| 7 | 0 | 38 |
| 下载次数 | 被引频次 | 阅读次数 |
近年来，免疫代谢已成为一个新的研究领域，旨在探讨代谢与免疫之间的相互关系。大量研究表明，为了满足与增殖、活化和特定功能相关的能量需求，T细胞在分化过程中会重编程其代谢模式。例如，效应T细胞的增殖与分化需要启动脂肪酸合成代谢，而调节性T细胞和记忆T细胞的分化与成熟则主要依赖于脂肪酸氧化代谢。脂肪酸不仅是细胞膜的重要组成部分，在生物学过程中也发挥多种功能。本文综述了脂肪酸代谢的2个关键过程（脂肪酸合成和脂肪酸氧化）对T细胞增殖、分化和功能的调控作用，以期为临床自身免疫性疾病的干预提供新靶点和新策略。
Abstract：In recent years, immunometabolism has emerged as a new research field aimed at exploring the interrelationship between metabolism and immunity. Numerous studies have shown that to meet the energy demands associated with proliferation, activation, and specific functions, T cells reprogram their metabolic patterns during differentiation. For instance, the proliferation and differentiation of effector T cells require the activation of fatty acid synthesis metabolism, while the differentiation and maturation of regulatory T cells and memory T cells primarily rely on fatty acid oxidation metabolism. Fatty acids are not only essential components of cell membranes but also play multiple roles in biological processes. This review summarizes the regulatory roles of two key processes in fatty acid metabolism(fatty acid synthesis and fatty acid oxidation) in T cell proliferation, differentiation, and function, with the aim of providing new targets and strategies for the intervention of clinical autoimmune diseases.
[1]Chang J T, Wherry E J, Goldrath A W. Molecular regulation of effector and memory T cell differentiation[J]. Nat Immunol, 2014, 15(12):1104-1115.
[2]Nakayama T, Hirahara K, Onodera A, et al. Th2 cells in health and disease[J]. Annu Rev Immunol, 2017, 35(1):53-84.
[3]Pulendran B, Ahmed R. Immunological mechanisms of vaccination[J]. Nat Immunol, 2011, 12(6):509-517.
[4]Glaviano A, Foo A S C, Lam H Y, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer[J]. Mol Cancer, 2023, 22(1):138.
[5]Fontana F, Giannitti G, Marchesi S, et al. The PI3K/Akt pathway and glucose metabolism:a dangerous liaison in cancer[J]. Int J Biol Sci, 2024, 20(8):3113-3125.
[6]Oumeddour D Z, Al-Dalali S, Zhao L, et al. Recent advances on cyanidin-3-O-glucoside in preventing obesityrelated metabolic disorders:a comprehensive review[J].Biochem Biophys Res Commun, 2024, 729:150344.
[7]Hsu C C, Peng D, Cai Z, et al. AMPK signaling and its targeting in cancer progression and treatment[J]. Semin Cancer Biol, 2022, 85:52-68.
[8]Cui Y, Chen J, Zhang Z, et al. The role of AMPK in macrophage metabolism, function and polarisation[J]. J Transl Med, 2023, 21(1):892.
[9]Sancak Y, Peterson T R, Shaul Y D, et al. The rag GTPases bind raptor and mediate amino acid signaling to mTORC1[J]. Science, 2008, 320(5882):1496-1501.
[10]Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function[J]. Trends Immunol, 2015, 36(2):81-91.
[11]Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells[J]. Nat Med, 2014, 20(11):1327-1333.
[12]Mamareli P, Kruse F, Lu C W, et al. Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection[J]. Mucosal Immunol, 2021, 14(1):164-176.
[13]Young K E, Flaherty S, Woodman K M, et al. Fatty acid synthase regulates the pathogenicity of Th17 cells[J]. J Leukoc Biol, 2017, 102(5):1229-1235.
[14]Xu X, Wang Y, Wei Z, et al. Madecassic acid, the contributor to the anti-colitis effect of madecassoside,enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway[J]. Cell Death Dis,2017, 8(3):e2723.
[15]Miao Y, Wu X, Xue X, et al. Morin, the PPARγ agonist, inhibits Th17 differentiation by limiting fatty acid synthesis in collagen-induced arthritis[J]. Cell Biol Toxicol, 2023, 39(4):1433-1452.
[16]Haghikia A, J?Rg S, Duscha A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine[J]. Immunity, 2015, 43(4):817-829.
[17]Nakajima T, Kanno T, Yokoyama S, et al. ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice[J]. J Exp Med,2021, 218(12):e20210639.
[18]Lim S A, Wei J, Nguyen T M, et al. Lipid signalling enforces functional specialization of Treg cells in tumours[J]. Nature, 2021, 591(7849):306-311.
[19]Liu Y J, Tang B, Wang F C, et al. Parthenolide ameliorates colon inflammation through regulating Treg/Th17balance in a gut microbiota-dependent manner[J].Theranostics, 2020, 10(12):5225-5241.
[20]Field C S, Baixauli F, Kyle R L, et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function[J]. Cell Metab, 2020, 31(2):422-437. e5.
[21]Wang R, Dillon C P, Shi L Z, et al. The transcription factor myc controls metabolic reprogramming upon T lymphocyte activation[J]. Immunity, 2011, 35(6):871-882.
[22]Yang K, Shrestha S, Zeng H, et al. T cell exit from quiescence and differentiation into Th2 cells depend on raptor-mTORC1-mediated metabolic reprogramming[J].Immunity, 2013, 39(6):1043-1056.
[23]Kidani Y, Elsaesser H, Hock M B, et al. Sterol regulatory element–binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity[J]. Nat Immunol, 2013, 14(5):489-499.
[24]DüVel K, Yecies J L, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1[J]. Mol Cell, 2010, 39(2):171-183.
[25]Kidani Y, Elsaesser H, Hock M B, et al. Sterol regulatory element–binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity[J]. Nat Immunol, 2013, 14(5):489-499.
[26]Endo Y, Onodera A, Obata-Ninomiya K, et al. ACC1determines memory potential of individual CD4+T cells by regulating de novo fatty acid biosynthesis[J]. Nat Metab, 2019, 1(2):261-275.
[27]Ibitokou S A, Dillon B E, Sinha M, et al. Early inhibition of fatty acid synthesis reduces generation of memory precursor effector T cells in chronic infection[J]. J Immunol, 2018, 200(2):643-656.
[28]Eaton S, Bartlett K B, Pourfarzam M. Mammalian mitochondrial β-oxidation[J]. Biochem J, 1996, 320(2):345-357.
[29]Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation[J]. Nat Commun, 2015, 6(1):6692.
[30]Loschinski R, B?Ttcher M, Stoll A, et al. IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner[J]. Oncotarget,2018, 9(17):13125-13138.
[31]Zhang P, Smith R, Chapkin R S, et al. Dietary(n-3)polyunsaturated fatty acids modulate murine Th1/Th2balance toward the Th2 pole by suppression of Th1 development[J]. J Nutr, 2005, 135(7):1745-1751.
[32]Monk J M, Hou T Y, Turk H F, et al. Dietary n-3 polyunsaturated fatty acids(PUFA)decrease obesity-associated Th17 cell-mediated inflammation during colitis[J]. PLoS One, 2012, 7(11):e49739.
[33]Monk J M, Hou T Y, Turk H F, et al. n3 PUFAs reduce mouse CD4+T-cell ex vivo polarization into Th17cells[J]. J Nutr, 2013, 143(9):1501-1508.
[34]ChiurchiùV, Leuti A, Dalli J, et al. Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses[J]. Sci Transl Med, 2016, 8(353):353ra111.
[35]Angela M, Endo Y, Asou H K, et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells[J]. Nat Commun, 2016, 7(1):13683.
[36]Lim S A, Wei J, Nguyen T L M, et al. Lipid signalling enforces functional specialization of Treg cells in tumours[J]. Nature, 2021, 591(7849):306-311.
[37]Mcdonnell E, Crown S B, Fox D B, et al. Lipids reprogram metabolism to become a major carbon source for histone acetylation[J]. Cell Rep, 2016, 17(6):1463-1472.
[38]Zhang Q, Fang Y, Lv C, et al. Norisoboldine induces the development of Treg cells by promoting fatty acid oxidation-mediated H3K27 acetylation of Foxp3[J].FASEB J, 2022, 36(4):e22230.
[39]Fang Y, Zhang Q, Yuan X, et al. Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation[J]. Immunology, 2022, 166(4):492-506.
[40]Grajchen E, Loix M, Baeten P, et al. Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity[J]. Cell Mol Immunol, 2023, 20(6):666-679.
[41]Miao Y, Zhang C, Yang L, et al. The activation of PPARγ enhances Treg responses through up-regulating CD36/CPT1-mediated fatty acid oxidation and subsequent N-glycan branching of TβRII/IL-2Rα[J]. Cell Commun Signal, 2022, 20(1):48.
[42]Sivasami P, Elkins C, Diaz-Saldana P P, et al. Obesity-induced dysregulation of skin-resident PPARγ+Treg cells promotes IL-17A-mediated psoriatic inflammation[J]. Immunity, 2023, 56(8):1844-1861. e6.
[43]Michalek R D, Gerriets V A, Jacobs S R, et al. Cutting edge:distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+T cell subsets[J]. J Immunol, 2011, 186(6):3299-3303.
[44]Eleftheriadis T, Pissas G, Liakopoulos V, et al. IDO decreases glycolysis and glutaminolysis by activating GCN2K, while it increases fatty acid oxidation by activating AhR, thus preserving CD4+T-cell survival and proliferation[J]. Int J Mol Med, 2018, 42(1):557-568
[45]Curti A, Trabanelli S, Salvestrini V, et al. The role of indoleamine 2, 3-dioxygenase in the induction of immune tolerance:focus on hematology[J]. Blood, 2009,113(11):2394-2401.
[46]Haghikia A, J?Rg S, Duscha A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine[J]. Immunity, 2015, 43(4):817-829.
[47]Wang X, Sun L, Yang B, et al. Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation[J]. J Clin Investig, 2023, 133(20):e166628.
[48]Zhang Q, Zhu Y, Lv C, et al. AhR activation promotes Treg cell generation by enhancing Lkb1-mediated fatty acid oxidation via the Skp2/K63-ubiquitination pathway[J]. Immunology, 2023, 169(4):412-430.
[49]Kanno T, Nakajima T, Kawashima Y, et al. Acsbg1-dependent mitochondrial fitness is a metabolic checkpoint for tissue Treg cell homeostasis[J]. Cell Rep,2021, 37(6):109921.
[50]O’Sullivan D, Van Der Windt G J W, Huang S C, et al. Memory CD8+T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development[J]. Immunity, 2014, 41(1):75-88.
[51]Hunt E G, Hurst K E, Riesenberg B P, et al. AcetylCoA carboxylase obstructs CD8+T cell lipid utilization in the tumor microenvironment[J]. Cell Metab, 2024,36(5):969-983. e10.
[52]Zhang C, Yue C, Herrmann A, et al. STAT3 activation-induced fatty acid oxidation in CD8+T effector cells is critical for obesity-promoted breast tumor growth[J].Cell Metab, 2020, 31(1):148-161. e5.
[53]Xiao L, Ma X, Ye L, et al. IL-9/STAT3/fatty acid oxidation–mediated lipid peroxidation contributes to Tc9cell longevity and enhanced antitumor activity[J]. J Clin Investig, 2022, 132(7):e153247.
[54]Nian Z, Dou Y, Shen Y, et al. Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation[J]. Immunity, 2024, 57(10):2344-2361. e7.
[55]Ma L, Chen C, Zhao C, et al. Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer[J]. Signal Transduct Target Ther, 2024, 9(1):64.
[56]Pan Y, Tian T, Park C O, et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism[J]. Nature, 2017, 543(7644):252-256.
[57]Lin R, Zhang H, Yuan Y, et al. Fatty acid oxidation controls CD8+tissue-resident memory T-cell survival in gastric adenocarcinoma[J]. Cancer Immunol Res,2020, 8(4):479-492.
[58]Smith P M, Howitt M R, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis[J]. Science, 2013, 341(6145):569-573.
[59]Gon?Alves P, AraúJo J R, Di Santo J P. A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease[J]. Inflamm Bowel Dis, 2018, 24(3):558-572.
[60]Chen Y, Zhang J, Cui W, et al. CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate[J]. J Exp Med, 2022, 219(6):e20211314.
基本信息:
中图分类号:R392
引用信息:
[1]陶悦,邝莹,陈垒.脂肪酸代谢在T细胞分化与功能中的研究进展[J].赣南医科大学学报().
基金信息:
国家自然科学基金地区项目(82260803); 江西省自然科学基金项目(20252BAC200581)
2026-07-01
2026-07-01
2026-07-01