Metabolic switching and fuel choice during T-cell differentiation and memory development

Abstract

Clearance or control of pathogens or tumors usually requires T-cell-mediated immunity. As such, understanding the mechanisms that govern the function, maintenance, and persistence of T cells will likely lead to new treatments for controlling disease. During an immune response, T-cell development is marked by striking changes in metabolism. There is a growing appreciation that these metabolic changes underlie the capacity of T cells to perform particular functions, and this has led to a recent focus on the idea that the manipulation of cellular metabolism can be used to shape adaptive immune responses. Although interest in this area has grown in the last few years, a full understanding of the metabolic control of T-cell functions, particularly during an immune response in vivo, is still lacking. In this review, we first provide a basic overview of metabolism in T cells, and then we focus on recent studies providing new or updated insights into the regulation of metabolic pathways and how they underpin T-cell differentiation and memory T-cell development.

Fig. 1. ATP-generating metabolic pathways

Quiescent T cells mainly use oxidative phosphorylation (OXPHOS) to generate ATP, a process that takes place in mitochondria. A variety of substrates, such as glucose, amino acids, and lipids, are oxidized in the TCA cycle; these reactions generate biosynthetic precursors as well as the reducing agents NADH. The NADH coenzyme, which is used in many biochemical reactions, donates electrons to the electron transport chain for OXPHOS. Upon activation, T cells upregulate glycolysis, the process in which glucose is converted into pyruvate, thereby generating ATP and reducing NAD⁺ to NADH. To fuel OXPHOS, pyruvate can be shuttled into the TCA cycle; however, during Warburg metabolism, the majority of pyruvate is converted into lactate, which is excreted from the cell. In the process of converting pyruvate to lactate, NADH is oxidized to NAD⁺, which in turn can support continued glycolysis.

Fig. 2. Metabolic pathways in activated T cells

Activated T cells use glucose and glutamine as their main nutrients to support rapid proliferation and effector functions. Glucose uptake is dependent on glucose transporter expression, and once inside the cell, glucose is converted into glucose-6-phosphate. This intermediate is the starting point for glycolysis, which ultimately leads to the production of pyruvate. In Warburg metabolism, the majority of pyruvate is excreted as lactate. Glutamine uptake and metabolism is also critical in activated T cells. As proliferation requires rapid synthesis of macromolecules for the generation of daughter cells, biosynthetic intermediates provided by the TCA cycle are necessary to support this process. Citrate from the TCA cycle can be excreted into the cytosol and used for lipid synthesis. Lipid synthesis also requires reductive power in the form of NADPH. NADPH is generated by the conversion of malate, excreted from the mitochondria, into pyruvate. Alternatively, using glucose-6-phosphate in the pentose phosphate pathway also generates NADPH. This latter pathway is important for nucleotide synthesis. Dashed arrows indicate multiple steps. Red, green, and purple arrows indicate glycolysis, glutaminolysis, and pentose phosphate pathways, respectively.

Fig. 3. Factors regulating metabolism in T cells

Metabolism has a fundamental role in virtually every cellular process, and there has been a growing interest in how metabolic pathways regulate T-cell function and fate. This diagram highlights some of the factors recently described in the literature to regulate metabolism in quiescent and activated T cells. Factors promoting anabolic pathways support the metabolic needs of T cells during activation and proliferation (red). Factors that regulate quiescence maintain catabolic mitochondrial metabolism and promote cell survival and persistence (blue). Depending on the context, signaling through growth factor receptors (red) can drive proliferation and effector T-cell differentiation (e.g. IL-2 signals), or promote survival (blue) through enhanced mitochondrial function (e.g. IL-15 and IL-7 signals).

Fig. 4. Bioenergetic model of memory CD8⁺ T-cell survival after infection

As effector CD8⁺ T cells rapidly proliferate during an immune response, they primarily use glycolysis to support bioenergetic needs. We speculate that during this process, the majority of CD8⁺ effector T cells fail to maintain and/or induce mitochondrial biogenesis resulting in a reduction in the ratio between mitochondrial mass and overall cell mass and thereby lose reserve energy-generating capacity, i.e., spare respiratory capacity. Reduced mitochondrial mass increases dependence on glycolysis and renders effector T cells bioenergetically unstable due to a decline in their ability to create energy from diverse substrates via OXPHOS, and thus are unable to maintain viability when infection-associated signals decline and elements such as IL-2 that support glycolysis dissipate. Some antigen-specific T cells from the primary infection survive as long-lived memory T cells, because these cells have maintained mitochondrial mass via exposure to IL-15 or other growth factor cytokines. More mitochondrial mass allows greater use of fatty acids for energy via OXPHOS, thereby facilitating cell survival in the absence of pro-glycolysis signals. Moreover, the enhanced spare respiratory capacity provided by increased mitochondrial mass might allow memory T cells to respond quickly if pathogen is reencountered.