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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊宏志 | |
| dc.contributor.author | Pin-Hung Lin | en |
| dc.contributor.author | 林品宏 | zh_TW |
| dc.date.accessioned | 2021-06-17T03:39:53Z | - |
| dc.date.available | 2021-03-29 | |
| dc.date.copyright | 2018-03-29 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-02-08 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70033 | - |
| dc.description.abstract | 因為流感病毒的高突變率，造成目前去活化疫苗刺激所產生的中和性抗體，無法有效的中和不同型流感病毒。T細胞是辨認流感病毒的高保留性抗原，所以可以有效的對抗不同型流感病毒。之前的研究指出，流感專一性記憶型T細胞有潛力對抗不同型或抗原差異大之流感病毒株，但其會隨著時間減少，因此如何建立良好的流感專一性T細胞免疫系統，顯得相當重要。先天免疫系統和後天免疫系統對於建立好的T細胞免疫扮演著重要角色，因此本篇論文分為兩部分去探討: (1) 調節型T細胞對於流感病毒專一性T細胞的影響。(2)介白素-1接受器對於流感病毒專一性記憶T細胞的影響。第一部份研究疫苗誘發的具病毒專一性之調節性T細胞對抗病毒能力之影響。胜肽疫苗可以針對病毒的高保留抗原產生專一性T細胞免疫，但因其免疫刺激效果不強，若無添加佐劑，不易有保護效果，且會產生抗原專一性調節型T細胞。目前對於疫苗誘導具病毒抗原專一性之調節型T細胞如何影響抗病毒免疫反應目前尚不清楚。因此，我們發展一特殊流感病毒之小鼠感染模式，利用過繼轉移給予小鼠OT-II CD4 T細胞的方式，發現OVA323-339胜肽可誘導產生具抗原專一性調節性T細胞，且專一性地去除這群調節性T細胞會提升小鼠抗病毒免疫反應。且流感病毒的感染，會使原先存在的疫苗誘導之調節性T細胞顯著增加。如果搭配不同佐劑，尤其是CpG，會抑制疫苗誘導調節性T細胞的產生，且在第二次免疫時，CpG也會抑制先前疫苗誘導調節性T細胞的增加。此外，疫苗搭配CpG並透過peripheral-priming-local-boosting方式給予，除了減少疫苗誘導調節性T細胞進入到肺中，也增加了effector在肺中的量。最後，我們發現，此種免疫方式，除了可用在胜肽疫苗外(OVAI/II或NPI/II 胜肽)和蛋白質疫苗(OVA蛋白、去活化流感病毒)之外，也能明顯的增加小鼠對抗異型流感病毒的感染。第二部份研究介白素-1接受器對於流感病毒專一性記憶T細胞的影響，之前的研究指出，介白素-1乙型可以經由NLR-發炎體路徑來產生，除了影響到先天免疫細胞的功能之外，也會影響到T細胞的功能和增生，且發現在初次流感病毒感染時，介白素-1接受器缺陷小鼠的病毒專一性T細胞相較野生型小鼠來的少，無法有效的清除流感病毒，使小鼠存活率下降。但我們發現，在初次感染後期，介白素-1接受器缺陷小鼠相較於野生型小鼠，卻有較多的病毒專一性T細胞。所以當介白素-1接受器缺陷小鼠在第二次異型流感病毒感染時，反而有較高的存活率和抗病毒能力。我們進一步發現，介白素-1接受器缺陷小鼠肺中的常駐型T細胞多於野生型小鼠，且不管是CD4或CD8肺常駐型T細胞，對於幫助介白素-1接受器缺陷小鼠的抗病毒能力和存活率都扮演著重要角色。最後，我們發現，介白素-1接受器缺陷小鼠有較多的調節性T細胞，且病毒抗原較晚清除，這可能與其有較多的肺常駐型T細胞有關。綜合以上結果，我們證明了，疫苗誘導調節型T細胞會抑制抗流感病毒的免疫反應，且含有CpG的疫苗，可以藉由抑制調節型T細胞的發展和刺激T細胞免疫反應，進而增加對抗異型流感病毒感染的能力。我們也證明了缺少介白素-1，會因為調節型T細胞的增加或抗原清除的太晚，使的肺常駐型T細胞的量增加，進而讓IL-1R1缺陷小鼠可以對抗異型流感病毒的感染。 | zh_TW |
| dc.description.abstract | Because of the high mutation rate of influenza virus, current inactivated influenza vaccine inducing neutralizing antibody against viral surface antigens cannot efficiently neutralize different subtypes of influenza virus. T cell immunity that recognizes the conserved epitopes derived from the internal proteins of influenza virus has the potential to protect against heterosubtypic and antigenically distinct influenza virus infection. Nevertheless, previous studies have shown memory T cells decrease along with time. Thus, establishment of a robust and long-lasting T cell immunity is important to protect from heterosubtypic influenza virus infection. Several factors have been shown to affect T cell responses induced by vaccination or infection. Therefore, this thesis aims to explore the factors that shape the antiviral T cell immunity against influenza virus infection in two parts. We have studied two specific factors: (1) the role of vaccine-induced antigen-specific regulatory T (Treg) cells in virus-specific T cell immunity. (2) the role of interleukin 1-recepter (IL-1R) signaling in the development of virus-specific memory T cells following acute influenza virus infection. In the first part, we aim to explore the influence of vaccine-induced antigen-specific Treg cells on antiviral T cell immunity. It has been known that peptide-based vaccines are subimmunogenic, and often induce Treg cells. However, it remains unclear about how vaccine-induced antigen-specific Treg cells affect antiviral immunity, and how repeated vaccination and infection influence antigen-specific Treg cells. Using an adoptive transfer system, we found that vaccination with the OVA323-339 peptide induced antigen-specific Treg cells and repeated vaccination further expanded them. Depletion of vaccine-induced antigen-specific Treg cells enhanced antiviral immunity against influenza virus infection. We also found that influenza virus infection drove the expansion of pre-existing vaccine-induced Treg cells in a dose-dependent manner. In addition, vaccination combined with certain adjuvants, especially with CpG, suppressed the generation and expansion of vaccine-induced antigen-specific Treg cells. Furthermore, CpG-adjuvanted vaccines by using the peripheral-priming-local-boosting strategy not only decreased vaccine-induced antigen-specific Treg cells but also increased effector cells in lung, so conferred a more effective viral control than unadjuvanted vaccines. Collectively, antigen-specific Treg cells induced by peptide vaccines attenuated the antiviral immunity against influenza virus infection. CpG-adjuvanted peptide vaccines provide influenza protection probably by inhibiting Treg development and enhancing T cell immunity. In the second part, IL-1, including IL-1α and IL-1β influences the survival and function of immune cells, and regulates certain adaptive immune responses directly and indirectly. Previous studies have shown IL-1R signaling promotes the development of antiviral T cell immunity, which confers a better viral control in acute viral infection. Surprisingly, we found that compared to wildtype (WT) mice, IL-1R type 1 (IL-1R1)-deficient mice had a higher survival rate and more effective viral control when they had primary infection with sublethal dose of HKx31 influenza virus and then re-challenged by heterosubtypic PR8 influenza virus infection. We also found that IL-1R1-/- mice had more resident and circulatory memory T cells in late phase of infection up to 28 days post infection. Both resident CD4 and CD8 T cells contributed to the better control of heterosubtypic influenza virus infection in IL-1R1-/- mice. Finally, we also observed longer stimulation of viral antigen and more regulatory T cells in lung of IL-1R1-/- mice, which may contribute to more resident T cells in the lung of IL-1R1-/- mice. In summary, we discovered the role of vaccine-induced antigen-specific Treg cells and the detrimental effect of IL-1R signaling and in the development of antiviral T cell immunity against acute influenza virus infection. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:39:53Z (GMT). No. of bitstreams: 1 ntu-107-D01445005-1.pdf: 8613510 bytes, checksum: cf64ea26641da8b23ef549afe3ec065e (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要 I
ABSTRACT IV TABLE OF CONTENTS VII INTRODUCTION XIV Part I: The role of vaccine-induced antigen-specific regulatory T (Treg) cells in virus-specific T cell immunity PART I: INTRODUCTION 1 1.1 Influenza T cell vaccine and regulatory T cells 1 1.2 Treg cells in acute influenza virus infection 2 1.3 The role of Treg cells in repeated influenza vaccination and infection remains unclear 3 1.4 The effect of adjuvants on the development of antigen-specific Treg cells 4 1.5 Vaccination strategy 4 1.6 Aim for this study 5 PART I: MATERIALS AND METHODS 7 2.1 Mice 7 2.2 Viruses, infection, and virus quantification 8 2.3 Adoptive transfer of naïve CD4+ T cells 8 2.4 Infection of mice 9 2.5 Generation of dendritic cells from murine bone marrows 9 2.6 Quantification of viral titers. 10 2.7 Measurement of virus-specific T cells 10 2.8 Intracellular staining 11 2.9 Immunization of mice 12 2.10 The in vitro suppression assay for vaccine-induced Treg cells 13 2.11 Induction and depletion of antigen-specific Treg in CD45.1 mice. 14 2.12 Priming and boosting strategy (OVA protein vaccination) 14 2.13 Whole inactivated virus (WIV) preparation 15 2.14 Statistical analyses. 15 PART I: RESULTS 17 3.1 Antigen‐specific Treg cells are induced by unadjuvanted peptide vaccines in a dose‐dependent manner. 17 3.2 Levels of vaccine-induced antigen‐specific Treg cells are independent of the number of adoptively transferred cells. 18 3.3 Antigen‐specific regulatory T cells suppress T cell proliferation in vitro. 19 3.4 Adjuvants antagonize the induction of antigen-specific Treg cells by peptide vaccine priming. 19 3.5 Adjuvants antagonize the proliferation of antigen-specific Treg cells and promote effector cytokine production by peptide vaccine priming. 20 3.6 Adjuvants restrict the expansion of pre-existing vaccine-induced regulatory T cells. 22 3.7 Influenza virus infection promotes the expansion of pre-existing vaccine-induced Treg cells. 23 3.8 Primary vaccination condition affects the level of vaccine-induced Treg cells. 25 3.9 Depletion of vaccination-induced antigen-specific Treg cells enhances the antiviral immunity against influenza virus infection. 26 3.10 CpG adjuvanted peptide vaccine suppresses recruitment of Treg cells to the lung and provides protective antiviral T cell immunity against acute influenza virus infection. 28 3.11 CpG adjuvanted protein vaccine suppresses recruitment of Treg cells to the lung and provides protective antiviral T cell immunity against acute influenza virus infection. 32 PART I: DISCUSSION 35 Part II: The role of interleukin 1-recepter (IL-1R) signaling in the development of virus-specific memory T cells following acute influenza virus infection PART II: INTRODUCTION 43 1.1 IL-1α, IL-1β, and IL-1 receptor (IL-1R) 43 1.2 IL-1 and influenza virus 43 1.3 Aim for this study 45 PART II: MATERIALS AND METHODS 46 2.1 Mice 46 2.2 Viruses, infection, and virus quantification 46 2.3 Adoptive transfer of naïve CD4+ T cells 47 2.4 Infection of mice 48 2.5 Generation of dendritic cells from murine bone marrows 48 2.6 Measurement of virus-specific T cells 49 2.7 Intracellular staining 49 2.8 In vivo staining 50 2.9 FTY720 treatment 50 2.10 Antigen persistence 50 2.11 Systemic or local depletion of CD4 and CD8 T cells 51 2.12 Histological staining. 51 2.13 Statistical analyses. 51 PART II: RESULTS 53 3.1 IL-1R signaling is critical for viral control in primary influenza A virus infection. 53 3.2 IL-1R1-deficient mice develop stronger viral control upon secondary challenge by heterosubtypic influenza virus. 53 3.3 Lack of IL-1R signaling increases virus-specific T cell immunity in the late stage of primary influenza virus infection. 55 3.4 IL-1R1-deficient mice have more resident T cells and Treg cells accumulated in lungs. 56 3.5 Resident memory T cells in IL-1R1-/- mice play an important role in control of secondary heterosubtypic influenza virus infection. 58 3.6 Both lung-resident CD4 and CD8 T cells contribute to the control of heterosubtypic influenza virus infection in IL-1R1-deficient mice. 59 3.7 Clearance of viral antigens following primary influenza virus infection is slower in IL-1R1-deficient mice. 62 PART II: DISCUSSION 63 FIGURES 70 Fig 1. The dose effect of peptide vaccination on induction of antigen-specific Treg cells... 71 Fig 2. The dose effect of peptide vaccination on induction of antigen-specific Treg cells by using fewer adoptively transferred cells. 73 Fig 3. Vaccine-induced antigen-specific Treg cells suppress T cells proliferation. 75 Fig 4. Effects of adjuvants on the development of antigen-specific Treg cells in primary vaccination. 77 Fig 5. Vaccines combined with indicated adjuvants stimulate the proliferation and cytokine secretion of antigen-specific T and Treg cells in the primary vaccination. 79 Fig 6. Effects of adjuvants on the development of antigen-specific Treg cells in secondary vaccination. 81 Fig 7. The pre-existing antigen-specific Treg cells are expanded during influenza virus infection. 84 Fig 8. Primary vaccination experience affects the expansion of antigen-specific Treg cells upon subsequent influenza virus infection. 86 Fig 9. Depletion of antigen-specific Treg cells enhances the antiviral immunity against acute influenza virus infection. 89 Fig 10. CpG adjuvant inhibits the recruitment and accumulation of vaccine-induced Treg cells in lung by peripheral-prime-local-boost immunization strategy. 92 Fig 11. HKx31-HA-OVAI/II virus infection induces the proliferation of CFSE-labeled OT-I and OT-II T cell. 94 Fig 12. Vaccination with CpG‐adjuvanted OVA OT‐I/OT‐II peptide by peripheral-prime-local-boost strategy protects mice from HKx31‐HA‐OVAI/II influenza virus infection. 98 Fig 13. Mice treated with CpG‐adjuvanted NPI/NPII peptide by peripheral-prime-local-boost strategy are more resistant to PR8 influenza virus infection. 103 Fig 14. Vaccination with CpG adjuvant by the peripheral-prime-local-boost strategy protects mice from heterosubtypic influenza virus infection. 105 Fig 15. CpG-adjuvanted whole-inactivated vaccine (WIV) protects mice from heterosubtypic influenza virus infection. 106 Fig 16. IL-1R1-/- mice are more susceptible to acute PR8 virus infection. 108 Fig 17. IL-1R1-/- mice are more susceptible to acute HKx31 virus infection. 111 Fig 18. The percentage of IFN-γ-producing cells in WT and IL-1R1-/- mice after acute HKx31 virus infection. 112 Fig 19. The protection against secondary PR8 virus challenge can be observed up to two months after HKx31 priming of IL-1R1-/- mice. 114 Fig 20. IL1-R1-/- mice exhibited higher antiviral immunity against heterosubtypic virus infection than WT mice. 116 Fig 21. IL1-R1-/- mice have more cell infiltration in lung after heterosubtypic virus infection influenza A. 118 Fig 22. IL-1R1-/- mice are more susceptible to non-lethal dose of acute primary HKx31 virus infection. 120 Fig 23. In vivo staining of tissue resident and circulatory T cells. 122 Fig 24. More memory T cell reside in lungs following influenza A virus infection of IL-1R1-/- mice. 124 Fig 25. IL-1R1 knockout mice have more antigen-specific resident Treg cells accumulated in lung after HKx31-HA-OVAI/II virus infection. 126 Fig 26. IL-1R1-/- mice infected by influenza virus recruit more CD4 and CD8 T cells to lung after cognate peptide re-stimulation 127 Fig 27. Resident T cells protect IL-1R1-/- mice from secondary PR8 challenge. 130 Fig 28. Antibody depletion through intratracheal injection depletes most of CD4+ and CD8+ T cells in lung. 132 Fig 29. Lung CD4 and circulatory CD8 T cells protect IL-1R1-/- mice from heterosubtypic influenza A virus infection. 134 Fig 30. Both of lung CD4 and CD8 T cells in lungs play an important role in control viral replication in IL-1R1-/- mice after secondary PR8 challenge. 136 Fig 32. The induction and expansion of vaccine-induced Treg cells by vaccination and infection. 138 Fig 33. CpG adjuvanted vaccination through peripheral priming and local boosting strategy enhances local immunity against influenza virus infection. 139 REFERENCES 140 | |
| dc.language.iso | en | |
| dc.subject | 介白素-1 | zh_TW |
| dc.subject | 異型流感病毒 | zh_TW |
| dc.subject | 肺常駐型T細胞 | zh_TW |
| dc.subject | T細胞免疫 | zh_TW |
| dc.subject | 胜?疫苗 | zh_TW |
| dc.subject | 疫苗專一性調節性T細胞 | zh_TW |
| dc.subject | 佐劑 | zh_TW |
| dc.subject | heterosubtypic influenza virus | en |
| dc.subject | resident memory T cells | en |
| dc.subject | adjuvant | en |
| dc.subject | vaccine-induced regulatory T cells | en |
| dc.subject | T cell immunity | en |
| dc.subject | IL-1 | en |
| dc.title | 疫苗誘導之調節性T細胞和第一介白素接受器的訊息在建立流感病毒專一性記憶型T細胞的角色 | zh_TW |
| dc.title | The role of vaccination-induced regulatory T cells and interleukin-1-receptor signaling in establishment of influenza virus-specific memory T cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 黃景泰,顧家綺,陳俊任,林俊彥 | |
| dc.subject.keyword | 異型流感病毒,T細胞免疫,胜?疫苗,疫苗專一性調節性T細胞,佐劑,介白素-1,肺常駐型T細胞, | zh_TW |
| dc.subject.keyword | heterosubtypic influenza virus,T cell immunity,vaccine-induced regulatory T cells,adjuvant,IL-1,resident memory T cells, | en |
| dc.relation.page | 146 | |
| dc.identifier.doi | 10.6342/NTU201800439 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-02-08 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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