Regulation of T cell immunity by cellular metabolism

Abstract

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. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.

Keywords

T cell immunity / metabolic pathways / nutrient uptake / metabolic checkpoints

Introduction

Different types of immune cells play specialized roles in host defense against tumor cells or pathogens [¹,²]. These diverse types of immune cells are stimulated by all kinds of threats and activated by extracellular and intracellular cues to exert their function through diverse, as well as complicated, signaling cascades. Different stimuli also mediate the migration of immune cells to different cell microenvironments and initiate their proliferation and differentiation. In the processes of leukocyte immunity, immune cells depend on nutrients and metabolites to facilitate and enhance their functions to meet the energy and biosynthesis demands [³,⁴]. Therefore, the metabolic characteristics of immune cells are crucial for their diverse functions.

T cell lineage is an important immune cell population, which is an essential component of the adaptive immune system. The ligation of the T cell receptor (TCR) by antigen/MHC complexes and the interaction of co-stimulation receptors regulate T cell activation. After stimulation, naïve T cells begin to proliferate and differentiate into highly specific effector T cells (Teff), such as Th1, Th2, Th17, T follicular helper (Tfh) cells, regulatory T cells (Treg), and cytotoxic CD8⁺ T lymphocytes [⁵–⁷]. Diverse T cell subsets serve different but specific functions in response to a wide variety of stimuli. Indeed, T lymphocyte and other lymphocyte subsets share several common characteristics, such as the capability to sense and respond to extracellular and intracellular dangerous signals. When the T cells differentiate from the naïve T cells into different subsets of T cells, stringent metabolic regulation is required. Indeed, specific metabolic pathways are critically associated with T cell homeostasis, differentiation, and function. In this review, we provide a general overview of the metabolic regulation of T cell immunity.

Metabolism of different T cell subsets

Without antigen stimulation, naïve T cells are relatively quiescent. The energy metabolic demands of naïve T cells mainly come from oxidative phosphorylation (OXPHOS). Upon TCR stimulation, naïve T cells increase glycolytic metabolism to differentiate into activated T cells and enter secondary lymphoid organs or tissues. During T cell activation, proliferation, and differentiation, energy metabolism mainly depends on aerobic glycolysis and OXPHOS. Notably, glycolytic metabolism can distinguish Th1, Th2, and Th17 effector cells from Treg. When the antigenic stimulus decreases or disappears, most of the Teff cells undergo apoptosis [⁸] and a small number of Teff cells are converted into memory T cells (Tmem) [⁹,¹⁰]. The development of Treg and Tmem mainly depends on fatty acid oxidation (FAO) and catabolism. Tmem reenter the resting state, and their energy metabolism depends on OXPHOS (Fig. 1).

Recent reports have indicated that the metabolic regulation of Tfh cells is different from that of Th1 cells upon viral infection [¹¹,¹²]. The metabolic demands of Tfh cells come from mitochondrial metabolism, and the metabolic activity of LCMV-specific Tfh cells is less than that of Th1 cells. Lower levels of AKT and mammalian target of rapamycin (mTOR) signaling were observed in Tfh cells than in Th1 cells, thereby inhibiting glycolysis and promoting Tfh cell differentiation. Bcl6 is essential for Tfh cell differentiation [¹³,¹⁴] and inhibits IL-2-mediated glycolysis pathways in Th1 cells [¹⁵], indicating that Bcl6 and its regulatory proteins may suppress the glycolysis pathway in Tfh cells. Other reports indicate that IL-2 signaling can differentially regulate the binding of the transcription factor FOXO1/3a to the Bcl6 locus [¹⁶], indicating that IL-2 is likely to regulate the FOXO/Bcl6 axis to mediate Tfh cell glycolysis and differentiation.

In the case of persistent antigenic stimuli, such as cancer and chronic infection, Teff cells gradually lose their function, resulting in T cell exhaustion. Until now, how different cellular metabolic pathways participate in the T cell exhaustion process is not yet clear. In tumor models, tumor-infiltrating T lymphocytes have a phenotype of reduced mitochondrial mass and OXPHOS [¹⁷]. In early chronic LCMV infection, the expression of genes involved in OXPHOS, citric acid cycling, and fatty and amino acid metabolism increased in exhausted T cells [¹⁸]. Although mitochondrial respiration is decreased in early exhausted T cells, the mitochondrial mass was greater in early exhausted T cells than that in Teff cells. Moreover, early exhausted T cells showed depolarization of the mitochondrial membrane with a reduced OXPHOS phenotype. Studies have shown that the transcriptional regulatory factor PPAR-g coactivator 1a (PGC-1a) is a potential regulatory target for metabolic dysfunction in exhausted T cells. Earlier studies have shown that PGC-1a is involved in mitochondrial biosynthesis [¹⁹], and the overexpression of PGC-1a can maintain Teff cell function in tumor models and in chronic infections [¹⁷,¹⁸]. In a mouse model of B cell leukemia, mTORC1 activity and the expression level of the glucose transporter Glut1 are decreased in exhausted T cells, resulting in decreased glucose uptake and reduced level of glycolytic enzyme hexokinase [²⁰]. Thus, T cell exhaustion is accompanied by impaired T cell metabolism. Whether the impaired metabolism is the cause or consequence, or only a correlation, of T cell exhaustion requires further investigation.

Key metabolic pathways of T cell immunity

Glycolysis and tricarboxylic acid cycle

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, b-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.

Aerobic glycolysis

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 [²¹,²²]. 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 [²³–²⁵].

Fatty acid oxidation

T cell growth and organelle biosynthesis are mainly dependent on fatty acid metabolism [²⁶]. Treg and Tmem support their function and survival mainly through lipid metabolism mediated by FAO [²⁵,²⁷]. 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 [²⁷]. The inhibition of the key metabolic regulator, mTOR, during CD4⁺ T cell activation enhances FAO and reduces aerobic glycolysis favor Treg production [²⁸]. Metabolic regulation is involved in the rapid reactivation of Tmem cells. Within the CD8⁺ memory lineage, the production and persistence of Tmem, as well as repeat-antigen-induced reactivation, has been reported to be dependent on FAO regulation [²⁵,²⁹]. Tmem cells have a greater mitochondrial mass than other T cell subsets, specifically expressing the FAO-related enzymes and the carnitine palmitoyl transferase system proteins [²⁹–³¹], resulting in a stronger spare respiratory capacity (SRC). SRC represents the capability of cells to generate energy in response to activation or stress signals [²⁹,³²]. Thus, the stronger SRC capacity of the Tmem cell promotes their survival under harsh conditions [³³].

Nutrient uptake and T cell immunity

Following TCR ligation and co-stimulatory factor activation, T cells show a rapid proliferation and reprogramming, resulting in the high expression of cytotoxins, cell surface molecules, and cytokines. The growth, proliferation, and differentiation of T cells, as well as related protein synthesis, are accompanied by metabolite uptake that provides the energy required for T cell metabolism [³⁴,³⁵]. T cell activation relies on nutrient uptake; thus, glucose and amino acid are crucial for T cell growth and activation [³⁶].

Glucose uptake

In mammals, glucose uptake depends on the expression of the cell surface glucose transporter family (Glutl–14) [³⁷–³⁹]. Glucose transporters are selectively expressed on the T cell surface, including Glut1, 2, 3, 6 and 8, of which Glut1 is the most important glucose transporter responsible for basal glucose transport in all immune cells [⁴⁰]. During the activation process, T cells need to uptake nutrients to promote their proliferation and differentiation and to meet the metabolic needs of the effector molecules. For the Teff subset, glucose uptake is crucial for activation-associated functions [⁴⁰]. The activation of costimulatory signals promotes PI3K/Akt signaling to upregulate Glut1 [⁴¹]. A high expression of Glut1 alone on the cell surface is sufficient to promote a dramatic increase in glucose influx, which meets the rapidly increasing cell demands for glycolysis [⁴²,⁴³]. The overexpression of Glut1 enhances naïve T cell proliferation and activation [⁴⁴]. Conversely, the deletion of Glut1 inhibits the proliferation and differentiation of murine Teff subsets when activated in vivo [⁴⁰].

Amino acid uptake

T cell activation also depends on amino acid uptake, and the high expression of amino acid transporter proteins increases the activation of T cells. During the T cell activation process, glutamine is the most important amino acid. Glutaminolysis is required to absorb and break down glutamine, and its derivatives can be fed into the TCA cycle for the de novo synthesis of lipid and NADPH, which benefits T cell activation. Several specific transporters play an important role in glutamine uptake. The antiporter, ASC amino acid transporter 2 (ASCT2; also known as Slcla5), is upregulated during TCR activation [⁴⁵]. In the mouse EAE model, CD4⁺ T-cell-specific deletion of ASCT2 significantly suppresses the immune response of Th1 and Th17 and alleviates the progress of EAE in mice [⁴⁵]. CD8⁺ T cell function depends primarily on the leucine transport pathway. Following exposure to activating signals through TCR ligation and co-stimulation, system L neutral amino acid transporter 1 (LAT1; also referred to as Slc7a5) is upregulated in the CD4⁺ and CD8⁺ T cell surface. LAT1 is primarily responsible for the absorption of important branched chain (e.g., leucine and isoleucine) and aromatic (e.g., tryptophan and phenylalanine) amino acids. LAT1 also participates in a small amount of glutamine transport [⁴⁶–⁴⁸]. CD8⁺ T cell differentiation and migration are dependent on LAT1-mediated leucine influx [⁴⁹–⁵¹]. Therefore, LAT1 deficiency impairs T cell proliferation and effector differentiation. Taken together, an appropriate intracellular concentration of amino acids is critical to establish an effective immune response during T cell activation.

Key metabolic checkpoints of T cell immunity

Mammalian target of rapamycin

mTOR is a serine/threonine kinase discovered as the cellular target of rapamycin [⁵²], which exists in the form of two complexes, namely, mTORC1 and mTORC2. The activity of mTORC1 and mTORC2 significantly affects CD4⁺ T cell differentiation. Treatment with rapamycin inhibits Teff cell differentiation by primarily affecting the mTORC1 activity [⁵³–⁵⁵]. Inhibition of the mTORC1 and mTORC2 activities by deleting mTOR affects the differentiation of Th1, Th2, and Th17 [⁵³]. However, specific knockout of Rheb in T cells, which inhibits mTORC1 activity alone, impairs Th1 and Th17 cell differentiation but does not affect Th2 cell differentiation [²⁸]. Several studies further indicated that Th17 differentiation is inhibited in the T-cell-specific deletion of Raptor mice, whereas Th1 differentiation is unaffected [⁵⁶]. mTORC1 reportedly promotes the expression of S6K2, thus affecting the differentiation of Th17. mTORC1 also promotes the nucleus translocation RORgt, a major transcription factor of Th17 [⁵⁶]. Treatment with arctigenin, a chemical inhibitor of mTORC1, inhibits the Th1 and Th17 differentiation [⁵⁷]. Using a T-cell-specific deletion of the Raptor model, another group observed that the loss of mTORC1 restricts Th2 differentiation [⁵⁸]. Notably, the role of mTORC2 in Teff cell differentiation is complicated. Although most studies showed that deletion of Rictor in T cells suppresses Th2 differentiation [²⁸,⁵⁹], mTORC2 has also been shown to promote Th1 differentiation [⁵⁹]. In the case of T-cell-specific deletion of Sin1, another key component of mTORC2, no obvious preference for Th1, Th2, and Th17 cell differentiation in vitro was observed, indicating that the role of mTORC2 in T helper cell differentiation and effector function is more complex than previously thought (Ouyang, Omotooke, & Su, unpublished data).

mTOR signaling plays an important role in the metabolic regulation of T cells. In view of glycolysis, mTORC1 promotes Glut1gene expression and in turn enhances glycolysis [⁶⁰]. Glutamine uptake is significantly increased in the early stages of Th17 differentiation [⁶¹], and the activation of mTORC1 in CD4⁺ T cells is dependent on ASCT2. By contrast, Th17 differentiation is impaired in ASCT2-deficient mice, illustrating that glutamine regulated Th17 differentiation [⁴⁵]. Notably, mTOR induces Th17 differentiation by promoting the expression of hypoxia-inducible factor 1a (HIF1a). mTOR and HIF1a promote glucose uptake and glycolysis at the transcriptional and translational levels [⁶²]. Previous studies have shown that Th17 cells are more dependent on glycolysis than any other subset of T cells [²⁸,⁵⁶,⁶³]. Without HIF1a, Th17 development in mice is significantly impaired [58]. HIF1a can enhance glucose uptake and promote glycolysis by upregulating the expression of Glut1 and pyruvate dehydrogenase kinase 1 (PDK1). Glut1 promotes glucose transport across the cell membrane, and PDK1 prevents pyruvate from entering the TCA cycle, driving it to lactate, and promoting glycolysis. The activation of mTOR signaling promotes fatty acid synthesis (FAS) and aerobic glycolysis, thereby further inhibiting Treg differentiation. In the absence of mTORC1 and mTORC2 activities, naïve CD4⁺ T cells only differentiate into Treg [²⁸,⁵⁶]. Several studies have shown that a certain connection exists between the proliferation of Treg and the transient inhibition of mTOR signaling. However, thus far, the underlying mechanism of these phenomena is still unclear [²⁸,⁶⁴].

AMP-activated protein kinase

AMP-activated protein kinase (AMPK) is an enzyme that responds to the harsh survival environment of the cells and is activated in the absence of energy or other physiological stresses. Therefore, AMPK is an important cellular sensor of energy stress. The activation of AMPK results in the downregulation of energy-consuming metabolism, such as fatty acid or protein synthesis, and the upregulation of catabolic metabolism, such as glucose and FAO [⁶⁵,⁶⁶]. AMPK activation regulates many of the important enzymes involved in the metabolic pathways of FAO and FAS, such as ACC1, ACC2, CPTI, and SREBP-1c. CPT1, as the rate-limiting enzyme in FAO, is critical for the metabolism of FAO. The phosphorylation of ACC1/2 and SREBP-1c inhibits FAS but activates FAO [90].

AMPK activation inhibits anabolic metabolism, and AMPK can inhibit glycolysis [⁶⁵,⁶⁷,⁶⁸]. AMPK activation also inhibits T cell differentiation. As mentioned previously, Th17 cells are more dependent on glycolysis and Treg cells are more dependent on FAO, such that the capability of AMPK-mediated metabolism regulates the balance between Th17 and Treg. AMPK activation can drive naïve T cells to differentiate into Treg in vitro and in vivo. By contrast, the loss of AMPK results in upregulated mTOR activity and increased glycolysis [⁶⁷]. Studies have shown that metformin, an activator of AMPK, can inhibit Th1 and Th17 differentiation [⁶⁹,⁷⁰]. Treatment with metformin or AICAR, a direct activator of AMPK, alleviates the progress in some inflammatory mouse models [⁷¹–⁷⁵]. Notably, metformin treatment increases the population of Treg in an asthmatic mouse model, further indicating that AMPK activation mediates FAO upregulation [²⁷] (Fig. 2).

Cellular Myc (c-Myc)

c-Myc is discovered as a driving transformative factor for lymphoma, which is caused by dysregulated Myc gene expression [⁷⁶,⁷⁷]. c-Myc is rapidly upregulated in the early TCR and co-stimulatory molecule-triggered signaling cascade. In the in vivo models, systemic knockout of c-Myc is lethal, but in vitro c-Myc deficiency can significantly inhibit glycolysis metabolism. Lack of c-Myc downregulates the expression of enzymes involved in the pentose phosphate pathway. Notably, specific deletion of c-Myc in T cells reduces the expression of LAT1 and ASCT2 [⁴⁵,⁷⁸] and inhibits T cell uptake of amino acids. c-Myc promotes T cell activation mainly by upregulating the transporters of glucose and amino acid, as well as promoting glycolysis and glutaminolysis [⁷⁸,⁷⁹]. Instability of c-Myc expression leads to the downregulation of Glut1, which reduces glutamine and arginine uptake of T cells and inhibits glutamine glutaminolysis and T cell glycolysis [⁷⁹]. These findings indicate that c-Myc plays a multifaceted role in T cell activation and T cell metabolism.

Tumor microenvironment and T cell metabolism

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 [⁸⁰] and T cell metabolism is altered [⁸¹], which promotes tumor escape and development [⁸²,⁸³]. Recent studies have shown that antitumor functions of effector T cells are impaired in the tumor microenvironment [⁸⁴]. In fact, the tumor microenvironment forms a complex immunosuppression network that inhibits metabolic regulation during tumor development [⁸⁵], thereby limiting T cell activation and inducing T cell anergy [⁸⁶,⁸⁷]. 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 [⁸⁸]. In the tumor microenvironment, metabolic interference and nutrients competition exist between cancer and T cells, which are important to drive cancer development [⁸⁹,⁹⁰]. Tumor cells require a large amount of energy metabolism to proliferate by increasing glycolysis and glucose uptake from the surrounding environment [⁹¹]. 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 [⁹²].

Studies have shown that Treg differentiation is inconducive to tumor immunity [⁹³,⁹⁴]. In contrast to effector T cells, Treg are more likely to be activated in the tumor microenvironment [⁹⁵]. When the AMPK signaling pathway inhibits the mTOR signaling pathway, the balance between Teff and Treg may be directly disturbed in the tumor microenvironment [⁹⁶,⁹⁷]. In contrast to mTOR cascade, AMPK cascade is dominantly activated when nutrients are absent and oxidative metabolism is enhanced [⁹⁷]. 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.

Conclusions

Immune cells play an important role in maintaining homeostasis and regulating cellular functions. T lymphocytes act as an important immune cell population involved in immunoregulation. Recently, many studies have shown that metabolism and T cell immunity are closely related. Metabolites are utilized to provide energy during T cell activation, and glycolysis and FAO are important cellular metabolic pathways involved in this process. Intermediates produced by cell metabolism and glucose and amino acid intake promote T cell activation, and the expression of glucose and amino acid transporters on the cell surface benefits T cell activation.

During activation, T cells differentiate into diverse effector molecules and T cell subsets, which possess specialized function, resulting in dynamic T cell immunity. Metabolic pathways involved in mediating T cell function within diverse T cell subsets are different, and specific nutrient uptake is different in these subsets.

Numerous studies have shown that the regulation of T cell immunity effectively controls the occurrence of immune diseases and maintains T cell homeostasis. Metabolic regulation is important for T cell function, which is crucial for immune disease therapy. Although a large number of studies have reported the relationship between metabolic regulation and immune diseases, thus far, how to control cell metabolism effectively to provide precise immunotherapy still requires extensive research.

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