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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 繆希椿(Shi-Chuen Miaw) | |
dc.contributor.author | Yi-Chung Huang | en |
dc.contributor.author | 黃奕中 | zh_TW |
dc.date.accessioned | 2021-07-10T21:59:17Z | - |
dc.date.available | 2021-07-10T21:59:17Z | - |
dc.date.copyright | 2021-02-25 | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021-01-18 | |
dc.identifier.citation | 1. Zhu, J. and W.E. Paul, CD4 T cells: fates, functions, and faults. Blood, 2008. 112(5): p. 1557-1569. 2. Fallon, P.G., et al., IL-4 Induces Characteristic Th2 Responses Even in the Combined Absence of IL-5, IL-9, and IL-13. Immunity, 2002. 17(1): p. 7-17. 3. Zhu, J., T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine, 2015. 75(1): p. 14-24. 4. Paul, W.E. and J. Zhu, How are T(H)2-type immune responses initiated and amplified? Nature reviews. Immunology, 2010. 10(4): p. 225-235. 5. Tumes, Damon J., et al., The Polycomb Protein Ezh2 Regulates Differentiation and Plasticity of CD4+ T Helper Type 1 and Type 2 Cells. Immunity, 2013. 39(5): p. 819-832. 6. Allan, R.S., et al., An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature, 2012. 487(7406): p. 249-253. 7. Pua, Heather H., et al., MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity, 2016. 44(4): p. 821-832. 8. Burkett, P.R., G. Meyer zu Horste, and V.K. Kuchroo, Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. The Journal of clinical investigation, 2015. 125(6): p. 2211-2219. 9. Muranski, P. and N.P. Restifo, Essentials of Th17 cell commitment and plasticity. Blood, 2013. 121(13): p. 2402-2414. 10. Wu, C., et al., Induction of pathogenic T H 17 cells by inducible salt-sensing kinase SGK1. 2013. 496(7446): p. 513. 11. Vignali, D.A.A., L.W. Collison, and C.J. Workman, How regulatory T cells work. Nature Reviews Immunology, 2008. 8(7): p. 523-532. 12. Josefowicz, S.Z., L.-F. Lu, and A.Y. Rudensky, Regulatory T Cells: Mechanisms of Differentiation and Function. Annual Review of Immunology, 2012. 30(1): p. 531-564. 13. Rathmell, J.C., et al., In the Absence of Extrinsic Signals, Nutrient Utilization by Lymphocytes Is Insufficient to Maintain Either Cell Size or Viability. Molecular Cell, 2000. 6(3): p. 683-692. 14. Chakrabarti, R., et al., Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. Journal of Immunology, 1994. 152(6): p. 2660-2668. 15. Zheng, Y., et al., Anergic T cells are metabolically anergic. Journal of immunology (Baltimore, Md. : 1950), 2009. 183(10): p. 6095-6101. 16. Düvel, K., et al., Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular cell, 2010. 39(2): p. 171-183. 17. Tozzi, M.G., et al., Pentose phosphates in nucleoside interconversion and catabolism. 2006. 273(6): p. 1089-1101. 18. Michalek, R.D., et al., Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. Journal of immunology (Baltimore, Md. : 1950), 2011. 186(6): p. 3299-3303. 19. Sipula, I.J., N.F. Brown, and G. Perdomo, Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metabolism, 2006. 55(12): p. 1637-1644. 20. Frauwirth, K.A., et al., The CD28 Signaling Pathway Regulates Glucose Metabolism. Immunity, 2002. 16(6): p. 769-777. 21. Zoncu, R., A. Efeyan, and D.M. Sabatini, mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Reviews Molecular Cell Biology, 2011. 12(1): p. 21-35. 22. Ma, X.M. and J. Blenis, Molecular mechanisms of mTOR-mediated translational control. Nature Reviews Molecular Cell Biology, 2009. 10(5): p. 307-318. 23. Lee, K., et al., Mammalian Target of Rapamycin Protein Complex 2 Regulates Differentiation of Th1 and Th2 Cell Subsets via Distinct Signaling Pathways. Immunity, 2010. 32(6): p. 743-753. 24. Sengupta, S., T.R. Peterson, and D.M. Sabatini, Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Molecular cell, 2010. 40(2): p. 310-322. 25. O’Neill, H.M., et al., AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia, 2014. 57(8): p. 1693-1702. 26. Dang, C.V. and G.L. Semenza, Oncogenic alterations of metabolism. Trends in Biochemical Sciences, 1999. 24(2): p. 68-72. 27. Wang, R., et al., The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation. Immunity, 2011. 35(6): p. 871-882. 28. Chou, C., et al., c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nature Immunology, 2014. 15: p. 884. 29. Shi, L.Z., et al., HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. The Journal of experimental medicine, 2011. 208(7): p. 1367-1376. 30. Iyer, N.V., et al., Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes development, 1998. 12(2): p. 149-162. 31. Yin, H.-M., et al., Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism. Science Advances, 2020. 6(19): p. eaay9466. 32. Glal, D., et al., ATF3 Sustains IL-22-Induced STAT3 Phosphorylation to Maintain Mucosal Immunity Through Inhibiting Phosphatases. Frontiers in Immunology, 2018. 9(2522). 33. Klingenberg, R., et al., Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. The Journal of Clinical Investigation, 2013. 123(3): p. 1323-1334. 34. Delgoffe, G.M., et al., The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nature Immunology, 2011. 12(4): p. 295-303. 35. Dang, Eric V., et al., Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1. Cell, 2011. 146(5): p. 772-784. 36. Gerriets, V.A., et al., Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. The Journal of Clinical Investigation, 2015. 125(1): p. 194-207. 37. Yang, W. and Z. Lu, Pyruvate kinase M2 at a glance. Journal of Cell Science, 2015. 128(9): p. 1655. 38. Angiari, S., et al., Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity. Cell Metabolism, 2020. 31(2): p. 391-405.e8. 39. Lanning, Nathan J., et al., A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels. Cell Reports, 2014. 7(3): p. 907-917. 40. Fujisawa, K., et al., Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4. Journal of experimental clinical cancer research : CR, 2016. 35: p. 48-48. 41. O'Neill, L.A.J., R.J. Kishton, and J. Rathmell, A guide to immunometabolism for immunologists. Nature Reviews Immunology, 2016. 16(9): p. 553-565. 42. Menk, A.V., et al., Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Reports, 2018. 22(6): p. 1509-1521. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77385 | - |
dc.description.abstract | 第二型輔助型T細胞主要的免疫功能是:釋放細胞素吸引嗜酸性球和肥大細胞,並促進這些細胞增殖以抵抗寄生蟲等胞外病原體。第十七型輔助型T細胞主要是扮演胞外細菌的清除者;然而,過度的第十七型輔助型T細胞免疫反應會造成自體免疫反應。調節型T細胞透過分泌抑制性的細胞素,或是競爭使用介白素-2等方式以調節輔助型T細胞的功能。第四型腺苷酸激酶位於粒腺體內,主要的功能是平衡細胞質中的單磷酸、二磷酸及三磷酸腺苷的濃度;有報導指出第四型腺苷酸激酶還具有將粒腺體內的三磷酸腺苷運送到細胞質的能力。過去我們實驗室證明第四型腺苷酸激酶在基因減弱下,促進第一型輔助型T細胞的γ型干擾素分泌。本實驗證明第四型腺苷酸激酶的基因減弱,可促使第二型輔助型T細胞的介白素-4,-5,-13和第十七型輔助型T細胞的介白素-17A,-21分泌量提升。但是,第四型腺苷酸激酶的基因減弱會降低介白素-10的分泌量。而丙酮酸脫氫酶可能是第四型腺苷酸激酶潛在的下游代謝調控者,於第四型腺苷酸激酶的基因減弱時表現量提升,同時促進輔助型T細胞的細胞素的產生。我們的研究推測第四型腺苷酸在T細胞中可能扮演維持三羧酸循環的功能,並且調節輔助型T細胞的細胞素分泌。 | zh_TW |
dc.description.abstract | TH2 cells are known to confront extracellular pathogens such as parasites and helminths by mediating the proliferation and recruitment of eosinophils and mast cells. TH17 cells play a role in expelling extracellular bacteria. In addition, TH17 cells are involved in the pathogenesis of autoimmune disease. Regulatory T cells (TREG) limit the function of effector T cells by several mechanisms, including secreting inhibitory cytokines and competing for IL-2 with effector T cells. Adenylate kinase 4 (Ak4) in mitochondria regulates the homeostasis of AMP, ADP and ATP. It also controls the ATP transportation toward cytosol. Previous study in our laboratory showed that Ak4 knockdown (KD) promotes the expression of TH1 cytokine, IFN-γ. Here, we hypothesized that Ak4 regulates the function of TH2, TH17 and regulatory T cells. Our data showed that Ak4 KD in TH2 cells upregulated the expression of IL-4, IL-5 and IL-13. Moreover, Ak4 silencing promoted the secretion of IL-17A and IL-21 in TH17 cells. Conversely, the expression of IL-10 was compromised in induced regulatory T cells with Ak4 KD. We also identified pyruvate dehydrogenase kinase 1 as the potential metabolic mediator that upregulates the cytokine production in T helper cells. Our research illustrated that Ak4 may promote the function of TCA cycle and further negatively regulate the function of T helper cells. | en |
dc.description.provenance | Made available in DSpace on 2021-07-10T21:59:17Z (GMT). No. of bitstreams: 1 U0001-1801202122141800.pdf: 3007818 bytes, checksum: b4827a762ade386c5d0e2dcd34a0e89d (MD5) Previous issue date: 2021 | en |
dc.description.tableofcontents | I. Introduction……………………………………………………………...…………...1 1. T helper cells……………………………………………………………………….1 1.1 Function of TH2 cells……………………………………………………………..1 1.2 Function of TH17 cells…………………………………………………………....2 1.3 Function of regulatory T cells…………………………….……………………..3 2. The crosstalk between metabolism and signaling pathway in the function of CD4 T cells……………………………..……………………………………………..4 2.1 Metabolic pathways in immune cells…………………………………………...4 2.2 Signal transduction and metabolism…………………………………………....5 2.3 Metabolic regulation of CD4 T cells…………………………………………….7 3. Adenylate kinase 4 (Ak4): The intracellular ATP modulator…………………..9 4. Rationale…………………………………………………………...……………..10 5. Significance……………………………………………………………………….10 II. Materials and Methods……………………………………………...…………….11 1. Materials……………………………………………………………………….....11 2. Methods…………………………………………………………………………..15 III. Results…………………………………………………………………………......20 1 Ak4 expression upon T cell activation and re-stimulation.……………...……..20 2. Ak4 KD in TH2 cells promotes IL-4 production………………………………..21 3. Ak4 KD in TH17 cells promotes IL-17 production……………………………..21 4. Ak4 KD downregulates Foxp3 expression in iTreg cells………...…………….22 5. TGFβ attenuates the effect of Ak4 in TH17 cells…………………………….....23 6. Pdk1 is upregulated in Ak4 KD TH2, TH17 and Treg cells with anti-CD3/28 re-stimulation………………………………………………………………………......23 IV. Discussion………………………………………………………………………….25 V. References………………………………………………………………………......28 VI. Table…………………………………………………………………………..…...34 1. Quantitative PCR primer pairs……………………….………………………...34 VII. Figures……………………………………………………………………..……..36 1. Ak4 expression were induced upon T cell activation and re-stimulation in TH2, TH17 cells…………………………………………………………………………....36 2. Ak4 KD promotes IL-4 production in TH2 cells………………………………..38 3. Ak4 KD promotes IL-17 production in TH17 cells……………………...……...41 4. Ak4 KD inhibits IL-10 production in iTreg cells……………………......……..45 5. Ak4 KD does not promote IL-17 production in TGFβ, IL-6, IL-1β and IL-23 derived TH17 cells…………………………………………………………………..49 6. Pdk1 is upregulated with Ak4 KD in CD4 T cells with anti-CD3/28 stimulation for 4hr…………………………………………………………………………….…51 7. Pdk1 is upregulated with Ak4 KD in TH2 and iTreg cells with anti-CD3/28 for 24hr……………………………………………………………………………….…53 | |
dc.language.iso | en | |
dc.title | 探討第四型腺苷酸激酶在輔助性第二、第十七型及調節性T細胞中扮演的角色 | zh_TW |
dc.title | Role of Adenylate Kinase 4 in TH2, TH17 and Treg Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 李建國(Chien-Kuo Lee),賴明宗(Ming-Zong Lai) | |
dc.subject.keyword | 第四型腺苷酸激酶,免疫代謝,輔助性第二型T細胞,輔助性第十七型T細胞,調節性T細胞, | zh_TW |
dc.subject.keyword | Adenylate kinase 4,Immunometabolism,TH2,TH17,Treg, | en |
dc.relation.page | 54 | |
dc.identifier.doi | 10.6342/NTU202100087 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2021-01-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
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