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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 | Yu-Ling Hsiao | en |
dc.contributor.author | 蕭又綾 | zh_TW |
dc.date.accessioned | 2021-06-08T04:01:50Z | - |
dc.date.copyright | 2018-08-30 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-06 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22088 | - |
dc.description.abstract | 樹突細胞包含漿狀樹突細胞和傳統樹突細胞,這兩種細胞皆在免疫反應中扮演重要的角色。由於樹突細胞的生命週期相當短,所以他們必須不斷地從造血前驅幹細胞分化而來。有趣的是,這些造血前驅幹細胞,包含共同淋巴前驅細胞(common lymphoid progenitor, CLP)會表現不同種類的模式識別受體(pattern recognition receptors),包括類鐸受體(Toll-like receptors, TLRs),而這些TLR會辨認病原體上的病原體相關分子模式(pathogen-associated molecular patterns),以保護宿主免於感染。目前這些造血前驅幹細胞如何對TLR配體做出反應並造成什麼結果還不太清楚。我們先前發現在穩定狀態的時候,CLP在Flt3配體的培養下會主要發育成漿狀樹突細胞,而生成較少的傳統樹突細胞。但是在發炎和感染的狀態時,樹突細胞的發育過程仍不是很了解。在我們的研究中,發現不論是在體內或是體外的R848 (TLR7配體)刺激下,會大幅改變樹突細胞的發育程序,增加傳統樹突細胞並減少漿狀樹突細胞的分化,而這個現象也發生在兩種骨髓系前驅細胞,包括共同骨隨前驅細胞(common myeloid progenitor, CMP)和共同樹突前驅細胞(common dendritic cell progenitor, CDP),但是相較於CMP和CDP,CLP對於TLR7所誘導樹突細胞發育的改變還要更為敏感。另一方面,除了漿狀樹突細胞和傳統樹突細胞的發育,在R848的刺激下,也會減少第一型傳統樹突細胞(cDC1)的分化,而去增加第二型傳統樹突細胞(cDC2)的分化。除此之外,R848的刺激下會造成漿狀樹突細胞上的sialic acid binding Ig-like lectin H (Siglec-H)的表現量的減少以及CD5的表現量的增加。除了TLR7 ligand外,水疱性口炎病毒(vascular stomatitis virus, VSV)的感染也會造成和R848一樣的結果。更重要的是,從在體內處理過R848的老鼠中分離出CLP和CDP,體外培養後,即使不加R848也會使這兩種前驅細胞產生較多的傳統樹突細胞。野生型及Myd88-/-CLP的共培養實驗中,發現TLR7誘導傳統樹突細胞增加的現象可能是透過主要和次要的TLR7訊息傳導路徑包括完全依賴STAT1及部分依賴第一型干擾素的訊息路徑來達成的。此外,TLR7的訊號會透過對serine磷酸化在727位點的方式來活化STAT1,如果將STAT1上的第727位點的serine突變成alanine,就會部分抑制TLR7促進傳統樹突細胞生成的現象。另一方面,STAT1和第一型干擾素也會調控TLR7所誘導Siglec-H表現降低的現象,但是,只有STAT1會調控TLR7所誘導CD5表現上升的現象,而第一型干擾素則不會參與其中。總結來說,我們發現在發炎及感染狀態下,樹突細胞發育的過程是相當多變的,此外我們也確定了STAT1的serine磷酸化和第一型干擾素在TLR7誘導CLP生成樹突細胞的發育過程的作用機制。 | zh_TW |
dc.description.abstract | Dendritic cells (DCs), including plasmacytoid DCs (pDCs) and conventional DCs (cDCs) play an essential role in the immune response. DCs are short-lived and are constantly replenished from hematopoietic stem and progenitor cells (HSPCs). Interestingly, HSPCs including common lymphoid progenitors (CLPs) express different kinds of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) which sense pathogen-associated molecular patterns (PAMPs) from pathogens and protect hosts from infection. It is still largely illusive whether HSPCs can respond to TLR ligands and what the consequences are following the stimulation. We have previously shown that Flt3 ligand (FL) preferentially promotes the development of pDCs, as opposed to cDCs, from CLPs at steady state. However, the developmental program of DCs during inflammation or infection is unclear. Here, we demonstrate that the administration of R848, a TLR7 agonist, dramatically alters the developmental program by enhancing cDC production at the expense of pDC population in vitro and in vivo, this phenotype is also observed in common myeloid progenitors (CMPs) and common DC progenitors (CDPs), two progenitors of myeloid lineage. CLPs, however, are more sensitive to TLR7-induced reprograming of DC development than CMPs and CDPs. In addition to pDC and cDC, the ratio cDC1 to cDC2, two subsets of cDC, also decreases upon TLR stimulation. Moreover, expression of Siglce-H and CD5, two functional markers of pDC is oppositely regulated by the stimulation. In addition to TLR ligand, VSV infection in vitro also exerts the same effects as R848. More importantly, ex vivo DC developmental potential of CLPs and CDPs from mice previously treated with R848 also prefer cDC generation even though R848 is omitted in the culture condition. Coculture of WT and Myd88-/- CLPs showed that the effect may be dependent on primary and secondary signaling events downstream of TLR7. The mechanism of TLR7-dependent enhancement of cDC generation is mainly STAT1-dependent and partially IFN-I-dependent. Surprisingly, ligation of TLR7 activates STAT1 phosphorylation on serine 727 residues, and mutation of serine to alanine in STAT1 partially blocked TLR-induced cDC formation from CLPs. On the other hand, STAT1 and IFN-I is required for TLR7 signaling-dependent reduction of Siglec-H, while only STAT1, but not IFN-I, is required for higher expression of CD5 during inflammation. In sum, these findings reveal that DC developmental program from their progenitors is very dynamic during inflammation or infection. Moreover, we define a novel function of serine phosphorylation of STAT1 and IFN-I signaling in TLR-mediated reprogramming of DC development from CLPs. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:01:50Z (GMT). No. of bitstreams: 1 ntu-107-R05449004-1.pdf: 4796575 bytes, checksum: cbb0e85def46ed7d668deb3476345aad (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 致謝 i
摘要 ii Abstract iv Abbreviation vi Chapter I Introduction 1 1.1 Dendritic cell subsets 2 1.2 Dendritic cell development 6 1.3 Hematopoiesis during inflammation 7 1.4 Rationale and specific aims 10 Chapter II Materials and Methods 11 2.1 Mice 12 2.2 Sorting of progenitor cells 12 2.3 In vitro culture of progenitor cells 13 2.4 Flow cytometry 13 2.5 Intracellular staining 14 2.6 In vivo R848 treatment 15 2.7 In vitro viral infection 16 2.8 Enzyme-Linked Immunosorbent Assay (ELISA) 16 2.9 Statistical analysis 16 Formula of reagent 17 Table 18 Chapter III Result 20 3.1 Dose-dependent effect of TLR7 signaling on reprogramming of DC development from CLPs in vitro 21 3.2 TLR7 signaling-induced reprogramming of DC development from CLPs is greater than that from CMPs and CDPs 22 3.3 CLPs are more sensitive to TLR7 stimulation than CMPs and CDPs 23 3.4 TLR7 signaling induces cDC2 development, reduces expression of Siglec-H but increases expression of CD5 on progenitors-derived pDCs in vitro 24 3.5 Effects of TLR7 signaling on the reprogramming of DC development in vivo 25 3.6 Effects of TLR7 signaling on the differentiation of cDC subtypes and the expression of Siglec-H and CD5 on pDC in vivo 26 3.7 Involvement of primary and secondary effector molecules in TLR signaling-induced reprogramming of DC development 27 3.8 IL-6 is induced from CLPs by TLR7 agonist in a dose-dependent manner 28 3.9 TLR7-mediated enhancement of cDC production from CLPs is partially IFN-I-dependent 29 3.10 TLR7-mediated enhancement of cDC production from CLPs is STAT1-dependent 30 3.11 TLR7 signaling activates STAT1 phosphorylation on serine 727, but not tyrosine 701, which regulates the reprogramming of DC development from CLPs 31 3.12 TLR7 signaling-mediated enhancement of cDC production in BM is partially STAT1-dependent in vivo 32 3.13 VSV infection induces the reprogramming of DC development from CLPs in vitro 33 3.14 VSV-induced reprogramming of DC development is MyD88-dependent 34 3.15 STAT1 and IFN-I partially regulate TLR7-dependent reduction of Siglec-H expression in vitro and in vivo 34 3.16 STAT1, but not IFN-I, regulates TLR7-dependent higher CD5 expression on pDC in vitro and in vivo 36 Chapter IV Discussion 38 4.1 Dendritic cell development at steady state 39 4.2 Reprogramming of dendritic cell development during inflammation 40 4.3 Reprogramming of dendritic cell development during viral infection 43 4.4 The mechanisms of TLR7 signaling pathways controlling DC development 44 4.5 The role of STAT1 on DC development 45 Concluding remarks 48 Chapter V Figure 50 Figure 1. Dose-dependent effect of TLR7 signaling on reprogramming of DC development from CLPs in vitro. 51 Figure 2. TLR7 signaling-induced reprogramming of DC development from CLPs is greater than that from CMPs and CDPs. 53 Figure 3. CLPs are more sensitive to TLR7 stimulation than CMPs and CDPs. 56 Figure 4. TLR7 signaling induces cDC2 development and the expression of Siglec-H and CD5 on pDCs in vitro. 59 Figure 5. Effects of TLR7 signaling on the reprogramming of DC development in vivo. 62 Figure 6. Effects of TLR7 signaling on cDC subtypes and the expression of Siglec-H and CD5 on pDC in vivo. 65 Figure 7. The effect of coculture of WT and Myd88-/- CLPs in vitro. 68 Figure 8. IL-6 is induced from CLPs by TLR7 agonist in a dose-dependent manner. 69 Figure 9. TLR7-mediated enhancement of cDC production from CLPs is partially IFN-I-dependent. 70 Figure 10. TLR7-mediated enhancement of cDC production from CLPs is partially IFN-I-dependent. 72 Figure 11. TLR7-mediated enhancement of cDC production from CLPs is STAT1-dependent. 74 Figure 12. TLR7 signaling activates STAT1 phosphorylation on serine 727, but not tyrosine 701. 76 Figure 13. TLR7-mediated enhancement of cDC production from CLPs is partially regulated by serine phosphorylation of STAT1. 78 Figure 14. TLR7 signaling-mediated enhancement of cDC production in BM is partially STAT1-dependent in vivo. 80 Figure 15. VSV infection induces the reprogramming of DC development from CLPs in vitro. 82 Figure 16. VSV-induced reprogramming of DC development is MyD88-dependent. 86 Figure 17. STAT1 and IFN-I partially regulate TLR7-dependent lower Siglec-H expression in vitro. 87 Figure 18. STAT1 partially regulates TLR7-dependent lower Siglec-H expression on pDC in vivo. 89 Figure 19. STAT1, but not IFN-I, regulates TLR7-dependent higher CD5 expression on pDC in vitro. 90 Figure 20. STAT1 regulates TLR7-dependent higher CD5 expression on pDC in vivo. 92 Figure 21. Hypothetic model of regulation of reprogramming of DC development by inflammation. 93 Chapter VI References 95 | |
dc.language.iso | en | |
dc.title | 在發炎和感染下重新改變樹突細胞的發育 | zh_TW |
dc.title | Reprogramming of dendritic cell development by inflammation and infection | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林國儀(Kuo-I Lin),嚴仲陽(Jeffrey J.Y Yen) | |
dc.subject.keyword | 樹突細胞發育,發炎,感染, | zh_TW |
dc.subject.keyword | dendritic cell development,inflammation,infection, | en |
dc.relation.page | 101 | |
dc.identifier.doi | 10.6342/NTU201802330 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2018-08-07 | |
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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