Biochemical Underpinnings of Immune Cell Metabolic Phenotypes

Abstract

The metabolism of immune cells affects their function and influences host immunity. This review explores how immune cell metabolic phenotypes reflect biochemical dependencies and highlights evidence that both the metabolic state of immune cells and nutrient availability can alter immune responses. The central importance of oxygen, energetics, and redox homeostasis in immune cell metabolism, and how these factors are reflected in different metabolic phenotypes, is also discussed. Linking immune cell metabolic phenotype to effector functions is important to understand how altering metabolism can impact the way in which immune cells meet their metabolic demands and affect the immune response in various disease contexts.

Figure 1. The metabolic phenotype of quiescent and activated T cells

Quiescent T cells including naïve and memory cells exhibit a more oxidative metabolic phenotype characterized by low nutrient uptake and minimal lactate production. In contrast, activated T cells utilize aerobic glycolysis with increased glucose uptake and lactate production. Activated T cells still oxidize glucose in the mitochondrial TCA cycle, and the rate of glucose oxidation in activated T cells can be greater than that found in quiescent T cells. These different metabolic phenotypes may reflect the different metabolic requirements of these different cell states. Quiescent T cells oxidize limiting nutrients to maintain energy state and promote cell survival, while activated T cells alter metabolism to support cell proliferation and effector functions. The increased demand for synthesizing nucleotides and other oxidized biomass in proliferating cells results in a lower NAD⁺/NADH ratio and contributes to increased lactate production.

Figure 2. Relationship between glycolysis, oxygen consumption, ATP production and redox metabolism

Glycolysis and mitochondrial respiration both supply cellular ATP. Production of lactate from pyruvate allows NAD⁺ regeneration and maintenance of redox balance for glycolysis. Redox balance is maintained when pyruvate or fatty acids from lipids are oxidized in the mitochondrial TCA cycle by transfer of electrons to O₂ via the electron transport chain. When O₂ consumption is coupled to ATP production, the proton (H+) gradient across the inner mitochondrial membrane generated by the electron transport chain is used to drive ATP synthesis (oxidative phosphorylation). Oxygen consumption can also be uncoupled from ATP production if there is another route for protons to cross the inner mitochondrial membrane (uncoupled respiration). This can occur via endogenous uncoupling proteins or via pharmacologic agents such as FCCP that are used to assess spare respiratory capacity. Production of lactate or consumption of O₂ at rates that are stoichiometric with nutrient oxidation is necessary for electron disposal and redox homeostasis in cell metabolism.

Figure 3. Model relating metabolic state of different T cell subsets to cell function

Naïve T cells exhibit low glucose transporter expression and nutrient uptake, with metabolism directed toward nutrient oxidation and cell survival. Nutrient uptake and mitochondrial mass are increased upon T cell activation, facilitating the production of new biomass for proliferation. Memory T cells return to a low nutrient uptake state, again relying on nutrient oxidation to support cell survival; however, these cells retain more mitochondria (oxidation capacity) facilitating their ability to re-engage a proliferative program when reactivated. Exhausted T cells become limited for nutrient uptake and/or oxidizing capacity secondary to dysfunctional mitochondria limiting their ability to support a proliferative metabolic program.