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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李建國(Chien-Kuo Lee) | |
dc.contributor.author | YI-WEN LIN | en |
dc.contributor.author | 林怡文 | zh_TW |
dc.date.accessioned | 2021-05-19T17:50:25Z | - |
dc.date.available | 2022-09-13 | |
dc.date.available | 2021-05-19T17:50:25Z | - |
dc.date.copyright | 2017-09-13 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-16 | |
dc.identifier.citation | Banchereau, J., and Steinman, R.M. (1998). Dendritic cells and the control of immunity. Nature 392, 245-252.
Barton, K., Muthusamy, N., Fischer, C., Ting, C.N., Walunas, T.L., Lanier, L.L., and Leiden, J.M. (1998). The Ets-1 transcription factor is required for the development of natural killer cells in mice. Immunity 9, 555-563. Carotta, S., Dakic, A., D'Amico, A., Pang, S.H., Greig, K.T., Nutt, S.L., and Wu, L. (2010). The transcription factor PU.1 controls dendritic cell development and Flt3 cytokine receptor expression in a dose-dependent manner. Immunity 32, 628-641. Chen, Y.L., Chen, T.T., Pai, L.M., Wesoly, J., Bluyssen, H.A., and Lee, C.K. (2013). A type I IFN-Flt3 ligand axis augments plasmacytoid dendritic cell development from common lymphoid progenitors. J Exp Med 210, 2515-2522. Cisse, B., Caton, M.L., Lehner, M., Maeda, T., Scheu, S., Locksley, R., Holmberg, D., Zweier, C., den Hollander, N.S., Kant, S.G., et al. (2008). Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135, 37-48. Colonna, M., Trinchieri, G., and Liu, Y.J. (2004). Plasmacytoid dendritic cells in immunity. Nat Immunol 5, 1219-1226. Eyquem, S., Chemin, K., Fasseu, M., Chopin, M., Sigaux, F., Cumano, A., and Bories, J.C. (2004). The development of early and mature B cells is impaired in mice deficient for the Ets-1 transcription factor. Eur J Immunol 34, 3187-3196. Fogg, D.K., Sibon, C., Miled, C., Jung, S., Aucouturier, P., Littman, D.R., Cumano, A., and Geissmann, F. (2006). A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83-87. Gabrilovich, D.I., Ostrand-Rosenberg, S., and Bronte, V. (2012). Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12, 253-268. Garrett-Sinha, L.A. (2013). Review of Ets1 structure, function, and roles in immunity. Cell Mol Life Sci 70, 3375-3390. Gilliet, M., Boonstra, A., Paturel, C., Antonenko, S., Xu, X.L., Trinchieri, G., O'Garra, A., and Liu, Y.J. (2002). The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J Exp Med 195, 953-958. Grenningloh, R., Tai, T.S., Frahm, N., Hongo, T.C., Chicoine, A.T., Brander, C., Kaufmann, D.E., and Ho, I.C. (2011). Ets-1 maintains IL-7 receptor expression in peripheral T cells. J Immunol 186, 969-976. Guilliams, M., Ginhoux, F., Jakubzick, C., Naik, S.H., Onai, N., Schraml, B.U., Segura, E., Tussiwand, R., and Yona, S. (2014). Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 14, 571-578. Hacker, C., Kirsch, R.D., Ju, X.S., Hieronymus, T., Gust, T.C., Kuhl, C., Jorgas, T., Kurz, S.M., Rose-John, S., Yokota, Y., and Zenke, M. (2003). Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol 4, 380-386. Han, J., Jiang, Y., Li, Z., Kravchenko, V.V., and Ulevitch, R.J. (1997). Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 386, 296-299. Inaba, K., Inaba, M., Romani, N., Aya, H., Deguchi, M., Ikehara, S., Muramatsu, S., and Steinman, R.M. (1992). Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176, 1693-1702. Kee, B.L. (2009). E and ID proteins branch out. Nat Rev Immunol 9, 175-184. Kobari, L., Dubart, A., Le Pesteur, F., Vainchenker, W., and Sainteny, F. (1995). Hematopoietic-promoting activity of the murine stromal cell line MS-5 is not related to the expression of the major hematopoietic cytokines. J Cell Physiol 163, 295-304. Li, H.S., Yang, C.Y., Nallaparaju, K.C., Zhang, H., Liu, Y.J., Goldrath, A.W., and Watowich, S.S. (2012). The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. Blood 120, 4363-4373. Mashayekhi, M., Sandau, M.M., Dunay, I.R., Frickel, E.M., Khan, A., Goldszmid, R.S., Sher, A., Ploegh, H.L., Murphy, T.L., Sibley, L.D., and Murphy, K.M. (2011). CD8alpha(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites. Immunity 35, 249-259. McKinsey, T.A., Zhang, C.L., and Olson, E.N. (2002). MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci 27, 40-47. Merad, M., Sathe, P., Helft, J., Miller, J., and Mortha, A. (2013). The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31, 563-604. Mildner, A., and Jung, S. (2014). Development and function of dendritic cell subsets. Immunity 40, 642-656. Molkentin, J.D., Black, B.L., Martin, J.F., and Olson, E.N. (1996). Mutational analysis of the DNA binding, dimerization, and transcriptional activation domains of MEF2C. Mol Cell Biol 16, 2627-2636. Muthusamy, N., Barton, K., and Leiden, J.M. (1995). Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature 377, 639-642. Naik, S.H., Proietto, A.I., Wilson, N.S., Dakic, A., Schnorrer, P., Fuchsberger, M., Lahoud, M.H., O'Keeffe, M., Shao, Q.X., Chen, W.F., et al. (2005). Cutting edge: generation of splenic CD8+ and CD8- dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J Immunol 174, 6592-6597. Naik, S.H., Sathe, P., Park, H.Y., Metcalf, D., Proietto, A.I., Dakic, A., Carotta, S., O'Keeffe, M., Bahlo, M., Papenfuss, A., et al. (2007). Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 8, 1217-1226. Onai, N., Kurabayashi, K., Hosoi-Amaike, M., Toyama-Sorimachi, N., Matsushima, K., Inaba, K., and Ohteki, T. (2013). A clonogenic progenitor with prominent plasmacytoid dendritic cell developmental potential. Immunity 38, 943-957. Redecke, V., Wu, R., Zhou, J., Finkelstein, D., Chaturvedi, V., High, A.A., and Hacker, H. (2013). Hematopoietic progenitor cell lines with myeloid and lymphoid potential. Nat Methods 10, 795-803. Robinette, M.L., Fuchs, A., Cortez, V.S., Lee, J.S., Wang, Y., Durum, S.K., Gilfillan, S., Colonna, M., and Immunological Genome, C. (2015). Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat Immunol 16, 306-317. Sathe, P., Vremec, D., Wu, L., Corcoran, L., and Shortman, K. (2013). Convergent differentiation: myeloid and lymphoid pathways to murine plasmacytoid dendritic cells. Blood 121, 11-19. Sawai, C.M., Sisirak, V., Ghosh, H.S., Hou, E.Z., Ceribelli, M., Staudt, L.M., and Reizis, B. (2013). Transcription factor Runx2 controls the development and migration of plasmacytoid dendritic cells. J Exp Med 210, 2151-2159. Scott, C.L., Soen, B., Martens, L., Skrypek, N., Saelens, W., Taminau, J., Blancke, G., Van Isterdael, G., Huylebroeck, D., Haigh, J., et al. (2016). The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2. J Exp Med 213, 897-911. Stehling-Sun, S., Dade, J., Nutt, S.L., DeKoter, R.P., and Camargo, F.D. (2009). Regulation of lymphoid versus myeloid fate 'choice' by the transcription factor Mef2c. Nat Immunol 10, 289-296. Steinman, R.M., and Cohn, Z.A. (1973). Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. The Journal of experimental medicine 137, 1142-1162. Steinman, R.M., Kaplan, G., Witmer, M.D., and Cohn, Z.A. (1979). Identification of a novel cell type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro. The Journal of experimental medicine 149, 1-16. Stirewalt, D.L., and Radich, J.P. (2003). The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3, 650-665. Swanson, B.J., Jack, H.M., and Lyons, G.E. (1998). Characterization of myocyte enhancer factor 2 (MEF2) expression in B and T cells: MEF2C is a B cell-restricted transcription factor in lymphocytes. Mol Immunol 35, 445-458. Swiecki, M., and Colonna, M. (2015). The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol 15, 471-485. Tussiwand, R., Everts, B., Grajales-Reyes, G.E., Kretzer, N.M., Iwata, A., Bagaitkar, J., Wu, X.D., Wong, R., Anderson, D.A., Murphy, T.L., et al. (2015). Klf4 Expression in Conventional Dendritic Cells Is Required for T Helper 2 Cell Responses. Immunity 42, 916-928. Watowich, S.S., and Liu, Y.J. (2010). Mechanisms regulating dendritic cell specification and development. Immunol Rev 238, 76-92. Xu, Y., Zhan, Y., Lew, A.M., Naik, S.H., and Kershaw, M.H. (2007). Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. Journal of immunology 179, 7577-7584. Zhuang, Y., Cheng, P.F., and Weintraub, H. (1996). B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Molecular and Cellular Biology 16, 2898-2905. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7694 | - |
dc.description.abstract | 樹突狀細胞 (Dendritic cell, DC)主要分為傳統樹突細胞以及漿狀樹突細胞,而他們兩者的功能是連結先天免疫以及適應免疫,因此對於免疫的調節極為重要。雖然我們已知樹突細胞對於免疫調節的重要性,但相關於樹突細胞的分化途徑以及其調控的機轉仍然不清楚。而在這裡我們利用shRNA去靜默造血幹細胞與前期細胞株 (immortalized stem and progenitor cell line, iHSPC)的基因表現量,以此實驗方法去作為篩選策略,研究這些基因對於樹突細胞發育的影響。我們總共篩選了14個在漿狀樹突細胞中相較於傳統樹突細胞有較高量表現的轉錄因子,接著我們發現Mef2c跟Tcf12這兩個基因對於漿狀樹突細胞的生成有非常明顯的影響,因此我們以這兩個基因作為我們主要研究的目標。我們抑制了這兩個基因在iHSPC細胞株裡的表現量,並且利用MS-5滋養層細胞去進行培養,也發現漿狀樹突細胞的生成有減少的情形。有關於機制層面的研究則顯示了在此兩基因被抑制的iHSPC細胞株發育過程中Tcf4 (目前已知影響漿狀樹突細胞最重要的轉錄因子)的表現量有降低的傾向。並且我們利用報導基因系統分析,當Mef2c被過度表現的時候其Tcf4的活性相較於控制組增加了近一倍。最後,我們分析了Mef2c基因剔除的小鼠裡樹突細胞的分群,並且發現漿狀樹突細胞在骨髓、脾臟、淋巴結都有明顯減少的情形,而且在脾臟以及淋巴結內的減少比骨髓更顯著,暗示著漿狀樹突細胞可能有遷徙的缺陷。而我們利用慢病毒感染小鼠骨髓細胞,以進行體外剔除基因的方式,也觀察到漿狀樹突細胞生成的減少。除此之外,Mef2c也會正向調控Flt3受器的表現,我們在靜默Mef2c的iHSPC細胞株內也觀察到Flt3表現量下降的情形。藉由這些機制層面,我們認為Mef2c對於漿狀樹突細胞的調節機轉可能有二個層面分別是透過Tcf4/Flt3來控制生成及未知因素來調控細胞自骨髓遷移到周邊。 | zh_TW |
dc.description.abstract | Dendritic cells (DC) can classified into two subsets, namely conventional dendritic cells (cDC) and plasmacytoid dendritic cells (pDC), both of which play important roles in bridging the innate and adaptive immunity. Although the functions of DCs are critical for immunomodulation, the regulatory mechanisms of DC developmental process still unclear. Here, we performed a powerful screening strategy and identified Mef2c as a transcription factor which regulates DC development. Through shRNA-mediated knockdown of target genes in immortalized hematopoietic stem and progenitor (iHSPC) cell line, we have screen 14 transcription factors that are preferentially expressed in pDC versus cDC, we identified two transcription factors Mef2c and Tcf12, which significantly affected pDCs generation in feeder free culture system. Knockdown of Mef2c and Tcf12 in iHSPC cell line decrease pDC generation in MS-5 feeder system. Mechanistically, expression of Tcf4 (encodes E-2.2), a master regulation of pDC development, was reduced in iHSPC stably express shMef2c and shTcf12. Reporter assay also showed the Tcf4 reporter activity was up-regulated by overexpression of Mef2c. We analyzed the DC populations from Mef2cf/f Tie2-Cre mice and proved that Mef2c deficiency indeed alter DCs generation, it reduce pDCs generation from bone marrow, spleen to lymph node. Also, in vitro deletion of Mef2c in primary bone marrow cell decreased pDCs frequency compared to control which show coherence to ex vivo results. Moreover, Mef2c also positively regulate Flt3 receptor expression. Mef2c knockdown decreased Flt3 expression in iHSPC. These results suggest Mef2c may regulate pDC development through control the expression of Tcf4. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:50:25Z (GMT). No. of bitstreams: 1 ntu-106-R04449008-1.pdf: 2576332 bytes, checksum: 04b690730079918a04a70e2c25605df3 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 致謝...........................................................................................................I
摘要..........................................................................................................II Abstract...............................................................................................III-IV Chapter I Introduction………………………………………. 1 1.1 Dendritic cell subsets…………………………………………2-3 1.2 Dendritic cell progenitors………………………………… …....3 1.3 Transcription factors and cytokines involved in dendritic cells development ............................................................................3-4 1.4 Mef2c ………………………………………………………...4-5 1.5 Tcf12……………………………………………………………5 1.6 Rationale and specific aims………………………….…….…5-6 Chapter II Materials and Methods………………….……7-16 Chapter III Results…………………………………….…17-23 Chapter IV Discussion…………………...………….…...24-33 Chapter V Figures………………………………………..34-55 Figure 1 Immortalized hematopoietic stem and progenitor (iHSPC) cell line is able to differentiate into cDC and pDC in response to Flt3L……...35-36 Figure 2 Knockdown of Mef2c and Tcf12 severely impairs pDC development from iHSPC……….………………………………….…37-39 Figure 3 Ets-1 deficiency did not show alteration in DCs development…………………………………………………………...40-41 Figure 4 Ets-1 deficiency did not alter the pDC potential of CLP in vitro……………………………………………………………………….42 Figure 5 Knockdown of Mef2c or Tcf12 gene in iHSPC cell line decreases pDCs generation……………………………………………………….43-44 Figure 6 Knockdown of Mef2c or Tcf12 in iHPC cell line also show decreases pDC generation in MS-5 feeder culture system………...….45-46 Figure 7 Mef2c positively regulates Tcf4 expression……………...…..47-48 Figure 8 Mef2c positively regulates Flt3 receptor expression in iHSPC……………………………………………………………..……...49 Figure 9 Mef2c deletion from primary bone marrow cells decrease generation of pDCs………………………………………………...….50-51 Figure 10 Mef2c deficiency decreases pDC generation and migration………………………………………………………...…….52-54 Figure 11 Hypothetic model of Mef2c dependent pDC development and migration……………………………………………………………….....55 Chapter VI References……………………………….....…56-63 | |
dc.language.iso | zh-TW | |
dc.title | Mef2c轉錄因子調控漿狀樹突細胞發育 | zh_TW |
dc.title | Transcription factor Mef2c regulates the development of plasmacytoid dendritic cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林國儀(Kuo-I Lin),嚴仲陽(Jeffrey J.Y.-Yen) | |
dc.subject.keyword | 漿狀樹突細胞, | zh_TW |
dc.subject.keyword | plasmacytoid dendritic cell, | en |
dc.relation.page | 63 | |
dc.identifier.doi | 10.6342/NTU201703495 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2017-08-16 | |
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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