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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
dc.contributor.author | Szu-Yu Lin | en |
dc.contributor.author | 林思妤 | zh_TW |
dc.date.accessioned | 2021-06-17T01:38:51Z | - |
dc.date.available | 2019-09-12 | |
dc.date.copyright | 2017-09-12 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-07-31 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67584 | - |
dc.description.abstract | B細胞可作為抗原呈現細胞誘導出⼀群Foxp3-的調節性T細胞,稱為B細胞誘發的調節性T細胞 (Treg-of-B cells),B細胞需通過與T細胞接觸的方式進⾏誘導,非以分泌介白素10 (IL-10) 的機制,⽽B細胞誘發的調節性T細胞也是透過緊密的細胞接觸來執行抑制的功能,因此相較於天然調節性T細胞 (nTreg) 及第⼀型調節性T細胞 (Tr1),B細胞誘發的調節性T細胞是不同的族群。
目前的研究指出B細胞誘發的調節性T細胞可發展成治療移植排斥和風溼性疾病的⽅方式之⼀,然⽽在我們的研究中發現B細胞誘發的調節性T細胞的分化過程中,有訊息傳遞轉錄活化因⼦子6 (STAT6)的磷酸化和介白素4 (IL-4)分泌的現象,因此本研究將探討介白素4的訊息傳遞路徑在B細胞誘發的調節性T細胞中扮演的角色,我們透過中和介白素4來探討B細胞在誘發調節性T細胞對於其發育或細胞激 素分泌的影響;而實驗結果發現,實驗組與對照組的抑制能⼒力並無顯著性的差異,但實驗組分泌較少的介白素4和介白素10; 另外也利用介白素4基因剔除鼠進行研究,探討介白素4在誘發調節性T細胞其發育及功能上所扮演的角色,實驗結果發現,介白素4基因剔除的B細胞誘發的調節性T細胞依然保有抑制能力但分泌較少的介白素10,此結果顯示,介白素4可能未影響B細胞誘發的調節性T細胞的誘導及免疫調控能⼒; 先前研究指出介白素4能促使許多免疫細胞的⽣長與存活,因此,我們同時也探討介白素4是否會影響B細胞誘發的調節性T細胞的⽣存,藉由誘發細胞凋亡後,以Annexin V/ PI染⾊色的⽅方式,比較實驗組與對照組在 細胞凋亡比例上的差異,或分析與細胞凋亡相關基因的表現,實驗結果顯示,中和介白素4及介白素4基因剔除的B細胞誘發的調節性T細胞有較多的細胞凋亡,儘管外加介白素2和介白素4可減少對照組的細胞凋亡,⽽實驗組在外加介白素2也有部分降低細胞凋亡的效果,但兩個細胞激素結合給予可提升實驗組與對照組比列上差距,另外,分析B細胞淋巴瘤-2 (B-cell lymphoma 2, bcl-2) 基因家族的抗細胞凋亡基因bcl-x和bcl-w,或促細胞凋亡基因bax的表現,實驗結果顯示,中和介白素4實驗組的bcl-x基因有些微降低,在介白素4基因剔除的B細胞誘發的調節性T 細胞有較明顯的的差異,bcl-x和bcl-w基因表現皆下降,因此結果暗示,介白素4可能會維持B細胞誘發的調節性T細胞的生存,若細胞的微環境中缺乏介白素4,則可能會促使B細胞誘發的調節性T細胞更傾向細胞凋亡。 總結來說,我們的研究結果顯示介白素4對於B細胞誘發的調節性T細胞的發育及功能沒有顯著的影響,然⽽在缺乏介白素4的情況下,會促使B細胞誘發的調 節性T細胞更傾向細胞凋亡,因此介白素4可能參與在維持B細胞誘發的調節性T細 胞的⽣存。在未來的研究,可持續探討介白素4是否透過轉錄活化因⼦子6的訊息傳遞路徑來調控細胞激素的分泌或細胞凋亡。 | zh_TW |
dc.description.abstract | Naïve B cells could act as antigen-presenting cells to induce a subpopulation of Foxp3- regulatory T cells, called Treg-of-B cells. Naïve B-cell-primed T cells is through cell-cell contact and independent of IL-10. The suppressive function of Treg-of-B cells partly requires close cell-cell proximity. Therefore, Treg-of-B cells is a population different from natural Treg cells (nTreg) and Type 1 regulatory T cells (Tr1).
Recent studies had demonstrated that Treg-of-B cells could be developed as a therapeutic approach against transplant rejection, allergy and rheumatological diseases. However, our studies showed that the differentiation of Treg-of-B cells involved STAT6 phosphorylation and IL-4 secretion. Hence, IL-4 might play a role in induction and/or function of Treg-of-B cells. This study was performed to examine the role of IL-4 signaling pathway in the development and function of Treg-of-B cells. We blocked IL-4 by anti-IL4 antibodies to study the suppressive function and cytokines profile of Treg-of-B cells. However, the result showed no significant difference between experimental group and control group in the suppressive ability, but the levels of IL-4 and IL-10 were lower in neutralized group. We next used Il4-/- mice for further investigation by suppressive function analysis, cytokines profile comparison. the result showed nosignificant difference between WT, Il4-/- Treg-of-B cells in suppressive ability but the level of IL-10 was lower in Il4-/- Treg-of-B(WT) cells. These results might indicate that IL-4 did not affect the induction and function of Treg-of-B cells. Previous study had demonstrated that IL-4 control several immune cell growth and survival. Therefore, we also examined whether IL-4 might maintain the survival of Treg-of-B cells. After induced cell death, we compared the cell death rate experimental group and control group by Annexin V/ PI staining or analyzed apoptosis-related gene expression. The results showed that more cell death induced in IL-4 blocking Treg-of-B cells and Il4-/- Treg-of-B cells. Although IL-2 and IL-4 could rescue the cell death in control group, IL- 2 also partially rescued the cell death of experimental group, but the combination of these two cytokines might enlarged the gap of cell death rate between IL-4 neutralization or not. Furthermore, we analyzed bcl-2 gene family, including anti- apoptotic gene bcl-x, bcl-w and pro-apoptotic gene bax. The results showed that IL-4 blocking Treg-of-B cells expressed slightly lower level of bcl-x. Il4-/- Treg-of-B cells showed more significant difference with lower levels of bcl-x and bcl-w gene expression. The results hinted that IL-4 might involve in maintaining Treg-of-B cells survival. In the deficient of IL-4, more apoptosis might be induced on Treg-of-B cells. In summary, our studies suggested that IL-4 might not affect the induction and function of Treg-of-B cells. In the deficient of IL-4, Treg-of-B cells might tend to go on apoptosis. Therefore, IL-4 might maintain the survival of Treg-of-B cells. In the future, the regulatory mechanism of cytokines production and apoptosis by IL-4-STAT6 signaling pathway might require further researches. | en |
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dc.description.tableofcontents | ⼝試委員會審定書 i
致謝 ii 中⽂文摘要 iii Abstract v Contents viii Figure contents xiii Chapter I---Introduction 1 1. Background 2 1.1 B cells 2 1.2 The immune roles of B cells 3 1.3 T cells 3 1.4 Differentiation of T cell subsets 5 1.5 Treg cell populations 6 1.6 The immune roles and regulatory mechanisms of Treg cells 7 1.7 Regulatory T cells induced by B cells (Treg-of-B cells) 8 1.8 IL-4 9 1.9 The role of IL-4 in immune system 10 1.10 IL-2 11 1.11 IL-2 on regulatory T cells 12 2. Hypothesis and specific aims 13 Chapter II---Materials and Methods 14 1. Materials 15 1.1 Animals 15 1.2 Culture medium 15 1.3 Buffer 16 1.4 EasySepTM system 17 1.5 BD IMagTM system 17 1.6 Monoclonal antibodies (mAbs) and cytokines 17 1.7 Flow cytometry 18 1.8 [3H]-incorporation assay 19 1.9 Enzyme-linked immunosorbent assay (ELISA) 19 1.10 RNA extraction 20 1.11 Reverse transcription polymerase chain reaction (RT-PCR) 20 1.12 Real-time polymerase chain reaction (quantitative PCR, qPCR) 21 2. Methods 22 2.1 Preparation of splenocytes 22 2.2 Cell isolation 22 2.3 Preparation of Treg-of-B cells 24 2.4 Neutralization of IL-4 24 2.5 Flow cytometry 24 2.6 [3H]-incorporation assay 25 2.7 Cytokine analysis 26 2.8 RNA extraction 27 2.9 Reverse transcription polymerase chain reaction (RT-PCR) 27 2.10 Real-time polymerase chain reaction (quantitative PCR, qPCR) 28 2.11 Statistical analysis 29 Chapter III---Results 30 1. The purity of B220+ B and CD4+CD25- T cells were more than 90% 31 2. Treg-of-B cells expressed Treg-related molecules and suppressed responder T cells proliferation 31 3. IL-4 blocking Treg-of-B cells still expressed all the surface molecules with slightly lower level of ICOS 32 4. Treg-of-B cells were hypoproliferation and IL-4 might not play a crucial role in Treg-of-B cells induction 33 5. IL-4 blocking Treg-of-B cells produced less IL-4 and IL-10 34 6. Not IL-10, LAG3 or CTLA-4 played a crucial role of Treg-of-B cells suppressive ability 34 7. Treg-of-B cells did not express TH2-related genes 35 8. Il4-/- Treg-of-B(WT) cells remained the suppressive function 36 9. Il4-/- Treg-of-B(WT) cells produced less IL-4 and IL-10 36 10. Il4-/- Treg-of-B cells still expressed all the surface molecules with slightly lower level of ICOS and CTLA-4 37 11. WT and Il4-/- Treg-of-B cells were hypoproliferation and both with suppressive function 38 12. Il4-/- Treg-of-B(WT) cells expressed lower level of bcl-x 38 13. IL-4 blockade increased cell death rate after rested Treg-of-B cells in medium 39 14. Il4-/- Treg-of-B cells increased cell death rate after rested cells in medium 40 15. The combination of IL-2 and IL-4 could rescue cell death however enlarged the gap of cell death rate between Treg-of-B cells with or without IL-4 neutralization 40 16. Treg-of-B cells expressed lower level of bcl-x or bcl-w when IL-4 deficiency 41 Chapter IV---Discussion 42 References 50 Figures 57 | |
dc.language.iso | en | |
dc.title | 探討介白素4在B細胞誘導調節性T細胞的發育與功能之角色 | zh_TW |
dc.title | The role of IL-4 in the development and function of regulatory T
cells induced by B cells (Treg-of-B cells) | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 朱清良(Ching-Liang Chu),沈家瑞(Chia-Rui Shen) | |
dc.subject.keyword | 調節性T細胞,B細胞誘發的調節性T細胞,介白素4,細胞凋亡, | zh_TW |
dc.subject.keyword | regulatory T cells,Treg-of-B cells,IL-4,apoptosis, | en |
dc.relation.page | 74 | |
dc.identifier.doi | 10.6342/NTU201702217 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-07-31 | |
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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檔案 | 大小 | 格式 | |
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ntu-106-1.pdf 目前未授權公開取用 | 6.33 MB | Adobe PDF |
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