autoimmune diseases.

Figure 1. Metabolic differences between effector, Treg and memory T cells

Upon stimulation, CD4⁺ and CD8⁺ effector T cells upregulate glucose uptake and glycolysis to provide biosynthetic precursors necessary for growth and proliferation. Glucose enters the pentose phosphate pathway (PPP) to generate ribose and NADPH necessary for nucleotide synthesis and is converted to citrate in the citric acid cycle (TCA) for lipid synthesis. Lactate is produced as a byproduct of the rapid rate of glycolysis in effector T cells. Treg and CD8⁺ memory cells instead burn lipids through beta-oxidation (β-ox) in the mitochondria and generate ATP through electron transport and oxidative phosphorylation (ET/OXPHOS).

Figure 2. Signaling molecules involved in T cell metabolism and differentiation

(A) Activation of a naïve CD4⁺ T cell requires appropriate TCR and co-stimulation as well as metabolic reprogramming and the signaling molecules mTOR, Myc and ERRα contribute to this metabolic transition. An activated CD4⁺ T cell can differentiate into an effector T cell (Th1, Th2 or Th17) or regulatory T cell (Treg) depending on the cytokine environment. mTORC1 is important for Th1 and Th17 differentiation, mTORC2 for Th2, HIF1α for Th17 and AMPK for Treg differentiation. (B) Activation of a naïve CD8⁺ T cell also requires appropriate TCR and co-stimulation as well as metabolic reprogramming and the signaling molecules Akt and mTOR contribute to this metabolic transition. TRAF6 and AMPK are involved in the transition from an effector to memory CD8⁺ T cell.