Metabolic Reprogramming and Reactive Oxygen Species in T Cell Immunity

Abstract

T cells undergo metabolic reprogramming and multiple biological processes to satisfy their energetic and biosynthetic demands throughout their lifespan. Several of these metabolic pathways result in the generation of reactive oxygen species (ROS). The imbalance between ROS generation and scavenging could result in severe damage to the cells and potential cell death, ultimately leading to T cell-related diseases. Interestingly, ROS play an essential role in T cell immunity. Here, we introduce the important connectivity between T cell lifespan and the metabolic reprogramming among distinct T cell subsets. We also discuss the generation and sources of ROS production within T cell immunity as well as highlight recent research concerning the effects of ROS on T cell activities.

Keywords: T cells; cell metabolism; disease; immunity; reactive oxygen species.

Figure 1

Various T cell subsets development with metabolic reprogramming status. There are five metabolic profile categories: the pentose phosphate pathway, glutaminolysis, aerobic glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO). Different T cell subsets alter their metabolic status at different developmental stages. Double negative (DN) cells are the initial stage of thymocytes. These cells will mainly use aerobic glycolysis during proliferation. In later stages of thymocyte development, double-positive (DP) cells and single CD4 or CD8 T cells mature and prepare to migrate through the bloodstream to the secondary organs. During this stage, the matured thymocytes preferentially utilize OXPHOS and FAO to meet their metabolic needs. Naive T cells in spleens and LNs continue in quiescence as thymocytes to minimize energy consumption. Once encountering antigens, T cells activate and proliferate to face foreign assailants. In order to combat foreign pathogens, effector T cells transition their metabolism from OXPHOS to aerobic glycolysis. T cells will progress into the differentiation stage where there are multiple T-cell subsets, such as T helper 1 (Th1), T helper 2 (Th2), T helper 9 (Th9), T helper 17 (Th17), regulatory T (Treg), and T follicular B helper (Tfh) cells. Although all T cell subsets utilize aerobic glycolysis, the varying subsets employ different metabolic processes. Th17 can utilize glutaminolysis and both Th1 and Tfh can conduct OXPHOS in addition to aerobic glycolysis. Memory T cells exhibited both OXPHOS and FAO to maintain their function.

Figure 2

Different sources of ROS impacting T cell activation. There are three ROS generation sources mentioned in this review that impact T cell activation: NOXs, mitochondrial complexes for OXPHOS, and TCA enzymes. NOXs are a group of enzymes responsible for the transfer of electrons from oxygen to cytoplasmic superoxide. In this figure, black solid arrows indicate the production of these pathways while purple solid arrows indicate the electrons transfer reactions for coenzymes within the TCA cycle and mitochondrial complexes. Colored dashed arrows designate the inductions of transcription factors, such as NFAT, AP-1, NFkB, and further upregulate various cytokines. The orange-colored box denotes protein complexes while the compounds that are produced from the TCA cycle are shown in blue. The red spiked border indicates ROS generation.

Figure 3

ROS regulation of activation-induced T cell death (AICD). This figure indicates multiple signal pathways involved in T cell death, including PD1 (below), Gal3, NOX2, and FasL-mediated (above) pathways. The orange color denotes protein complexes. Black solid arrows indicate the products and interactions of these pathways. The early stages denote TCR activation while the later stages indicate apoptosis. The dashed arrow affiliated with the PKCθ protein indicates translocation from the cytosol to the mitochondria. Cytochrome c release from the mitochondria to the cytosol is shown by yellow dots. The dashed line associated with IP3 designates the induction of calcium release (shown in brown dots) and the complexes’ impact on DUOX1 in the endoplasmic reticulum.