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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 顧家綺 | |
dc.contributor.author | Jian-Fu Chen | en |
dc.contributor.author | 陳建甫 | zh_TW |
dc.date.accessioned | 2021-06-17T08:15:09Z | - |
dc.date.available | 2022-08-27 | |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-14 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73965 | - |
dc.description.abstract | 單純疱疹病毒-1(HSV-1)是感染人類常見的病原體。 HSV-1在原發感染期間。發病於粘膜上皮細胞處並且在神經元中建立終生潛伏期。以HSV-1感染小鼠的側腹皮膚,在接種部位產生潰瘍病變,並且可以在背根神經節(DRG)中建立潛伏感染。抗原特異性CD8+ T細胞對於控制原發性HSV-1感染及其再活化中扮演重要作用。為了幫助CD8+ T細胞的抗病毒活性,IL-15是支持毒殺型T細胞的產生與增殖所需的細胞因子,並維持CD8+記憶T細胞的長期存活。我們利用ENU誘變小鼠(系譜191)進行研究,其在IL-15基因的外顯子7中具有點突變,因此提高選擇性剪切的IL-15異構物(IL-15ΔE7)的表現。根據我們的初步研究,與C57BL / 6野生型(WT)小鼠相比,在P191小鼠中觀察到更嚴重和延長的HSV-1帶狀疱疹病變。此外,在P191小鼠中發現CD44hi記憶型CD8+ T細胞減少。這些結果使我們假設P191小鼠中CD44hi記憶型CD8+ T細胞的減少可能影響抵抗HSV-1免疫反應。在本研究中,我們使用Kb-gB408-505四聚體進行染色,並透過流式細胞儀以研究與WT小鼠相比,gB特異性CD8 + T細胞的產生,輸出和歸巢模式是否可能在P191小鼠中受到影響。我們的結果發現,gB特異性CD8+ T細胞在P191小鼠的引流淋巴結和周邊血中觀察到在感染後第7天減少。此外,在P191小鼠中,gB特異性CD8+ T細胞的皮膚歸巢受體CXCR3的表現顯著降低。在免疫組織化學染色的分析中,CD8+ T細胞的浸潤在感染後第7天的p191小鼠的疱疹傷痂中觀察到減少的現象。我們進一步研究了遷移性樹突細胞 (DC) 和CD8α+ DC的數量以及成熟,我們發現朗格漢斯細胞和CD8α+ DC在P191小鼠中觀察到減少的現象,其可能與IL-15∆E7表現分佈有關。
整體而言,這些數據表明,可能由於受到朗格漢斯細胞和CD8α+ DC減少的影響,gB特異性CD8 + T細胞的產生和歸巢模式在191小鼠中發生偏離,並揭示了IL-15E7可能透過調節DC而導致gB特異性CD8 + T細胞的活化不足而影響對抗HSV-1感染的免疫反應。 | zh_TW |
dc.description.abstract | Herpes simplex virus-1 (HSV-1) is a common pathogen for human infection. Infection of HSV-1 is initiated at mucosal epithelial cells during primary infection and establishes a lifelong latency in neurons. Cutaneous infection of mouse flank skin with HSV-1 creates an epidermal ulcerated lesion at the inoculated site and may establish latent infection in the innervating dorsal root ganglia (DRG). Viral glycoprotein B (gB498-505) specific CD8+ T cells are known to play an important role in viral clearance and a long-term surveillance against viral reactivation form DRG. Moreover, IL-15 is an essential cytokine to support proliferation and generation of cytotoxic T lymphocyte and maintains long-term survival of CD8+ memory T cell.
Our investigations with an ENU-mutagenized mice pedigree 191 (P191) which has a point mutation in exon 7 of the IL-15 gene and thus expressed an elevated level of an alternatively spliced IL-15 isoform (IL-15ΔE7). According to our preliminary studies, a more severe and prolonged HSV-1 zosteriform lesion was observed in P191 mice compared with C57BL/6 wild type (WT) mice. Furthermore, a reduced expression of CD44hi CD8+ T cells was found in P191 mice. Therefore, we hypothesized that reduced CD44hi CD8+ T cells in P191 mice may bring impacts on effective anti-viral immunity against HSV-1 infection. In this study, we used Kb-gB408-505 tetramers for flow cytometry to investigate whether the generation, output, and homing pattern of gB specific CD8+ T cells may be affected in P191 compared to WT mice. By flow cytometry analysis, reduced gB specific CD8+ T cells on day 7 post infection were observed in both draining lymph nodes and peripheral blood of P191 mice. Furthermore, the CXCR3 expression of gB specific CD8+ T cells was significantly reduced in P191. Moreover, reduced CD8+ T cell infiltration in lesional skin was observed in p191 mice on day 7 post infection by immunohistochemical staining analysis. We further investigated the profile of migratory DCs and CD8α+ DCs. Reduced Langerhans cells and CD8α+ DCs were observed in P191 mice which may correlate to expression kinetics of IL-15ΔE7. Collectively, these data suggested that generation and homing pattern of gB-specific CD8+ T cells was deviated in 191 mice, which was probably influenced by reduced Langerhans cells and CD8α+ DCs, and revealed the possibilities of IL-15ΔE7 in modulation of DCs biology and lead to an insufficient priming of gB-specific CD8+ cells against HSV-1 infection. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T08:15:09Z (GMT). No. of bitstreams: 1 ntu-108-R06449007-1.pdf: 3794517 bytes, checksum: 2592d997699f3f7e05e6363f85153b9f (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract iv Content vi Figures content xi I. Introduction 1 1.1. Role of IL-15 in immune response 1 1.1.1. IL-15 1 1.1.2. Receptor and signaling of IL-15 1 1.1.3. Function of IL-15 2 1.2. ENU mutagenized mice 4 1.2.1. Pedigree 191 4 1.2.2. Phenotypes of P191 4 1.3. Anti-HSV-1 immunity 5 1.3.1. Herpes simplex virus-1 (HSV-1) 5 1.3.2. The immune responses against HSV-1 infection 5 1.3.3. Role of IL-15 in controlling HSV-1 infection 6 1.4. CD8+ T cell immunity against HSV-1 infection 7 1.4.1. Role of dendritic cells in initiating CD8+ T cells immunity 7 1.4.2. CD8+ T cells control HSV-1 primary infection 7 1.4.3. CD8+ T cells control HSV-1 reinfection and reactivation. 8 II. Rationale 10 2.1. Preliminary studies on P191 mice 10 2.1.1. Deviated immune responses in P191 10 2.1.2. Prolong and more severe HSV-1 lesion in P191 11 2.2. Aim of this study 11 2.2.1. To determine whether the generation of gB -specific CD8 + T cells in P191 is different after HSV-1 infection 12 2.2.2. To determine whether the homing pattern of gB-specific CD8 + T cells in P191 is different after HSV-1 infection 12 2.2.3. To determine whether the maturation of different DC subset in P191 is different after HSV-1 infection 13 2.2.4. To determine the kinetics of IL-15 and IL-15∆E7 expression of adherent cells in early stage of HSV-1 infection 13 III. Materials and methods 14 3.1. Methods 14 3.1.1. Mice 14 3.1.2. HSV-1 Infection 14 3.1.3. Cells 15 3.1.4. Baculovirus and titration 16 3.1.5. SF9 infection and immunization 17 3.1.6. Flow cytometry 18 3.1.7. RNA extraction 19 3.1.8. cDNA synthesis 20 3.1.9. Real-time quantitative PCR (q-PCR) by SYBR Green dye 20 3.1.10. TaqMan q-PCR 21 3.1.11. Immunohistochemical (IHC) staining 22 3.1.12. Statistical analysis 23 3.2. Materials 24 3.2.1. List of antibodies 24 3.2.2. Buffer and solution 25 3.2.3. Chemical, reagent, and kits 27 3.2.4. Primers sequences 29 IV. Results 30 4.1. To evaluate the detection of gB specific CD8+ T cells by Kb-gB498-505 tetramer 30 4.2. Reduced gB-specific CD8+ T cells was observed in P191 mice after HSV-1 infection 31 4.3. More CD8+ T cells expressing CXCR3 were induced by HSV-1 infection via the route of skin compared to intraperitoneal infection 33 4.4. Less gB-specific CD8+ T cells were output in the circulation in P191 compared to B6 mice after HSV-1 infection. 34 4.5. Reduced CXCR3+ gB-specific CD8+ T cells in the circulation in P191 compared to B6 mice after HSV-1 infection. 35 4.6. Reduced expression of CXCR3 in gB-specific CD8+ T cells in PBMC was observed in P191 mice after HSV-1 infection 36 4.7. Reduced CD8+ T cell infiltration in lesional skin was observed in P191 mice after HSV-1 infection 37 4.8. Reduced Langerhans cells were detected in P191 after HSV-1 infection 38 4.9. Reduced maturation of Langerhans cells were detected in P191 after HSV-1 infection 40 4.10. Less CD8α+ DCs expansion were detected in P191 after HSV-1 infection 40 4.11. Comparison of IL-15 and IL-15∆E7 expression kinetics of adherent cells in B6 and P191 after HSV-1 infection 42 V. Discussion 44 5.1. General view of CD8α+ DCs in HSV-1 infection 44 5.2. Development of CD8α+ DCs 45 5.3. Antigen source for CD8α+ DCs 45 5.4. Antigen transportation by migratory DCs 46 5.5. Activation and outcome of CD8α+ DCs on T cell priming 47 5.6. The possible mechanism for reducing gB-specific CD8+ T cells in P191 mice. 48 5.7. The possible effect of IL-15ΔE7 on antigen transportation for CD8α+ DCs. 49 5.8. The possible source and effect of IL-15ΔE7 in draining lymph node 49 5.8.1. Day 1 post infection 50 5.8.2. Day 2 post infection 50 5.8.3. Day 4 post infection or later 51 5.9. Future direction 52 VI. References 54 VII. Figures 68 | |
dc.language.iso | en | |
dc.title | 探討表現IL-15選擇性剪接異構體ENU突變鼠感染第一型疱疹病毒後產生抗原特異性CD8+ T細胞的差異 | zh_TW |
dc.title | The deviated outcomes of antigen specific CD8+ T cells generated in ENU mutagenized mice that express alternatively spliced IL-15 after HSV-1 infection | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 繆希椿,孔祥智 | |
dc.subject.keyword | 單純?疹病毒,抗原特異性CD8+ T細胞,樹突狀細胞,IL-15異構物, | zh_TW |
dc.subject.keyword | HSV-1,antigen specific CD8+ T cells,dendritic cells,IL-15ΔE7, | en |
dc.relation.page | 95 | |
dc.identifier.doi | 10.6342/NTU201903484 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-15 | |
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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