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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊宏志 | zh_TW |
| dc.contributor.advisor | Hung-Chih Yang | en |
| dc.contributor.author | 蘇怡瑄 | zh_TW |
| dc.contributor.author | Yi-Hsuan Su | en |
| dc.date.accessioned | 2025-09-22T16:10:56Z | - |
| dc.date.available | 2025-09-23 | - |
| dc.date.copyright | 2025-09-22 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-04 | - |
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Parallel detection of SARS-CoV-2 epitopes reveals dynamic immunodominance profiles of CD8+ T memory cells in convalescent COVID-19 donors. Clinical & translational immunology, 11(10), e1423. https://doi.org/10.1002/cti2.1423 | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99969 | - |
| dc.description.abstract | 流感病毒是一種高度變異的 RNA 病毒，具有高突變率與人畜共通感染的潛力，經常引發季節性流行與全球性大流行，對全球公共衛生構成重大威脅。目前市面上的流感疫苗多針對病毒外部蛋白如血球凝集素 (HA) 與神經胺酸酶 (NA) 設計，雖然這樣的設計可提供良好保護力，卻因病毒突變快速而需每年重新預測及更新。相較之下，T 細胞能辨識整個病毒蛋白體中的抗原，增加辨識保守性 T 細胞表位的可能性。T 細胞表位 (epitope) 的免疫優勢性層級 (immunodominance hierarchy) 對免疫反應的效果具有關鍵影響，其免疫原性、抗原表現量以及與 MHC 分子結合親和力的差異，皆可影響表位的優勢程度。免疫優勢表位 (dominant epitope) 通常誘發較強的免疫反應並提供較佳保護，但也可能因選擇壓力反而促使病毒產生逃脫突變株。相對地，次優勢表位 (subdominant epitopes) 雖引發的反應較弱，卻能在優勢表位突變時作為備用目標。瞭解這些保守性表位的免疫優勢性與保護力，是發展出可以廣泛對抗多種流感病毒株同時具有持久免疫力之 T 細胞疫苗的關鍵步驟。因此，本研究旨在利用表達人類常見 HLA 分子的 HLA 轉基因小鼠 (HLA-A02 或 HLA-A11)，去測量本實驗室先前鑑定或他人已發表過之保守性 T 細胞表位的免疫優勢層級與保護效果。首先我們在 HLA 轉基因小鼠量測台灣 2009 年臨床流行株 TW126 (H1N1) 的感染劑量，隨後以細胞內細胞激素染色 (ICS) 與 peptide-MHC 四聚體染色分析病毒感染後的 T 細胞反應，並進一步針對保守性表位分析其所誘發的 T 細胞免疫反應，以評估各表位的免疫優勢層級與保護潛力。未來，我們也將持續探討這些保守表位的保護效果及其開發更有效且具廣效性的流感T細胞疫苗之潛力。 | zh_TW |
| dc.description.abstract | Influenza is a rapidly evolving RNA virus characterized by high mutation rates and zoonotic potential, leading to seasonal outbreaks and pandemics that pose a major threat to global public health. Current influenza vaccines often target external viral proteins, hemagglutinin (HA) and neuraminidase (NA), offering strong protection but requiring annual updates. In contrast, T cells recognize antigens from the entire viral proteome, increasing the likelihood of identifying conserved T cell epitopes. The immunodominance hierarchy of T cell epitopes plays a critical role in shaping immune response effectiveness. Variations in immunogenicity, expression levels, and binding affinities to MHC molecules contribute to distinct dominance patterns, which typically induce stronger immune responses and offer better protection but can also exert selection pressure, leading to escape mutants. In contrast, subdominant epitopes, while eliciting weaker responses, serve as essential backups when mutations occur in dominant epitopes. Understanding the immunodominance hierarchy and protectivity of the conserved T cell epitopes is a key step to develop a universal influenza T cell vaccine to provide durable and cross-strain immunity. Therefore, this study aimed to evaluate the immunodominance hierarchy and protectivity of the conserved T cell epitopes identified in our lab using HLA-transgenic mice that expressing the prevalent human HLAs, either HLA-A02 or HLA-A11. We first titrated the dose of IAV strain TW126 (H1N1), an isolate in 2009 pandemic in Taiwan, in HLA transgenic mice. We then analyzed the T cell response to influenza virus infection using intracellular cytokine staining and pMHC tetramer staining. Furthermore, we evaluated the T cell response to the conserved T cell epitopes to investigate their immunodominance hierarchy and their protective potential. The protective efficacy of these conserved epitopes and their potential in developing a more effective and universal T cell-based influenza vaccine will also be examined in future studies. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-22T16:10:56Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-22T16:10:56Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Context
口試委員審定書 I 致謝 II 中文摘要 III Abstract IV 1. Introduction 1 1.1 Human influenza virus epidemiology and public health impact 1 1.2 Structure and genome organization of influenza A virus 1 1.3 Antigenic drift and shift in influenza virus evolution 3 1.4 Current strategies and limitations of influenza vaccines 4 1.5 Role of CD4+ and CD8+ T cells in influenza immunity 5 1.6 Broadening vaccine targets with epitope-based approaches 6 1.7 Immunodominance hierarchy of epitopes 7 1.8 Selection pressure and escape mutant of dominant epitopes 8 1.9 Protective potential of subdominant epitopes 9 2. Specific aim 12 3. Materials and Methods 13 3.1 Mice 13 3.2 Viruses 13 3.3 Infection and survival rate assessment 14 3.4 Immunization of mice with CFA and CPG 14 3.5 Collection and processing of tissue samples 15 3.6 Ex-vivo intracellular cytokine staining (ICS) 16 3.7 Tetramer staining 16 3.8 Viral titer measurement in lung 17 3.9 Cell staining and flow cytometry 18 3.10 Statistic analysis 18 4. Results 19 4.1 Determination of viral titer and assessment of infection dosage 19 4.2 Confirmation of epitope presentation and CD8+ T cell activation after infection in B6 mice 21 4.3 Selection of HLA-A*02:01 epitope candidates for further analysis 22 4.4 Immunodominance hierarchy of the five selected HLA-A*02:01 epitopes under natural infection 25 4.5 Evaluation of the immunogenicity of HLA-A*02:01 epitopes. induced by vaccination with CFA 28 4.6 Protective evaluation of PA-1 following vaccination and viral challenge 31 4.7 Selection of HLA-A*11:01 epitope candidates for further analysis 34 4.8 Immunodominance hierarchy of four identified HLA-A*11:01 epitopes 35 5. Discussion 38 5.1 Summary of findings 38 5.2 Limitations in this study 39 5.3 Establishing a reliable infection model and optimizing antigen dose for animal-to-human relevance 40 5.4 Potential mechanisms underlying GL9 immunodominance 41 5.5 Controlled evaluation of peptide immunogenicity 43 5.6 Protective effects of the dominant and subdominant epitopes 44 5.7 Limitation of HLA-transgenic mouse models in evaluating PB1413-421 46 5.8 Technical and biological constraints in HLA-A11 epitope evaluation 48 5.9 Balancing dominant and subdominant epitopes in vaccine formulation 49 6. Figures 52 Figure 1. Viral titer and testing of TW126 and Hybrid-TW126 virus strains 54 Figure 2. Successful presentation of NP366-374 and PA224-233 and activation of CD8+ T cells 56 Figure 3. GL9 could induce CD8+ T cell response in HLA-A2-transgenic mice 58 Figure 4. GL9 induced the greatest CD8+ T cell response among five HLA-A*02:01 epitopes under natural infection 61 Figure 5. GL9 induced the robust CD8+ T cell response, while PA-1 induced a weaker response 64 Figure 6. PA-1 vaccination reduced body weight loss, but its protectivity remains unclear 66 Figure 7. Lack of T cell responses to four identified HLA-A*11:01 epitopes may result from insufficient expression of HLA-A11 molecules in transgenic mice 69 7. References 71 8. Supplementary Information 79 Supplementary Table 1. Sequence alignment of NP366-374 and PA224-233 79 Supplementary Table 2. Identified HLA-A*02:01-restricted IAV(TW126) epitopes 79 Supplementary Table 3. Information of five selected HLA-A*02:01epitopes 80 Supplementary Table 4. Identified HLA-A*11:01-restricted IAV(TW126) epitopes 80 Supplementary Figure 1. Schematic illustration of TW126 (A/Taiwan/126/2009) and Hybrid-TW126 virus strain 81 Supplementary Figure 2. Hybrid-TW126 viral titration in HLA-A2 and HLA-A11-transgenic mice 82 Supplementary Figure 3. Data from referenced studies on epitope selection and T cell activation 85 Supplementary Figure 4. Stabilization assay of HLA-A*02:01 and HLA-A*11:01 epitopes in monoallelic HLA 293T cell lines 86 Supplementary Figure 5. Overall tetramer staining results for GL9 and PA-1 88 | - |
| dc.language.iso | en | - |
| dc.subject | 流感病毒 | zh_TW |
| dc.subject | T細胞免疫 | zh_TW |
| dc.subject | 保守T 細胞表位 | zh_TW |
| dc.subject | HLA 轉基因小鼠 | zh_TW |
| dc.subject | 免疫優勢性層級 | zh_TW |
| dc.subject | Influenza virus | en |
| dc.subject | immunodominance hierarchy | en |
| dc.subject | HLA-transgenic mice | en |
| dc.subject | conserved CD8+ epitopes | en |
| dc.subject | T cell immunity | en |
| dc.title | CD8+ T細胞保守性抗原於HLA轉基因小鼠流感病毒感染中之免疫主導階層與保護性研究 | zh_TW |
| dc.title | To explore the immunodominance hierarchy and protectivity of conserved CD8+ T cell epitopes against influenza virus infection in HLA-transgenic mice | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 陶秘華;林志萱 | zh_TW |
| dc.contributor.oralexamcommittee | Mi-Hua Tao;Jr-Shiuan Lin | en |
| dc.subject.keyword | 流感病毒,T細胞免疫,保守T 細胞表位,HLA 轉基因小鼠,免疫優勢性層級, | zh_TW |
| dc.subject.keyword | Influenza virus,T cell immunity,conserved CD8+ epitopes,HLA-transgenic mice,immunodominance hierarchy, | en |
| dc.relation.page | 88 | - |
| dc.identifier.doi | 10.6342/NTU202502579 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2025-08-04 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 微生物學研究所 | - |
| dc.date.embargo-lift | 2027-07-30 | - |
| 顯示於系所單位： | 微生物學科所 | |
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