6.1.2　T Cell

T cells are an important adaptive immune response arm that mediates cell-mediated immunity.T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function.Specific metabolic programs are tightly controlled to mediate T cell immune responses,and alterations in T cell metabolism may result in many immunological disorders.

After T cell receptor (TCR) stimulation, the naïve T cells differentiate into antigen-effector T cells,whose energy metabolism mainly depends on aerobic glycolysis and OXPHOS.Glycolytic metabolism distinguishes CD4 Th1, Th2, and Th17 effector cells from regulatory T cells (Treg).The development of Treg and memory T cells mainly depends on fatty acid oxidation (FAO) and catabolism.Membrane T cells reenter the resting state, and their energy metabolism depends on oxidative phosphorylation (OXPHOS).

During the activation of T cells, the production of ATP mainly comes from the catabolism of glucose and fatty acids.Upon entering the cell, glucose is rapidly phosphorylated by hexokinase,producing glucose 6-phosphate and consuming a molecule of ATP.The glycolysis process can generate high-energy molecules, such as nicotinamide adenine dinucleotide (NADH) and ATP, and form two molecules of pyruvate.Intermediates produced during glycolysis are transferred to the pentose phosphate pathway, serine biosynthetic pathway, β-oxidation pathway, or glycogenesis pathway, resulting in nucleotides, fatty acids, and glycogen generation, which are needed for T cell metabolism.After pyruvate is synthesized, it is delivered to the mitochondria and undergoes further breakdown through the tricarboxylic acid (TCA) cycle.Inside the mitochondrial matrix, pyruvate is carboxylated to produce oxaloacetate or decarboxylated and combined with coenzyme A (CoA) to form acetyl-CoA.Then, under the function of citric acid synthase, oxaloacetate combines with acetyl-CoA to produce citrate.During the TCA cycle, oxaloacetate is regenerated and recombined with a new molecule of acetyl-CoA.This cycle produces two reducing agents, namely, NADH and flavin adenine dinucleotide (FADH2), which donate electrons to the cytochrome of the electron transport chain, resulting in large amounts of ATP by OXPHOS, participating in T cell metabolic regulation.By contrast, without mitochondrial involvement, pyruvate can be catalyzed by lactate dehydrogenase to generate lactate.Lactate generation is involved in energy metabolism [18,19].(https://www.daowen.com)

Even in the presence of abundant oxygen, T cells can preferentially use glycolysis to produce ATP.The energy and metabolites produced by aerobic glycolysis can support T cell activation and rapid proliferation.The energy of many activated T lymphocytes comes primarily from aerobic glycolysis, such as Teff cells (Th1, Th2, and Th17 CD4+ subsets and cytotoxic CD8+ T cells).In this condition, the majority of pyruvate is rapidly converted into lactate and expelled.In CD4+ Teff cells, a part of the pyruvate produced during aerobic glycolysis remains to be metabolized via TCA and OXPHOS.Notably, CD8+ T cells do not boost OXPHOS upon activation [20-24].

T cell growth and organelle biosynthesis are mainly dependent on fatty acid metabolism.Treg and T mem support their function and survival mainly through lipid metabolism mediated by FAO.Excess exogenous fatty acids exhibit a dominant negative effect on the acquisition of the Th17 phenotype.Treg is crucial for maintaining immune homeostasis.Forced reliance on FAO during in vitro T cell differentiation favors Treg generation.The inhibition of the key metabolic regulator,mTOR, during CD4+ T cell activation enhances FAO and reduces aerobic glycolysis favor Treg production.Metabolic regulation is involved in the rapid reactivation of T mem cells.Within the CD8+ memory lineage, the production and persistence of T mem, as well as repeat-antigen-induced reactivation, has been reported to be dependent on FAO regulation.T mem cells have a greater mitochondrial mass than other T cell subsets, specifically expressing the FAO-related enzymes and the carnitine palmitoyl transferase system proteins, resulting in a stronger spare respiratory capacity(SRC).SRC represents the capability of cells to generate energy in response to activation or stress signals.Thus, the stronger SRC capacity of the T mem cell promotes their survival under harsh conditions [25,26].

Immunometabolism plays a key role in adaptive immunity and is particularly important for effective antitumor T cell responses.In the tumor microenvironment, T cells are affected by the inhibitory network and T cell metabolism is altered, which promotes tumor escape and development.Recent studies have shown that antitumor functions of effector T cells are impaired in the tumor microenvironment.In fact, the tumor micro environment forms a complex immunosuppression network that inhibits metabolic regulation during tumor development, thereby limiting T cell activation and inducing T cell anergy.However, the exact mechanism is still unclear.A previous study reported that changes in T cell metabolic regulation inhibit the antitumor capability of T cells, leading to tumor escape.In the tumor microenvironment, metabolic interference and nutrients competition exist between cancer and T cells, which are important to drive cancer development.Tumor cells require a large amount of energy metabolism to proliferate by increasing glycolysis and glucose uptake from the surrounding environment.Therefore, the abnormal metabolism of tumor cells inhibits the immune metabolism of T cells, weakens the T cells glycolytic pathway, and reduces the capability of T cells to secrete cytokines, resulting in the conversion of effector T cells into ineffective cells.Studies have shown that Treg differentiation is inconducive to tumor immunity.In contrast to effector T cells, Treg are more likely to be activated in the tumor microenvironment.When the AMPK signaling pathway inhibits the mTOR signaling pathway, the balance between Teff and Treg may be directly disturbed in the tumor microenvironment.In contrast to mTOR cascade, AMPK cascade is dominantly activated when nutrients are absent and oxidative metabolism is enhanced.Notably, AMPK can be mediated by hyperphosphorylation and thus activated in Treg.Therefore, Treg function is enhanced to impair effector T cell functions in the tumor microenvironment, which in turn facilitates tumor development [27-35].