Metabolic Control of γδ T Cell Function : Infectious Microbes & Diseases

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Review Article

Metabolic Control of γδ T Cell Function

Meng, Ziyu1; Cao, Guangchao2,3; Yang, Quanli2,3; Yang, Hengwen2,3; Hao, Jianlei2,3; Yin, Zhinan2,3

Editor(s): Wang, Fudi

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Infectious Microbes & Diseases 3(3):p 142-148, September 2021. | DOI: 10.1097/IM9.0000000000000054
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The immune system recognizes and eliminates invading pathogens and coordinates with other physiological systems to maintain the stability of the biological internal environment. Cell metabolism enables organisms to grow and reproduce and respond to their environment. There is a close link between immune response and cell metabolism. Activated immune cells are accompanied with rapid cell proliferation fueled by elevated glucose uptake and glycolysis. Various intermediates produced by metabolism also provide raw materials for the synthetic pathway of T cell proliferation. Different subsets of T cells have unique metabolic patterns. The up-regulated expression of glucose transporter 1 (GLUT-1) in Th17 cells can increase the ability of glucose uptake and promote glycolysis. However, the expression of GLUT-1 in Treg cells is down-regulated and the ability of glucose uptake is decreased. Treg cells obtain energy mainly through oxidation of fatty acids.1

γδ T cells are a subset of T cells, and their T cell receptors are composed of γ and δ chains. γδ T cells account for approximately 1%–5% of T cells, which are mainly distributed in the digestive tract, respiratory tract, mucosa, and skin. As a bridge between innate and adaptive immune responses, γδ T cells have a spontaneous activation phenotype and a major histocompatibility complex-independent antigen recognition process, which shows the unique function and potential application value of γδ T cells.2,3 Thymic selection induces γδ T cells to differentiate into two subsets. In the embryonic thymus development, γδ T cells are the first emerging and mature subset. Antigen-stimulated γδ T cells mainly produce interferon (IFN)-γ and express CD27, whereas antigen-naive γδ T cells are interleukin (IL)-17+CD27.4,5 These two subsets play different regulatory roles in diverse physiological processes.

In recent years, the immunometabolic mechanism of γδ T cells has been attracting researchers’ interests. At present, the metabolic pathways involved in relevant studies mainly include glucose, fatty acids, amino acids, vitamins, and plant extracts. In this review, we summarize the influence of metabolic pathways and nutrients on γδ T cell function, and metabolic features of γδ T cell subsets, which provide new insights into interventions targeting γδ T cells in disease control.

Glucose metabolism and γδ T cell development, differentiation, and function

Carbohydrate is the main energy source to sustain life activities, in which the most indispensable for cells is glucose metabolism. The energy metabolism of normal cells is characterized by the use of glucose for oxidative phosphorylation in the mitochondria, which is economical and efficient. In the absence of oxygen, glucose undergoes glycolysis in the presence of a series of enzymes in the cytoplasm, which generate pyruvic acid, lactic acid, adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NADPH). The glycolysis pathway is usually inhibited under aerobic conditions, but some rapidly proliferating cells, such as tumor cells, activated immune cells, and smooth membrane cells, can rapidly obtain energy by the glycolysis pathway, which is called aerobic glycolysis or Warburg effect.6

Our group has been studying the role of γδ T cells and their subsets in tumor immunity for nearly twenty years. We demonstrated that γδ T cells are able to differentiate into two groups in vitro, which respectively secretes IFN-γ and IL-4. However, unlike αβ T cells, γδ T cells mainly produce IFN-γ, even in the presence of IL-4.7 We also clarified the molecular mechanism of IFN-γ production by γδ T cells. The IFN-γ promoter region has a higher degree of demethylation, which indicates that the gene is more open and easy to initiate transcription, and is regulated by transcription factors T-bet and Eomes.8 Using a mouse tumor model, we further demonstrated that γδ T cells provide an early source of IFN-γ, and is also the first subset to infiltrate the tumor microenvironment and regulate IFN-γ production by αβ T cells.9 Further studies revealed that two subsets of γδ T cells play different roles in tumor immune responses. Activated Vγ4 γδ T cells protect against melanoma formation by producing IFN-γ and perforin, but Vγ1 γδ T cells negatively regulate anti-tumor immune responses by producing IL-4 to inhibit the expression of IFN-γ, perforin, and NKG2D.10,11

Early studies mainly focused on the role of γδ T cells in anti-tumor immune responses. In recent years, we were interested in the mechanism of immune metabolism of γδ T cells. Mammalian target of rapamycin (mTOR) is a serine/threonine protease that forms two specific protein complexes, namely mTORC1 and mTORC2, which are involved in the process of cell proliferation, apoptosis, autophagy, and energy metabolism.12,13 We found that the mTOR specific inhibitor rapamycin is able to enhance terminally differentiated Vγ4 γδ T cell cytotoxicity on a variety of tumor cell lines via upregulating the expression of tumor necrosis factor-α (TNF-α) and NKG2D. Rapamycin-treated Vγ4 γδ T cells showed better tumor suppressive effects in adoptive therapy in vivo.14 Next, we explored the effect of mTOR-mediated metabolic procedures on γδ T cell differentiation. mTORC1 contains the characteristic protein Raptor, which is highly sensitive to rapamycin. mTORC2 contains another protein, Rictor, which is relatively insensitive to rapamycin-mediated inhibition.15 mTORC1, but not mTORC2, is indispensable for the proliferation and survival of γδ T cells. In the process of cell differentiation, mTORC1 is essential for both γδ T1 (IFN-γ-producing γδ T cells) and γδ T17 (IL-17A-producing γδ T cells) differentiation, but mTORC2 is only essential for γδ T17 differentiation. In terms of energy metabolism mechanism, mTORC1 maintains γδ T17 differentiation by regulating glycolysis, whereas mTORC2 induces γδ T17 differentiation by inhibiting mitochondrial reactive oxygen species production, mainly via the oxidative phosphorylation process. Raptor-deficient γδ T cells are unable to perform IFN-γ–medicated anti-tumor immune responses, whereas both Raptor- and Rictor-deficient mice resist the IL-17A–mediated pathological process of psoriasis (Figure 1).16

Figure 1:
The cross-talk between glucose or fatty acid metabolism and γδ T cell function. γδ T cells express higher surface levels of glucose transporters (GLUT) to further promote glucose absorption and utilization. Glucose metabolism can also affect γδ T cell differentiation by mTOR-mediated metabolic pathways. γδ T cells are sensitive to fatty acids. Adipose-resident γδ T cells have regulatory effects on obesity-related inflammatory responses, glucose homeostasis and insulin resistance, and also participate in the thermogenesis and body-temperature control. γδ T cells may promote the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

Other researchers have also shared new insights on the role of glucose metabolism in γδ T cell differentiation. mTORC1 plays diverse roles in the differentiation of αβ T cells and γδ T cells.17 Moreover, the capacity of glucose uptake may also be different between αβ T cells and γδ T cells. Compared with αβ T cells, γδ T cells express higher surface levels of GLUT, especially GLUT1 and GLUT3, to further promote glucose absorption and utilization, which contributes to the differentiation of naive γδ T cells into effector γδ T cells that produce cytokines (Figure 1).18 As a bridge between innate and adaptive immunity, γδ T cells have the strong ability of tumor killing and are not restricted by major histocompatibility complex. mTOR acts as an energy sensor that can senses nutrients and signals, and also has specific inhibitors. Regulating mechanisms of γδ T cell metabolism by mTOR and related signaling pathways are worth further studying.

Diabetes mellitus (DM) is a metabolic disease characterized by dysfunction of glucose metabolism, including Type 1 (T1DM) and Type 2 (T2DM). T1DM is a T cell-mediated autoimmune disease. On the basis of genetic susceptibility, pancreatic β cells are damaged and release sensitizing proteins that cause cellular and humoral immune responses and apoptosis of β cells. Different from T1DM, insulin resistance caused by changes in lifestyle and diet is the main pathogenesis of T2DM.19 In the development of T1DM, the proportion of T cell subsets is unbalanced. The number of Th1 cells is increased, but the number of Th2 and CD8+ T cells is decreased in the peripheral blood of T1DM patients. Th1 cells can directly or indirectly induce the apoptosis of pancreatic β cells by secreting IFN-γ.20,21 Interestingly, both the absolute number and the proportion of γδ T cells were found to be decreased in the peripheral blood of pre-diabetics.22 Similar results have also been confirmed by other researchers. The proportion of γδ T cells in patients with new-onset T1DM was significantly lower than in controls. Even after insulin treatment for 12 months, the proportion of γδ T cells in insulin-treated T1DM patients was still lower than in new-onset T1DM patients.23 However, there was no difference in the proportion of γδ T cells between non-diabetics and T2DM patients.24 These results indicate that γδ T cells might play a regulatory role in T1DM, and further regulate glucose metabolism and insulin resistance. Application of γδ T cells may provide a potential therapeutic approach for treating T1DM.

Fatty acid metabolism and γδ T cell function

Fatty acids are the main components of triglyceride, phospholipids, and glycolipid. According to the length of carbon chain, fatty acids can be divided into short-chain fatty acids (SCFAs), medium-chain fatty acids, and long-chain fatty acids. Fatty acids can also be classified as essential fatty acids and non-essential fatty acids. Essential fatty acids, including linoleic acid, α-linolenic acid, and arachidonic acid, cannot be synthesized in the body and must be obtained from food. Dietary sources of polyunsaturated fatty acids (PUFAs) are mainly divided into Omega-6 (ω-6) and Omega-3 (ω-3) PUFAs. As a major source of energy for cell metabolism, fatty acids can also regulate the function of γδ T cells in different tissues. Dendritic epidermal T cells (DETCs) are a subset of γδ T cells in the skin epidermis that originate from yolk sac hematopoiesis.25 SCFAs, especially butyrate, can transform the energy metabolism form of DETCs from glycolysis to mitochondrial respiration. SCFAs can also significantly inhibit DETC-mediated inflammation by inhibiting IFN-γ production to maintain skin homeostasis.26 ω-3 PUFAs suppress IL-17A production by γδ T cells and CD4+ T cells to reduce skin inflammation, which further delays the pathologic process of psoriasis.27 In the development of dextran sulfate sodium (DSS)-induced ulcerative colitis, a lower ratio of ω-6/ω-3 PUFAs in the diet appears more effective to repair small intestinal injury, which is achieved by increasing the expression level of PPARγ in γδ T cell receptor+ intraepithelial lymphocytes (IEL).28 However, γδ T cells are also insensitive to some fatty acids, such as linoleic acid (Figure 1).29

As a classic endocrine organ, adipose tissue is indispensable for maintaining the homeostasis of lipid metabolism. Adipose tissue was originally defined as an energy storage organ, whereas recent studies reported that it also plays an important role in modulating immune responses. Adipose tissue contains most types of innate and adaptive immune cells, such as T cells, macrophages, dendritic cells, neutrophils, eosinophils, and mast cells.30,31 During high fat diet (HFD)-induced obesity, inflammation of adipose tissue may precede inflammation in the liver. γδ T cells can be activated by ketogenesis to mediate protective immunometabolic responses that reduce inflammation in the adipose tissue.32 Similar studies have also shown that a reduced ratio of αβ/γδ T cells can significantly inhibit inflammation, insulin resistance, and weight gain.33 This might be due to the fact that γδ T cell-derived IL-17A can negatively regulate adipogenesis and glucose homeostasis to delay the development of obesity.34 However, some studies suggested that γδ T cells can accelerate inflammation by regulating macrophage infiltration in the adipose tissue.35 Interestingly, HFD-induced obesity can exacerbate psoriasis by promoting IL-17A production in skin γδ T cells, especially Vγ4 γδ T cells.36 Although γδ T cells in the adipose tissue have regulatory effects on obesity-related inflammatory responses, glucose homeostasis and insulin resistance, the roles of adipose-resident γδ T cells are not well studied in the absence of obesity. A recent study revealed the cross-talk between γδ T cells and Treg cells in the adipose tissue, which regulates thermogenesis and body-temperature control. γδ T cells can promote thermogenesis by producing IL-17A and TNF-α to maintain catecholamine sensitivity (Figure 1).37 In summary, adipose-resident γδ T cells have multiple biological functions for maintaining immunometabolic homeostasis in the presence or absence of obesity. How do adipose-resident γδ T cells regulate immune homeostasis and body temperature in obesity? Continued research is needed to comprehensively elucidate regulatory roles of γδ T cells in adaptive thermogenesis.

The liver is another indispensable organ for fat synthesis and storage. The balance between fatty acid synthesis and oxidative decomposition in the liver is an important mechanism of lipid metabolism. Disruption of this balance may result in non-alcoholic fatty liver disease (NAFLD). NAFLD is a metabolic disease characterized by hepatocyte steatosis and lipid accumulation, including sample steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.38 NAFLD is closely related to insulin resistance, abnormal lipid metabolism, inflammation, mitochondrial dysfunction, and oxidative stress, among which inflammation plays a crucial role in the pathogenesis of NAFLD.39 Although macrophages, also called Kupffer cells, mainly mediate inflammatory responses in the progression of NAFLD, the role of γδ T cells has attracted researchers’ attention in recent years. During the development of NAFLD, liver-resident γδ T cells are the main source of IL-17A. IL-17A can aggravate the progression of NAFLD, especially the NASH stage.40,41 Neutralization of IL-17A partially reduces NAFLD-related liver injury.42 Hepatic γδ T17 cells accelerate the pathological process of NAFLD by lipid antigen presentation molecule CD1d.43 Similar to the results of animal experiments, hepatic CD161+ γδ T17 cells increasingly infiltrated the liver of NAFLD patients.44 In addition, some studies showed that γδ T cells can also accelerate NASH by promoting CD4+ T cell infiltration and activation of the inflammatory program, which is independent of IL-17A.45 Previous studies have shown that γδ T cells may promote the development of NAFLD (Figure 1). It is prospective to improve the biological functions of hepatic γδ T cells via drugs, which will provide new methods for NAFLD treatment and bring better social benefits in the future.

Amino acid metabolism in γδ T cell function

As the basic unit of protein and polypeptide synthesis, amino acids are indispensable to maintain normal growth and development of the body. At the same time, amino acids can also be used as metabolic intermediates and signal molecules to participate in a variety of physiological processes, such as immunometabolic regulation.46 Under normal physiological conditions, the concentration of plasma amino acids is relatively stable, but the concentration of amino acids in the circulation changes under some stress conditions, including infection and inflammation. Amino acids may be involved in regulating immune responses and the function of immune cells.47 Conversely, activated immune cells remodel the intracellular amino acid metabolism pathways to meet the changes of function.48

Compared with αβ T cells, the effects of amino acid metabolism on γδ T cell function has been relatively less studied. Recently we found the novel effects of glutamine metabolism on γδ T cell differentiation. Glutamine is the second most abundant metabolite in immune cells. The levels of key enzymes in glutamine synthesis or glutaminolysis can significantly influence the levels of glutamine. Glutaminase-1–mediated aberrant activation of glutaminolysis was demonstrated to accelerate the development of psoriasis by enhancing acetylation of histone H3 in the IL-17A promoter to further promote Th17 and γδ T17 differentiation both in psoriatic patients and mouse models.49 During the pathogenesis of psoriasis, amino acid transporters (LAT) also play regulatory roles. CD69 combined with LAT1 can promote the uptake of L-tryptophan and IL-22 production by γδ T cells, which further contributes to the development of psoriasis.50 LAT1 can also promote IL-17A production by Th17 cells and γδ T17 cells in psoriasis by the IL-23– and IL-1β–mediated PI3K/AKT/mTOR signaling pathway.51 Synergistic effects of amino acids and amino acid transporters may jointly regulate the differentiation and function of γδ T cells.

Different from psoriasis, glutamine may play protective roles by regulating the functions of γδ T cells in the pathogenesis of some other diseases. In the development of DSS-induced ulcerative colitis, glutamine can alleviate DSS-induced intestinal epithelial injury by increasing the proportion of γδ+ IEL and inhibiting the expression levels of inflammatory cytokines of γδ T cells, including IFN-γ, IL-17A, and TNF-α.52 Administration of glutamine can also attenuate acute lung injury by preventing apoptosis of γδ T cells and infiltration of neutrophils.53 In addition, arginine has been demonstrated to regulate IL-17A production by γδ T cells.54 Although the amino acid metabolism is a research hotspot at present, few studies investigated its effects on γδ T cell function. Whether amino acids and their derivatives can influence the fate of γδ T cells through epigenetic mechanisms remains to be investigated. How to combine amino acid metabolism with intracellular signaling pathways to study the fate of γδ T cells is also a worthwhile direction for further studies.

Vitamin metabolism and γδ T cell function

Vitamin is one of the most important essential nutrients for humans, and its receptors are distributed in many vital organs. Vitamins can not only participate in metabolic regulation, but also be closely related to the development of autoimmune diseases, tumors, cardiovascular diseases, and infectious diseases. There are many types of vitamins, but they can roughly be divided into two categories: fat-soluble vitamins (vitamin A, D, E, and K) and water-soluble vitamins (vitamin B and C). As an essential nutrient for growth and development, vitamins can also mediate innate and adaptive immune responses.55 Vitamins that influence the function of γδ T cells mainly include vitamin A, C, and D.

Vitamin A is a fat-soluble vitamin, and includes retinol, retinal, retinyl ester, and retinoic acid. Vitamin A is transported in the peripheral blood as retinol and stored in the liver as retinyl ester. As the most functional vitamin, vitamin A is indispensable for the development of the body from the embryo to adulthood, since it participates in the development of visual function, maintaining the integrity of cells and mediating immune responses.56,57 In the early stage of infection or inflammation, γδ T cells are the main source of IL-17A, and they can also secrete IFN-γ, TNF-α, and IL-22. In the development of intestinal inflammation, retinoic acid was demonstrated to control the proportion of intestinal effector αβ T cells and γδ T cells by inducing purinergic receptor P2X7 expression to inhibit inflammatory responses.58 Retinoic acid can also reduce intestinal inflammation by promoting IL-22 production by γδ T cells.59 However, some studies reported that retinoic acid aggravates ulcerative colitis by enhancing IFN-γ and IL-17A production by γδ T cells.60 Similarly, retinoic acid also plays a protective role during viral hepatitis by promoting IL-22 production by γδ T cells.7 In the pathogenesis of experimental autoimmune encephalomyelitis, retinoic acid inhibits IL-17A production by γδ T cells to reduce the activation of Th17 cells, which further suppresses inflammatory responses of the central nervous system.61,62

Vitamin C, also known as ascorbic acid, which is synthesized by most plants and animals, is an important nutrient that has a variety of biological functions. The demand of vitamin C can be satisfied by the daily diet in the physiological state. As a crucial reaction cofactor, vitamin C is involved in several key enzymatic reactions that are essential for energy metabolism.63,64 Vitamin C can control the activation and differentiation of T cells.65 Previous studies have reported that vitamin C can promote the maturation of αβ T cells.66 Excitingly, we recently demonstrated that vitamin C and its derivative phospho-modifed (pVC) can significantly promote proliferation and differentiation of human γδ T cells. Vitamin C mainly inhibits the apoptosis of γδ T cells, whereas pVC is able to promote cell cycle progression and cellular expansion. Both vitamin C and pVC can promote IFN-γ and TNF-α production by γδ T cells and enhance the oxidative respiration and glycolysis of γδ T cells. The vitamin C-mediated efficient amplification of γδ T cells can be applied for adoptive cellular immunotherapy.67 Similar results also showed that the amount of γδ T cells in human peripheral blood is positively correlated with the concentration of vitamin C.68 Moreover, pVC can also significantly increase FOXP3 expression of human γδ T cells to induce the suppressive capacity.69 Inflammation and oxidative damage are the common pathological processes of some acute and chronic diseases. Vitamin C has multiple therapeutic uses because of the capacities to prevent inflammation and oxidative damage. Regulating the function of γδ T cells by vitamin C may provide a potential therapeutic approach for adaptive immunotherapy.

Vitamin D is a steroid derivative, whose main biological role is the functional regulation of osteocytes and controlling bone metabolism by promoting the absorption of intestinal calcium.70 Vitamin D also has a range of non-calcium processive functions, such as stimulating the secretion of thyroxin and insulin, promoting cell differentiation, and regulating immune responses.71 1α,25-hydroxyvitamin D3 (vitD3) is the storage form of vitamin D, which is also an important indicator of vitamin D levels.72 Zoledronic acid infusion is a common treatment method for osteoporosis, but it also induces sterile inflammatory reactions because of the activation of γδ T cells. Vitamin D is able to alleviate musculoskeletal pain after zoledronic acid injection by decreasing inflammatory factors.73,74 The mechanism may be partially explained by the results of some other studies. Studies have shown that vitD3 can negatively regulate γδ T cell-mediated Th1-type inflammatory responses by inhibiting the proliferation and IFN-γ production of γδ T cells.75 A vitD3 analog is also able to inhibit IL-17A production by γδ T cells.76

Although these vitamins have different biological functions, they all can regulate the functions of γδ T cells to maintain immune homeostasis. At present, the mechanisms by which vitamins affect γδ T cells are still not fully understood, but they might be further elucidated by animal disease models combined with ingenious prospective studies. Application of multiple vitamins to regulate the function of γδ T cells for adoptive immunotherapy will have broad prospects in the future.

Plant extract metabolism and γδ T cell function

Plant extracts refer to the effective active ingredients obtained and concentrated by physical and chemical methods from plants, without changing their molecular structure. Plant extracts play regulatory roles in a variety of pathological processes because of their diversities in structures and functions, including anti-bacterial, anti-oxidant stress, anti-inflammatory, anti-tumor, and hypoglycemic effects.77

Apple polyphenols are compounds with benzene rings and multiple hydroxyl groups. As the secondary metabolites of plants, apple polyphenol is a superior antioxidant with anti-tumor, anti-atherosclerosis, anti-ultraviolet, and other functions. Intake of apple polyphenols prevents the development of food-induced allergies, which was shown to be related with the increased proportion of γδ+ IEL.78 Another study showed that apple polyphenols can induce γδ T cells to migrate to the inflammatory sites and regulate immune responses.79Viscum album, also called mistletoe, is a parasitic plant that lives on green plants. As a precious traditional Chinese medicine, mistletoe has anti-myocardial ischemia and anti-tumor effects. Interestingly, some studies demonstrated that mistletoe extract-treated human γδ T cells are sensitive to alkaline phosphatase, but not to proteinase K. Mistletoe extract is able to effectively activate human γδ T cells.80,81 Another plant-derived molecule, tannin, can also promote the proliferation of human γδ T cells.82,83 Our earlier results have confirmed that γδ T cells, especially Vγ4γδ T cells, can mediate anti-tumor immune responses by producing IFN-γ.9,10 Bioactive food components may mediate anti-tumor immune responses by activating γδ T cells.84 Whether plant extract-treated γδ T cells can further enhance anti-tumor effects is worth investigating in the future. As food additives or new drugs, plant extracts have the potential for diseases treatment by regulating the function of γδ T cells.

Metabolic features of γδ T cell subsets

Thymic selection induces γδ T cells to differentiate into two subsets. Antigen-stimulated γδ T cells mainly produce IFN-γ and express CD27 (γδ T1), whereas antigen-naive γδ T cells are IL-17+CD27 (γδ T17).4,5 These two subsets participate in different pathological and physiological processes. γδ T1 cells mainly perform anti-tumor effects by producing IFN-γ.9,10 Different from γδ T1 cells, γδ T17 cells can mediate inflammatory autoimmune diseases, regulate thermogenesis and body-temperature, and promote tumor proliferation.37,49,85 Next, we will further discuss the metabolic features of γδ T1 cells and γδ T17 cells.

γδ T1 cells prefer to utilize glucose for glycolysis to produce pyruvic acid and lactic acid.86 The transcription factor Myc, which controls glycolysis, is also highly expressed in γδ T1 cells. When stimulated with high doses of glucose, the proliferation of γδ T1 cells is increased with high expression levels of transcription factor T-bet, which leads to increased production of IFN-γ and enhanced capacity of tumor killing. IFN-γ+ γδ T1 cells can significantly inhibit tumor growth, especially in high glucose condition.87

With metabolic features different from γδ T1 cells, γδ T17 cells prefer to undergo oxidative phosphorylation with ROS production in the mitochondria. The citric acid cycle and oxidative phosphorylation are indispensable for IL-17 production by γδ T cells.86 The transcription factor Nrf1, which mainly regulates mitochondrial DNA transcription, is highly overexpressed in γδ T17 cells. In lipid-rich environments, such as after a high fat diet and cholesterol supplementation, the proliferation of γδ T17 cells is increased, which may promote tumor growth.87 Some other studies have also partially confirmed that γδ T17 cells prefer lipid metabolism. Adiponectin, which can promote the oxidation of fatty acids and perform hypolipidemic effects by inhibiting lipid synthesis, is a key regulator for maintaining the homeostasis of lipid metabolism. Adiponectin can also significantly inhibit IL-17 production by γδ T cells, which might suggest that γδ T17 cells are more sensitive to molecules related to lipid metabolism.88,89

Conclusions and prospects

There is a close link between the immune system and the metabolic system. It is prospective to improve the biological functions of γδ T cells via immunometabolic pathways, which will provide new methods for the clinical application of γδ T cells and bring better social benefits in the future.


[1]. Cluxton D, Petrasca A, Moran B, et al. Differential regulation of human Treg and Th17 cells by fatty acid synthesis and glycolysis. Front Immunol 2019;10:115.
[2]. Vantourout P, Hayday A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat Rev Immunol 2013;13(2):88–100.
[3]. Chien YH, Meyer C, Bonneville M. Gammadelta T cells: first line of defense and beyond. Annu Rev Immunol 2014;32:121–155.
[4]. Jensen KD, Su X, Shin S, et al. Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity 2008;29(1):90–100.
[5]. Ribot JC, deBarros A, Pang DJ, et al. CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets. Nat Immunol 2009;10(4):427–436.
[6]. Nakagawa T, Lanaspa MA, Millan IS, et al. Fructose contributes to the Warburg effect for cancer growth. Cancer Metab 2020;8:16.
[7]. Yin Z, Zhang DH, Welte T, et al. Dominance of IL-12 over IL-4 in gamma delta T cell differentiation leads to default production of IFN-gamma: failure to down-regulate IL-12 receptor beta 2-chain expression. J Immunol 2000;164(4):3056–3064.
[8]. Chen L, He W, Kim ST, et al. Epigenetic and transcriptional programs lead to default IFN-gamma production by gammadelta T cells. J Immunol 2007;178(5):2730–2736.
[9]. Gao Y, Yang W, Pan M, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 2003;198(3):433–442.
[10]. He W, Hao J, Dong S, et al. Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin. J Immunol 2010;185(1):126–133.
[11]. Hao J, Dong S, Xia S, et al. Regulatory role of Vgamma1 gammadelta T cells in tumor immunity through IL-4 production. J Immunol 2011;187(10):4979–4986.
[12]. Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002;110(2):163–175.
[13]. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124(3):471–484.
[14]. Cao G, Wang Q, Li G, et al. mTOR inhibition potentiates cytotoxicity of Vgamma4 gammadelta T cells via up-regulating NKG2D and TNF-alpha. J Leukoc Biol 2016;100(5):1181–1189.
[15]. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18(16):1926–1945.
[16]. Yang Q, Liu X, Liu Q, et al. Roles of mTORC1 and mTORC2 in controlling gammadelta T1 and gammadelta T17 differentiation and function. Cell Death Differ 2020;27(7):2248–2262.
[17]. Yang K, Blanco DB, Chen X, et al. Metabolic signaling directs the reciprocal lineage decisions of alphabeta and gammadelta T cells. Sci Immunol 2018;3(25):eaas9818.
[18]. Laird RM, Wolf BJ, Princiotta MF, et al. Gammadelta T cells acquire effector fates in the thymus and differentiate into cytokine-producing effectors in a Listeria model of infection independently of CD28 costimulation. PLoS One 2013;8(5):e63178.
[19]. Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature 2019;576(7785):51–60.
[20]. Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? Diabetes 1994;43(5):613–621.
[21]. Huang X, Yuang J, Goddard A, et al. Interferon expression in the pancreases of patients with type I diabetes. Diabetes 1995;44(6):658–664.
[22]. Kretowski A, Mysliwiec J, Szelachowska M, et al. Gammadelta T-cells alterations in the peripheral blood of high risk diabetes type 1 subjects with subclinical pancreatic B-cells impairment. Immunol Lett 1999;68(2–3):289–293.
[23]. Zubkiewicz-Kucharska A, Noczynska A. Abnormal distribution of gamma-delta T lymphocytes and their subsets in type 1 diabetes. Adv Clin Exp Med 2016;25(4):665–671.
[24]. Olson NC, Doyle MF, de Boer IH, et al. Associations of circulating lymphocyte subpopulations with type 2 diabetes: cross-sectional results from the multi-ethnic study of atherosclerosis (MESA). PLoS One 2015;10(10):e0139962.
[25]. Asarnow DM, Kuziel WA, Bonyhadi M, et al. Limited diversity of gamma delta antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell 1988;55(5):837–847.
[26]. Haselbarth L, Ouwens DM, Teichweyde N, et al. The small chain fatty acid butyrate antagonizes the TCR-stimulation-induced metabolic shift in murine epidermal gamma delta T cells. EXCLI J 2020;19:334–350.
[27]. Saito-Sasaki N, Sawada Y, Mashima E, et al. Maresin-1 suppresses imiquimod-induced skin inflammation by regulating IL-23 receptor expression. Sci Rep 2018;8(1):5522.
[28]. Pai MH, Liu JJ, Hou YC, et al. Soybean and fish oil mixture with different omega-6/omega-3 polyunsaturated fatty acid ratios modulates dextran sulfate sodium-induced changes in small intestinal intraepithelial gammadelta T-lymphocyte expression in mice. JPEN J Parenter Enteral Nutr 2016;40(3):383–391.
[29]. Pini M, Touch S, Poirier H, et al. Adipose tissue adaptive response to trans-10,cis-12-conjugated linoleic acid engages alternatively activated M2 macrophages. FASEB J 2016;30(1):241–251.
[30]. Chmelar J, Chung KJ, Chavakis T. The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost 2013;109(3):399–406.
[31]. Brestoff JR, Artis D. Immune regulation of metabolic homeostasis in health and disease. Cell 2015;161(1):146–160.
[32]. Goldberg EL, Shchukina I, Asher JL, et al. Ketogenesis activates metabolically protective gammadelta T cells in visceral adipose tissue. Nat Metab 2020;2(1):50–61.
[33]. Le Menn G, Sibille B, Murdaca J, et al. Decrease in alphabeta/gammadelta T-cell ratio is accompanied by a reduction in high-fat diet-induced weight gain, insulin resistance, and inflammation. FASEB J 2019;33(2):2553–2562.
[34]. Zuniga LA, Shen WJ, Joyce-Shaikh B, et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 2010;185(11):6947–6959.
[35]. Mehta P, Nuotio-Antar AM, Smith CW. Gammadelta T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. J Leukoc Biol 2015;97(1):121–134.
[36]. Nakamizo S, Honda T, Adachi A, et al. High fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing gammadelta T cells. Sci Rep 2017;7(1):14076.
[37]. Kohlgruber AC, Gal-Oz ST, LaMarche NM, et al. Gammadelta T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis. Nat Immunol 2018;19(5):464–474.
[38]. Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014;2(11):901–910.
[39]. Byrne CD. Fatty liver: role of inflammation and fatty acid nutrition. Prostaglandins Leukot Essent Fatty Acids 2010;82(4–6):265–271.
[40]. Harley IT, Stankiewicz TE, Giles DA, et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 2014;59(5):1830–1839.
[41]. He Q, Li F, Li J, et al. MicroRNA-26a-interleukin (IL)-6-IL-17 axis regulates the development of non-alcoholic fatty liver disease in a murine model. Clin Exp Immunol 2017;187(1):174–184.
[42]. Xu R, Tao A, Zhang S, et al. Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice. Acta Biochim Biophys Sin (Shanghai) 2013;45(9):726–733.
[43]. Li F, Hao X, Chen Y, et al. The microbiota maintain homeostasis of liver-resident gammadeltaT-17 cells in a lipid antigen/CD1d-dependent manner. Nat Commun 2017;7:13839.
[44]. Rajoriya N, Fergusson JR, Leithead JA, et al. Gamma delta T-lymphocytes in hepatitis C and chronic liver disease. Front Immunol 2014;5:400.
[45]. Torres-Hernandez A, Wang W, Nikiforov Y, et al. Gammadelta T cells promote steatohepatitis by orchestrating innate and adaptive immune programming. Hepatology 2020;71(2):477–494.
[46]. Li P, Yin YL, Li D, et al. Amino acids and immune function. Br J Nutr 2007;98(2):237–252.
[47]. Field CJ, Johnson IR, Schley PD. Nutrients and their role in host resistance to infection. J Leukoc Biol 2002;71(1):16–32.
[48]. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol 2016;16(9):553–565.
[49]. Xia X, Cao G, Sun G, et al. GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis. J Clin Invest 2020;130(10):5180–5196.
[50]. Cibrian D, Saiz ML, de la Fuente H, et al. CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat Immunol 2016;17(8):985–996.
[51]. Cibrian D, Castillo-Gonzalez R, Fernandez-Gallego N, et al. Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation. J Allergy Clin Immunol 2020;145(1):199–214.e11.
[52]. Pai MH, Liu JJ, Yeh SL, et al. Glutamine modulates acute dextran sulphate sodium-induced changes in small-intestinal intraepithelial gammadelta-T-lymphocyte expression in mice. Br J Nutr 2014;111(6):1032–1039.
[53]. Hu YM, Yeh CL, Pai MH, et al. Glutamine administration modulates lung gammadelta T lymphocyte expression in mice with polymicrobial sepsis. Shock 2014;41(2):115–122.
[54]. Singh K, Coburn LA, Barry DP, et al. Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL-17-predominant T cell response. Am J Physiol Gastrointest Liver Physiol 2013;305(3):G225–240.
[55]. Zitvogel L, Pietrocola F, Kroemer G. Nutrition, inflammation and cancer. Nat Immunol 2017;18(8):843–850.
[56]. Al Tanoury Z, Piskunov A, Rochette-Egly C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res 2013;54(7):1761–1775.
[57]. Larange A, Cheroutre H. Retinoic acid and retinoic acid receptors as pleiotropic modulators of the immune system. Annu Rev Immunol 2016;34:369–394.
[58]. Hashimoto-Hill S, Friesen L, Kim M, et al. Contraction of intestinal effector T cells by retinoic acid-induced purinergic receptor P2X7. Mucosal Immunol 2017;10(4):912–923.
[59]. Mielke LA, Jones SA, Raverdeau M, et al. Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med 2013;210(6):1117–1124.
[60]. Rampal R, Wari N, Singh AK, et al. Retinoic acid is elevated in the mucosa of patients with active ulcerative colitis and displays a proinflammatory role by augmenting IL-17 and IFNgamma production. Inflamm Bowel Dis 2020;27(1):74–83.
[61]. Raverdeau M, Breen CJ, Misiak A, et al. Retinoic acid suppresses IL-17 production and pathogenic activity of gammadelta T cells in CNS autoimmunity. Immunol Cell Biol 2016;94(8):763–773.
[62]. Almeida CF, Godfrey DI. Taming pathogenic gammadelta T cells with vitamin A. Immunol Cell Biol 2016;94(8):715–716.
[63]. D’Aniello C, Cermola F, Patriarca EJ, et al. Vitamin C in stem cell biology: impact on extracellular matrix homeostasis and epigenetics. Stem Cells Int 2017;2017:8936156.
[64]. Linster CL, Van Schaftingen E, Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J 2007;274(1):1–22.
[65]. Peters C, Kouakanou L, Kabelitz D. A comparative view on vitamin C effects on alphabeta- versus gammadelta T-cell activation and differentiation. J Leukoc Biol 2020;107(6):1009–1022.
[66]. Manning J, Mitchell B, Appadurai DA, et al. Vitamin C promotes maturation of T-cells. Antioxid Redox Signal 2013;19(17):2054–2067.
[67]. Kouakanou L, Xu Y, Peters C, et al. Vitamin C promotes the proliferation and effector functions of human gammadelta T cells. Cell Mol Immunol 2020;17(5):462–473.
[68]. Rowe CA, Nantz MP, Nieves C Jr, et al. Regular consumption of concord grape juice benefits human immunity. J Med Food 2011;14(1–2):69–78.
[69]. Kouakanou L, Peters C, Sun Q, et al. Vitamin C supports conversion of human gammadelta T cells into FOXP3-expressing regulatory cells by epigenetic regulation. Sci Rep 2020;10(1):6550.
[70]. Bell TD, Demay MB, Burnett-Bowie SA. The biology and pathology of vitamin D control in bone. J Cell Biochem 2010;111(1):7–13.
[71]. Ponsonby AL, Lucas RM, Lewis S, et al. Vitamin D status during pregnancy and aspects of offspring health. Nutrients 2010;2(3):389–407.
[72]. ACOG Committee Opinion No. 495: Vitamin D: Screening and supplementation during pregnancy. Obstet Gynecol 2011;118(1):197–198.
[73]. Catalano A, Morabito N, Atteritano M, et al. Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis. Calcif Tissue Int 2012;90(4):279–285.
[74]. De Santis M, Cavaciocchi F, Ceribelli A, et al. Gamma-delta T lymphocytes and 25-hydroxy vitamin D levels as key factors in autoimmunity and inflammation: the case of zoledronic acid-induced acute phase reaction. Lupus 2015;24(4–5):442–447.
[75]. Chen L, Cencioni MT, Angelini DF, et al. Transcriptional profiling of gamma delta T cells identifies a role for vitamin D in the immunoregulation of the V gamma 9 V delta 2 response to phosphate-containing ligands. J Immunol 2005;174(10):6144–6152.
[76]. Suzuki T, Tatsuno K, Ito T, et al. Distinctive downmodulation of plasmacytoid dendritic cell functions by vitamin D3 analogue calcipotriol. J Dermatol Sci 2016;84(1):71–79.
[77]. Chahal DS, Sivamani RK, Isseroff RR, et al. Plant-based modulation of Toll-like receptors: an emerging therapeutic model. Phytother Res 2013;27(10):1423–1438.
[78]. Akiyama H, Sato Y, Watanabe T, et al. Dietary unripe apple polyphenol inhibits the development of food allergies in murine models. FEBS Lett 2005;579(20):4485–4491.
[79]. Graff JC, Jutila MA. Differential regulation of CD11b on gammadelta T cells and monocytes in response to unripe apple polyphenols. J Leukoc Biol 2007;82(3):603–607.
[80]. Fischer S, Scheffler A, Kabelitz D. Activation of human gamma delta T-cells by heat-treated mistletoe plant extracts. Immunol Lett 1996;52(2–3):69–72.
[81]. Fischer S, Scheffler A, Kabelitz D. Stimulation of the specific immune system by mistletoe extracts. Anticancer Drugs 1997;8(Suppl 1):S33–37.
[82]. Holderness J, Hedges JF, Daughenbaugh K, et al. Response of gammadelta T cells to plant-derived tannins. Crit Rev Immunol 2008;28(5):377–402.
[83]. Holderness J, Jackiw L, Kimmel E, et al. Select plant tannins induce IL-2Ralpha up-regulation and augment cell division in gammadelta T cells. J Immunol 2007;179(10):6468–6478.
[84]. Percival SS, Bukowski JF, Milner J. Bioactive food components that enhance gammadelta T cell function may play a role in cancer prevention. J Nutr 2008;138(1):1–4.
[85]. Mensurado S, Rei M, Lanca T, et al. Tumor-associated neutrophils suppress pro-tumoral IL-17+ gammadelta T cells through induction of oxidative stress. PLoS Biol 2018;16(5):e2004990.
[86]. Chen X, Morrissey S, Chen F, et al. Novel insight into the molecular and metabolic mechanisms orchestrating IL-17 production in gammadelta T cells. Front Immunol 2019;10:2828.
[87]. Lopes N, Silva-Santos B. Functional and metabolic dichotomy of murine gammadelta T cell subsets in cancer immunity. Eur J Immunol 2021;51(1):17–26.
[88]. Shibata S, Tada Y, Hau CS, et al. Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from gammadelta-T cells. Nat Commun 2015;6:7687.
[89]. Luo Y, Liu M. Adiponectin: a versatile player of innate immunity. J Mol Cell Biol 2016;8(2):120–128.

γδ T cells; immunometabolism; glucose; fatty acid; amino acid; vitamins; plant extract

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