能量代谢调控γδT细胞活化的研究进展
Research Progress on Energy Metabolism Regulating the Activation of γδT Cells
DOI:10.12677/pi.2024.134038,PDF,HTML,XML,下载: 14浏览: 21
作者:白金金,戴 岳*:中国药科大学中药学院中药药理与中医药学系,江苏 南京
关键词:γδT细胞能量代谢细胞活化免疫应答γδT CellsEnergy MetabolismCell ActivationImmune Response
摘要:代谢重编程与T细胞的发育、存活、活化及分化密切相关。T细胞被激活后,对维持细胞生长、增殖以及发挥作用所需的能量增加,需要通过重构细胞代谢来满足。γδT细胞作为T细胞的一种亚群,在自身免疫性疾病和肿瘤中发挥重要作用,已成为近年来的研究热点。本文简要综述脂质代谢、氧化磷酸化、谷氨酰胺代谢和糖酵解在调控γδT细胞活化中的参与和重要性,为构建针对其活化相关疾病的治疗策略提供思路。
Abstract:Metabolic reprogramming is closely associated with the development, survival, activation, and differentiation of T cells. Upon activation, T cells require increased energy to sustain cell growth, proliferation, and effector functions, all of which need the reprogramming of cellular metabolism. γδT cells, as a subset of T cells, have emerged as a research focus in recent years due to their significant roles in autoimmune diseases and cancer. This article briefly reviews the involvement and importance of lipid metabolism, oxidative phosphorylation, glutamine metabolism, and glycolysis in regulating the activation of γδT cells, providing insights for developing therapeutic strategies targeting diseases associated with γδT cell activation.
文章引用:白金金, 戴岳. 能量代谢调控γδT细胞活化的研究进展[J]. 药物资讯, 2024, 13(4): 334-340. https://doi.org/10.12677/pi.2024.134038

1. 引言

γδT细胞是CD3 + T细胞的一个独特亚群,其表面具有独特T细胞受体(TCR)。大多数T细胞属于αβT细胞,其TCR由两条糖蛋白链组成,称为α和βTCR链[1]。相反,γδT细胞的TCR由一条γ链和一条δ链组成[2]。这种T细胞通常不如αβT细胞常见,但在黏膜和上皮部位富集,例如皮肤、呼吸道、消化道和生殖道等[3]。与αβT细胞相比,γδT细胞是不受主要组织相容性复合物(MHC)限制的先天样淋巴细胞,在生理和病理条件下具有不同的功能。γδT细胞通常可分为两个功能亚群,即产生IFN-γ的γδT1细胞和产生IL-17A (γδT17)的γδT细胞[4][5]。近些年的研究表明,γδT细胞在肿瘤免疫学和自身免疫性疾病中发挥重要作用。

营养物质和新陈代谢是T细胞命运的关键调节因素[6]。大多数T细胞处于静止状态时,细胞不进行克隆扩增以及炎症因子的产生,因此代谢成本较低[7]。但当受到外界环境刺激时,这种情况就会发生变化,T细胞需要大量能量,以支持快速增殖,产生趋化因子及细胞因子等免疫介质[8]。基于代谢重编程在T细胞活化中的重要作用,本文综述细胞代谢与γδT细胞活化的研究进展。

2. γδT细胞活化中的能量代谢

2.1. 脂质代谢

脂质代谢包括脂肪酸代谢(脂肪酸合成、氧化、摄取)、胆固醇代谢、磷脂代谢和甘油三酯代谢。近些年的研究表明,诱导细胞脂肪酸生物合成是T细胞活化程序不可或缺的一部分[9],这些发现挑战了脂质仅仅是膜形成和增殖所需的结构分子的经典学说,并提出了脂质代谢是调节T细胞命运的核心开关的观点[10]。此外,一些脂质分子还充当信号信使,传递生理功能效应[11][12]。因此,脂质代谢是生理学、化学生物学和生化信号之间的一个关键枢纽。

脂肪酸是维持淋巴细胞活化、增殖和功能的关键能量来源。脂肪酸合成直接将葡萄糖代谢与从头合成脂肪酸联系在一起,这一过程受到包括乙酰辅酶A羧化酶1 (ACC1)、脂肪酸合酶(FASN)等在内的关键酶的严格调控[13][14]。近年来的一系列研究揭示了脂肪酸代谢对T细胞分化及活化的重要性。通过检测小鼠脾脏、淋巴结和肺组织中γδT1和γδT17细胞内中性脂质的含量,发现γδT17细胞内脂质水平高于γδT1,且给予IL-1β和IL-23活化γδT17后胞内脂质含量进一步上调,为非活化状态的2.5倍[15]。Cheng等人发现γδT细胞的胆固醇水平高于αβT细胞,且随着γδT17细胞内胆固醇含量增多,脂筏形成增加,后者通过激活ERK1/2信号通路增强了TCR信号传导,促进γδT17细胞活化[16]

在采用咪喹莫特(IMQ)建立的银屑病小鼠模型中,高脂饮食组小鼠皮肤中的γδT细胞的数量是正常饮食组小鼠的10倍,且大多数增加的γδT细胞亚群是产生IL-17的Vγ4 γδ T细胞[17]。外源添加棕榈酸后,肝脏内γδT17细胞活化增加[18]。这表明脂质环境的变化对γ/δ T细胞活化具有明显的影响。

脂肪酸结合蛋白(fatty acid-binding protein, FABP)是胞内脂质结合蛋白超家族成员,广泛存在于哺乳动物的小肠、肝、心、脑、骨骼肌等多种器官内,其作用是促进脂肪酸增溶、运输和新陈代谢。FABP3缺失可导致小鼠脾脏、胸腺、淋巴结和皮肤内产生IL-17的Vγ4γδT细胞过度激活,分泌大量IL-17,增强接触性超敏反应[19]

肠上皮内淋巴细胞(IELs),是存在于小肠黏膜上皮的一类独特的细胞群。这些细胞在人体免疫系统中扮演着重要角色,特别是在黏膜免疫系统中[20]。IEL细胞有两种不同的来源,约40%的IEL为胸腺依赖性,主要为αβT细胞,约60%的IEL为胸腺非依赖性,主要为γδT细胞[21]。通过分析小肠记忆CD8 + T细胞和IELs细胞的转录谱,发现IEL细胞中参与脂质代谢和摄取的相关酶的表达明显高于CD8 + T细胞,尤其是参与甲羟戊酸、羊毛甾醇和胆固醇合成途径的酶。且脂质染色表明,IELs活化导致脂质代谢增加[22]

无独有偶,另一项研究分别对CD8 + αβT细胞和γδ IEL细胞进行了转录组分析。结果显示γδIEL细胞中许多与脂质和胆固醇代谢相关的基因表达明显高于CD8 + αβT细胞,且载脂蛋白E、磷脂结合蛋白、低密度脂蛋白受体以及一些参与脂肪酸、脂质和胆固醇生物合成的酶的mRNA仅在γδ IEL细胞中表达[23]。这一研究结果表明,γδ IEL细胞可能在脂蛋白颗粒的产生中发挥作用,包括乳糜微粒、极低密度脂蛋白和高密度脂蛋白。脂蛋白颗粒可以促进胆固醇从垂死细胞膜外流,并为快速分裂的上皮细胞提供胆固醇,从而维持体内平衡。

生酮饮食是一种极高脂肪、极低碳水化合物的饮食,其中约90%的热量来自脂肪,而碳水化合物的热量不足1%,从而限制了葡萄糖的供应,迫使代谢转向脂肪酸氧化。Emily L等分别对正常饮食和生酮饮食的小鼠组织中的CD45细胞进行了单细胞RNA测序(scRNA-seq),发现生酮饮食1周的小鼠组织内γδT细胞数目显著增多,且对γδT细胞进行表型鉴定后发现,饲以生酮饮食1周后小鼠体内优先扩增CD44CD27 + -γδT细胞亚群,而该亚群属于产生IL-17的γδ T细胞亚群[24]

2.2. 氧化磷酸化

氧化磷酸化(OXPHOS)发生在线粒体中,是细胞利用碳和氧气产生ATP的一种主要方式[25]。既往认为肿瘤细胞中OXPHOS会减少[26],糖酵解是产生ATP的关键途径。但近些年的研究表明,在很多类型的肿瘤细胞或免疫细胞中,OXPHOS在满足细胞的生物能和大分子合成代谢需求方面发挥着关键作用[27]

分别以AG1和OXA抑制异柠檬酸脱氢酶和丙酮酸激酶,浓度依赖性减少真皮γδT细胞IL-17的产生,表明OXPHOS在IL-17产生中发挥重要作用,而使用2-脱氧-D-葡萄糖(2-DG)抑制糖酵解则对真皮γδT的IL-17产生没有明显的影响[28],表明γδT17细胞主要利用OXPHOS作为能量供应途径。

mTOR信号传导在细胞代谢中起着关键作用。mTOR有两种不同的复合物,即mTORC1和mTORC2,它们分别含有支架蛋白Raptor或Rictor。在真皮γδT17细胞中,用IL-1β和IL-23刺激可直接激活mTOR,从而增加IL-17产生。由于线粒体的功能与OXPHOS密切相关,在Rictor条件敲除小鼠的真皮γδT细胞中,线粒体呼吸减少,而在Raptor条件敲除小鼠的真皮γδT细胞中则没有。线粒体呼吸减少导致OXPHOS降低,从而减少了Rictor条件敲除小鼠的真皮γδT细胞中IL-17的产生[28]。线粒体呼吸减少可能是由于细胞内产生了过量亚硝基氧化物(NO),后者可抑制OXPHOS[29]

Špela等人发现,IEL在激活后24 h左右OXPHOS能力明显爆发,并在48 h后恢复到基础水平。当外源添加葡萄糖时,不仅增强了细胞内的糖酵解能力,同时OXPHOS能力也明显增强。并且当抑制活化的IEL细胞内的脂肪酸氧化或谷氨酰胺代谢时,其OXPHOS能力也会明显增强。总的来说,IEL的活性受到环境中代谢物的直接调节,它可以最佳地利用其它代谢物增强细胞内的OXPHOS[30]

2.3. 谷氨酰胺代谢

谷氨酰胺是人体内含量最丰富的氨基酸[31],其浓度是其他氨基酸的10到100倍,可作为许多关键生物合成过程的底物[32]。除了对细胞完整性作出贡献外,谷氨酰胺也被认为是一种可以调节免疫的营养物质[33][34]。在快速分裂的免疫细胞(包括淋巴细胞)中,即使葡萄糖丰富,谷氨酰胺的消耗量也与葡萄糖相似或更高[35]。谷氨酰胺分解目前已被明确为T细胞的能量供应物质。

分别对γδT细胞及用IL-23和IL-1β处理的γδT使用超高效液相色谱–串联质谱(UPLC-MS/MS)进行代谢分析。结果显示,γδT细胞活化后,有7个氨基酸含量增加。其中谷氨酰胺、谷氨酸和天冬氨酸均参与谷氨酰胺代谢,由此推断谷氨酰胺代谢是γδT17细胞活化的关键。另外,谷氨酰胺缺乏或添加谷氨酰胺代谢拮抗剂(DON)均能抑制γδT17细胞活化,明显减少IL-17分泌[36]

在肝细胞癌患者体内,Vδ1T细胞富集在肿瘤组织内,而Vδ2T细胞富集在肿瘤周围组织和健康肝组织。对癌组织和癌旁组织中的γδT细胞进行单细胞RNA测序(scRNA-seq),分析发现肝癌肿瘤微环境中的γδT细胞内SLC1A5、OAT和GLS等基因表达上调,表明肝细胞癌肿瘤微环境的γδT细胞内谷氨酰胺代谢增加[37]

2.4. 糖酵解

在氧气不足的情况下,葡萄糖在细胞质中转化为丙酮酸,然后产生乳酸和ATP,这一过程称为糖酵解,是生物体产生ATP的一种主要方式[38][39]。通常,T细胞可以通过增加糖酵解的方式被激活以维持自身生长和增殖,促进能量增加和大分子生物合成[40],糖酵解在T细胞的活化、发育和成熟中起着重要作用[41]

CD27是区分分泌IFN-γ的γδT细胞(CD27 + γδT1)与分泌IL-17的γδT细胞(CD27-γδT17)的功能标记物。碳标记的葡萄糖进行稳定同位素分析代谢组学(Stable isotope-resolved metabolomics, SIRM)分析结果显示,CD27 + γδT1中丙酮酸和乳酸等同位素标记物增加,揭示了其以糖酵解为主要代谢途径,而在CD27-γδT17中,增加的同位素标记物如顺式乌头酸、α-酮戊二酸、苹果酸和谷氨酸等主要参与三羧酸循环循环,且使用2-DG或草酸盐抑制葡萄糖代谢,CD27-γδT17细胞的IL-17分泌水平没有明显改变,而CD27 + γδT1细胞分泌的IFN-γ显著降低[42]。表明与CD27-γδT17相比,CD27 + γδT1在活化时更依赖于糖酵解。

同样,使用一种名为SCENITH™的新方法分析了分别从成熟的乳腺癌和结肠癌小鼠模型的肿瘤病灶中分离出来的γδT的代谢谱。发现两种模型中产生IFN-γ的γδT1细胞,无论在癌症早期还是晚期,其糖酵解能力都大大提升,而γδT17细胞则强烈依赖线粒体活性[15]

3. 结语

综上所述,产生IL-17的γδT17细胞在活化过程中,其脂质代谢、谷氨酰胺代谢和氧化磷酸化会增强,而产生IFN-γ的γδT1细胞在活化中更依赖于糖酵解为其提供能量。随着研究的深入,γδT细胞在疾病发生发展中所发挥的作用越来越被重视。基于不同能量代谢在不同γδT细胞和疾病进展中的重要性,靶向其代谢途径有望成为防治γδT细胞相关疾病的有效策略。

然而,目前关于γδT细胞活化的机制研究尚不够深入,尤其是关于能量代谢方面。γδT1细胞活化后为什么更偏向于糖酵解?γδT17细胞活化后脂质代谢、氧化磷酸化和谷氨酰胺代谢均发生了显著变化,这三者之间是否存在串扰,其活化的关键代谢途径是是哪一种,同时调控多个代谢途径是否能更有效地抑制γδT细胞活化?这些问题有待深入探究。此外,虽然已有很多文献报道抑制γδT细胞活化与增殖可缓解癌症与自身免疫性疾病(如银屑病、结肠炎、EAE等)的发生发展,但缺乏进一步的临床研究进行验证。因此,进一步加强γδT细胞活化中能量代谢调控机制的认识,有助于提高对其活化途径及临床重要性的认识。

NOTES

*通讯作者。

参考文献

[1] Rao, A., Agrawal, A., Borthakur, G., Battula, V.L. and Maiti, A. (2024) Gamma Delta T Cells in Acute Myeloid Leukemia: Biology and Emerging Therapeutic Strategies.Journal forImmunoTherapyof Cancer, 12, e007981.
https://doi.org/10.1136/jitc-2023-007981
[2] Guo, J., Chowdhury, R.R., Mallajosyula, V., Xie, J., Dubey, M., Liu, Y.,et al. (2024)γδT Cell Antigen Receptor Polyspecificity Enables T Cell Responses to a Broad Range of Immune Challenges.Proceedings of the National Academy of Sciences, 121, e2315592121.
https://doi.org/10.1073/pnas.2315592121
[3] Gao, Z., Bai, Y., Lin, A., Jiang, A., Zhou, C., Cheng, Q.,et al. (2023) Gamma Delta T-Cell-Based Immune Checkpoint Therapy: Attractive Candidate for Antitumor Treatment.Molecular Cancer, 22, Article No. 31.
https://doi.org/10.1186/s12943-023-01722-0
[4] Ribot, J.C., Lopes, N. and Silva-Santos, B. (2020)γδT Cells in Tissue Physiology and Surveillance.Nature Reviews Immunology, 21, 221-232.
https://doi.org/10.1038/s41577-020-00452-4
[5] Bank, I. (2020) The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases.Cells, 9, Article No. 462.
https://doi.org/10.3390/cells9020462
[6] Lim, S.A., Su, W., Chapman, N.M. and Chi, H. (2022) Lipid Metabolism in T Cell Signaling and Function.Nature Chemical Biology, 18, 470-481.
https://doi.org/10.1038/s41589-022-01017-3
[7] van der Windt, G.J.W., O’Sullivan, D., Everts, B., Huang, S.C., Buck, M.D., Curtis, J.D.,et al. (2013) CD8 Memory T Cells Have a Bioenergetic Advantage That Underlies Their Rapid Recall Ability.Proceedings of the National Academy of Sciences, 110, 14336-14341.
https://doi.org/10.1073/pnas.1221740110
[8] Veldhoen, M., Blankenhaus, B., Konjar, Š. and Ferreira, C. (2018) Metabolic Wiring of Murine T Cell and Intraepithelial Lymphocyte Maintenance and Activation.European Journal of Immunology, 48, 1430-1440.
https://doi.org/10.1002/eji.201646745
[9] Webb, L.M., Sengupta, S., Edell, C., Piedra-Quintero, Z.L., Amici, S.A., Miranda, J.N.,et al. (2020) Protein Arginine Methyltransferase 5 Promotes Cholesterol Biosynthesis-Mediated Th17 Responses and Autoimmunity.Journal of Clinical Investigation, 130, 1683-1698.
https://doi.org/10.1172/jci131254
[10] Ramos, G.P., Bamidele, A.O., Klatt, E.E., Sagstetter, M.R., Kurdi, A.T., Hamdan, F.H.,et al. (2023) G9a Modulates Lipid Metabolism in CD4 T Cells to Regulate Intestinal Inflammation.Gastroenterology, 164, 256-271.e10.
https://doi.org/10.1053/j.gastro.2022.10.011
[11] Shin, J., O’Brien, T.F., Grayson, J.M. and Zhong, X. (2012) Differential Regulation of Primary and Memory CD8 T Cell Immune Responses by Diacylglycerol Kinases.The Journal of Immunology, 188, 2111-2117.
https://doi.org/10.4049/jimmunol.1102265
[12] Wang, F., Beck-García, K., Zorzin, C., Schamel, W.W.A. and Davis, M.M. (2016) Inhibition of T Cell Receptor Signaling by Cholesterol Sulfate, a Naturally Occurring Derivative of Membrane Cholesterol.Nature Immunology, 17, 844-850.
https://doi.org/10.1038/ni.3462
[13] Berod, L., Friedrich, C., Nandan, A., Freitag, J., Hagemann, S., Harmrolfs, K.,et al. (2014) De Novo Fatty Acid Synthesis Controls the Fate between Regulatory T and T Helper 17 Cells.Nature Medicine, 20, 1327-1333.
https://doi.org/10.1038/nm.3704
[14] Kidani, Y., Elsaesser, H., Hock, M.B., Vergnes, L., Williams, K.J., Argus, J.P.,et al. (2013) Sterol Regulatory Element-Binding Proteins Are Essential for the Metabolic Programming of Effector T Cells and Adaptive Immunity.Nature Immunology, 14, 489-499.
https://doi.org/10.1038/ni.2570
[15] Lopes, N., McIntyre, C., Martin, S., Raverdeau, M., Sumaria, N., Kohlgruber, A.C.,et al. (2021) Distinct Metabolic Programs Established in the Thymus Control Effector Functions ofγδT Cell Subsets in Tumor Microenvironments.Nature Immunology, 22, 179-192.
https://doi.org/10.1038/s41590-020-00848-3
[16] Cheng, H., Wu, R., Gebre, A.K., Hanna, R.N., Smith, D.J., Parks, J.S.,et al. (2013) Increased Cholesterol Content in Gammadelta (γδ) T Lymphocytes Differentially Regulates Their Activation.PLOS ONE, 8, e63746.
https://doi.org/10.1371/journal.pone.0063746
[17] Nakamizo, S., Honda, T., Adachi, A., Nagatake, T., Kunisawa, J., Kitoh, A.,et al. (2017) High Fat Diet Exacerbates Murine Psoriatic Dermatitis by Increasing the Number of Il-17-ProducingγδT Cells.Scientific Reports, 7, Article No. 14076.
https://doi.org/10.1038/s41598-017-14292-1
[18] Torres‐Hernandez, A., Wang, W., Nikiforov, Y., Tejada, K., Torres, L., Kalabin, A.,et al. (2019)γδT Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming.Hepatology, 71, 477-494.
https://doi.org/10.1002/hep.30952
[19] Kobayashi, S., Phung, H.T., Kagawa, Y., Miyazaki, H., Takahashi, Y., Asao, A.,et al. (2020) Fatty Acid‐Binding Protein 3 Controls Contact Hypersensitivity through Regulating Skin Dermal Vγ4+γ/δT Cell in a Murine Model.Allergy, 76, 1776-1788.
https://doi.org/10.1111/all.14630
[20] Konjar, Š., Frising, U.C., Ferreira, C., Hinterleitner, R., Mayassi, T., Zhang, Q.,et al. (2018) Mitochondria Maintain Controlled Activation State of Epithelial-Resident T Lymphocytes.Science Immunology, 3, eaan2543.
https://doi.org/10.1126/sciimmunol.aan2543
[21] Jaeger, N., Gamini, R., Cella, M., Schettini, J.L., Bugatti, M., Zhao, S.,et al. (2021) Single-Cell Analyses of Crohn’s Disease Tissues Reveal Intestinal Intraepithelial T Cells Heterogeneity and Altered Subset Distributions.Nature Communications, 12, Article No. 1921.
https://doi.org/10.1038/s41467-021-22164-6
[22] Lockhart, A., Mucida, D. and Bilate, A.M. (2024) Intraepithelial Lymphocytes of the Intestine.Annual Review of Immunology, 42, 289-316.
https://doi.org/10.1146/annurev-immunol-090222-100246
[23] Fahrer, A.M., Konigshofer, Y., Kerr, E.M., Ghandour, G., Mack, D.H., Davis, M.M.,et al. (2001) Attributes ofγδIntraepithelial Lymphocytes as Suggested by Their Transcriptional Profile.Proceedings of the National Academy of Sciences, 98, 10261-10266.
https://doi.org/10.1073/pnas.171320798
[24] Goldberg, E.L., Shchukina, I., Asher, J.L., Sidorov, S., Artyomov, M.N. and Dixit, V.D. (2020) Ketogenesis Activates Metabolically ProtectiveγδT Cells in Visceral Adipose Tissue.Nature Metabolism, 2, 50-61.
https://doi.org/10.1038/s42255-019-0160-6
[25] Jiang, Z., He, J., Zhang, B., Wang, L., Long, C., Zhao, B.,et al. (2024) A Potential “Anti-Warburg Effect” in Circulating Tumor Cell-Mediated Metastatic Progression?Aging and Disease.
https://doi.org/10.14336/ad.2023.1227
[26] Warburg, O. (1956) On the Origin of Cancer Cells.Science, 123, 309-314.
https://doi.org/10.1126/science.123.3191.309
[27] Ward, P.S. and Thompson, C.B. (2012) Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate.Cancer Cell, 21, 297-308.
https://doi.org/10.1016/j.ccr.2012.02.014
[28] Cai, Y., Xue, F., Qin, H., Chen, X., Liu, N., Fleming, C.,et al. (2019) Differential Roles of the Mtor-Stat3 Signaling in DermalγδT Cell Effector Function in Skin Inflammation.Cell Reports, 27, 3034-3048.e5.
https://doi.org/10.1016/j.celrep.2019.05.019
[29] Yamasaki, H., Shimoji, H., Ohshiro, Y. and Sakihama, Y. (2001) Inhibitory Effects of Nitric Oxide on Oxidative Phosphorylation in Plant Mitochondria.Nitric Oxide, 5, 261-270.
https://doi.org/10.1006/niox.2001.0353
[30] Konjar, Š., Ferreira, C., Carvalho, F.S., Figueiredo-Campos, P., Fanczal, J., Ribeiro, S.,et al. (2022) Intestinal Tissue-Resident T Cell Activation Depends on Metabolite Availability.Proceedings of the National Academy of Sciences, 119, e2202144119.
https://doi.org/10.1073/pnas.2202144119
[31] Xu, Y., Li, M., Lin, M., Cui, D. and Xie, J. (2024) Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.Journal of Inflammation Research, 17, 603-616.
https://doi.org/10.2147/jir.s443482
[32] Zhu, L., Zhu, X. and Wu, Y. (2022) Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.Biomolecules, 12, Article No. 580.
https://doi.org/10.3390/biom12040580
[33] Wang, A., Luan, H.H. and Medzhitov, R. (2019) An Evolutionary Perspective on Immunometabolism.Science, 363, eaar3932.
https://doi.org/10.1126/science.aar3932
[34] Kim, H. (2011) Glutamine as an Immunonutrient.YonseiMedical Journal, 52, 892-897.
https://doi.org/10.3349/ymj.2011.52.6.892
[35] Cruzat, V.F., Krause, M. and Newsholme, P. (2014) Amino Acid Supplementation and Impact on Immune Function in the Context of Exercise.Journal of the International Society of Sports Nutrition, 11, Article No. 61.
https://doi.org/10.1186/s12970-014-0061-8
[36] Li, G., Liu, L., Yin, Z., Ye, Z. and Shen, N. (2021) Glutamine Metabolism Is Essential for the Production of IL-17A inγδT Cells and Skin Inflammation.Tissue and Cell, 71, Article ID: 101569.
https://doi.org/10.1016/j.tice.2021.101569
[37] He, W., Hu, Y., Chen, D., Li, Y., Ye, D., Zhao, Q.,et al. (2022) Hepatocellular Carcinoma‐InfiltratingγδT Cells Are Functionally Defected and Allogenic Vδ2+γδT Cell Can Be a Promising Complement.Clinical and Translational Medicine, 12, e800.
https://doi.org/10.1002/ctm2.800
[38] Upadhyay, S., Khan, S. and Hassan, M.I. (2024) Exploring the Diverse Role of Pyruvate Kinase M2 in Cancer: Navigating Beyond Glycolysis and the Warburg Effect.BiochimicaetBiophysicaActa(BBA)-Reviews on Cancer, 1879, Article ID: 189089.
https://doi.org/10.1016/j.bbcan.2024.189089
[39] Ganapathy-Kanniappan, S. and Geschwind, J.H. (2013) Tumor Glycolysis as a Target for Cancer Therapy: Progress and Prospects.Molecular Cancer, 12, Article No. 152.
https://doi.org/10.1186/1476-4598-12-152
[40] Alegre, M., Frauwirth, K.A. and Thompson, C.B. (2001) T-Cell Regulation by CD28 and CTLA-4.Nature Reviews Immunology, 1, 220-228.
https://doi.org/10.1038/35105024
[41] Previte, D.M., O’Connor, E.C., Novak, E.A., Martins, C.P., Mollen, K.P. and Piganelli, J.D. (2017) Reactive Oxygen Species Are Required for Driving Efficient and Sustained Aerobic Glycolysis during CD4+ T Cell Activation.PLOS ONE, 12, e0175549.
https://doi.org/10.1371/journal.pone.0175549
[42] Chen, X., Cai, Y., Hu, X., Ding, C., He, L., Zhang, X.,et al. (2022) Differential Metabolic Requirement Governed by Transcription Factor C-Maf Dictates InnateγδT17 Effector Functionality in Mice and Humans.Science Advances, 8, eabm9120.
https://doi.org/10.1126/sciadv.abm9120

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