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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99577完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江伯倫 | zh_TW |
| dc.contributor.advisor | Bor-Luen Chiang | en |
| dc.contributor.author | 范家寧 | zh_TW |
| dc.contributor.author | Jia-Ning Fan | en |
| dc.date.accessioned | 2025-09-16T16:10:20Z | - |
| dc.date.available | 2025-09-17 | - |
| dc.date.copyright | 2025-09-16 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-07 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99577 | - |
| dc.description.abstract | 調節性T細胞（Regulatory T cells, Tregs）是一群具有抑制功能的淋巴細胞，在維持體內免疫反應中扮演重要角色。先前我們實驗室發現B細胞可誘導CD4+CD25- T細胞轉變為一群CD25+FOXP3-調節性T細胞（Treg-of-B cell），在自體免疫疾病與過敏模型中皆證明其免疫抑制功能。除了典型的CD4+調節性T細胞，許多研究也顯示CD8+ T細胞中也存在具有免疫抑制活性的族群。因此本研究的目的為探討B細胞誘導產生的CD8+調節性T細胞（CD8+ Treg-of-B cell）的特徵，並進一步研究其在小鼠發炎性疾病模型中的免疫調節作用。
此一研究結果發現，CD8+ Treg-of-B細胞表現CD25、ICOS、LAG3、OX40、GITR、PD-1、CTLA-4等分子，但並不表達轉錄因子Foxp3。與CD8+CD25- T細胞相比，活化後的CD8+ Treg-of-B細胞可分泌更多的IL-10、IFN-γ和TNF-α。此外CD8+ Treg-of-B細胞需透過細胞接觸機制對CD4+和CD8+ T細胞發揮抑制能力。為了探討CD8+ Treg-of-B細胞在體內的免疫調節功能，我們透過葡聚糖硫酸鈉（dextran sulfate sodium salt, DSS）與CD4+CD45RBhi T細胞建立小鼠結腸炎模式，以及利用卵清蛋白（ovalbumin, OVA）誘發小鼠氣喘模型。在發炎性腸道疾病模型中，CD8+ Treg-of-B細胞降低促發炎細胞因子IL-1β與IL-17的表現，並減輕DSS結腸炎的病理特徵。在CD4+CD45RBhi T細胞誘導的結腸炎中，接受CD8+ Treg-of-B細胞治療的小鼠也降低其結腸組織中IFN-γ的表現。此外CD8+ Treg-of-B細胞在體外也抑制第二型輔助性T細胞（T helper 2 cells, Th2）增生，並降低Th2細胞因子IL-4、IL-5和IL-13的產生。在OVA引發的氣喘小鼠中，以 CD8+ Treg-of-B細胞治療顯著下調呼吸道過度反應，並減少支氣管肺泡灌洗液中嗜酸性白血球的浸潤。此外，CD8+ Treg-of-B細胞與CD8+CD122+調節性T細胞具有相似表型特徵，且比起天然CD8+CD122+調節性T細胞表達更高水平的IL-10。 總結以上結果，我們的研究為CD8+調節性T細胞領域提供了新的發現。CD8+ Treg-of-B細胞是一種新型的CD8+調節性T細胞，在體外透過細胞接觸發揮抑制效果。我們也證明了CD8+ Treg-of-B細胞能減緩小鼠實驗性結腸炎與呼吸道發炎。這些數據可能支持CD8+ Treg-of-B細胞在發炎疾病中的治療潛力。 | zh_TW |
| dc.description.abstract | Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and mediating suppressive functions. In the previous studies, our laboratory found that naïve B cells facilitate the conversion of CD4+CD25- T cells into forkhead box protein 3 (Foxp3)-CD25+ regulatory T cells, named Treg-of-B cells. The immunosuppressive function of Treg-of-B cells has been demonstrated in a variety of allergic and autoimmune disease models. In addition to classical CD4+ Tregs, many studies have also revealed suppressive functions in CD8+ T cells. Hence, this study aimed to characterize CD8+ regulatory T cells induced by B cells (CD8+ Treg-of-B cells) and investigate their regulatory effects in murine models of inflammatory disease.
In this study, CD8+ Treg-of-B cells were characterized by expression of CD25, lymphocyte activation gene 3 (LAG3), inducible co-stimulator (ICOS), tumor necrosis factor receptor superfamily member 4 (OX40), glucocorticoid-induced TNFR-related protein (GITR), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), but did not express Foxp3. Activated-CD8+ Treg-of-B cells secreted higher levels of interleukin (IL)-10, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) compared to CD8+CD25- T cells. In addition, CD8+ Treg-of-B cells exerted suppressive ability on both CD4+ and CD8+ T cells through a cell-cell contact-dependent mechanism in vitro. To further investigate the immunomodulatory function of CD8+ Treg-of-B cells in vivo, chronic dextran sulfate sodium salt (DSS)-induced colitis, CD4+CD45RBhi T cell transfer colitis, and ovalbumin (OVA)-induced asthma models were used. Significant reductions in the levels of pro-inflammatory cytokine IL-1β and IL-17 were observed following treatment with CD8+ Treg-of-B cells, which also attenuated the pathological features of DSS-induced colitis. In addition, the level of IFN-γ was decreased in the colonic tissue of T cell transfer colitis mice. Moreover, CD8+ Treg-of-B cells effectively inhibited the proliferation and cytokine secretion of IL-4, IL-5, and IL-13 by T helper (Th) 2 cells in vitro. In asthmatic mice, CD8+ Treg-of-B cells down-regulated airway hyperresponsiveness and decreased eosinophilic infiltration in bronchoalveolar lavage. In addition, CD8+ Treg-of-B cells shared a similar phenotype with CD8+CD122+ Tregs and expressed a higher level of IL-10 than CD8+CD122+ Tregs. In conclusion, our study provided new insight into the characterization of CD8+ Tregs. CD8+ Treg-of-B cell is a novel Foxp3-CD8+ Treg subset with suppressive effects through cell contact in vitro. We also demonstrated that CD8+ Treg-of-B cells attenuated the severity of experimental colitis and airway inflammation in vivo. These data might suggest the therapeutic potential of CD8+ Treg-of-B cells in inflammatory diseases. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-16T16:10:20Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-16T16:10:20Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 目次
謝辭 I 中文摘要 II Abstract IV Abbreviations VI 目次 X 圖次 XV 表次 XVII Chapter 1. Introduction 1 Section 1. Regulatory T cells 2 1.1 Classification of regulatory T cells 2 1.2 Treg-of-B cells 3 1.3 CD8+ Tregs 5 Section 2. Inflammatory bowel diseases 7 2.1 Pathogenesis of IBD 7 2.2 Medical treatments of IBD 9 2.3 Tregs and IBD 10 Section 3. Asthma 12 3.1 Pathogenesis of asthma 12 3.2 Treatments of asthma 13 3.3 Tregs and asthma 14 Section 4. Study aims 15 Chapter 2. Materials & Methods 16 Section 1. Materials 17 1.1 Animals 17 1.2 Culture medium and reagents 17 1.3 Flow cytometry 19 1.4 Enzyme-linked immunosorbent assay (ELISA) 20 1.5 RNA extraction and reverse transcription-polymerase chain reaction (RT-PCR) 21 1.6 Quantitative polymerase chain reaction (qPCR) 21 1.7 Cell sorting 21 1.8 IBD model 22 1.9 Asthma model 22 Section 2. Methods 23 2.1 Characterization of CD8+ Treg-of-B cells 23 2.1.1 Cell isolation 23 2.1.2 CD8+ Treg-of-B cells generation 23 2.1.3 Flow cytometry 23 2.1.4 Cytokine analysis 24 2.1.5 Reverse-transcription and qPCR 24 2.2 Functional assays of CD8+ Treg-of-B cells 25 2.2.1 Suppression assay and antibody blocking experiments 25 2.2.2 Transwell experiments 25 2.3 Cell sorting 26 2.3.1 CD4+CD45RBhi T cell purification 26 2.3.2 CD8+CD122+ T cell purification 26 2.4 Establishment of IBD model 27 2.4.1 DSS-induced colitis and adoptive transfer 27 2.4.2 T cell transfer model of colitis and adoptive transfer 27 2.5 Evaluation of colonic tissue 28 2.5.1 Histological evaluation 28 2.5.2 Ex vivo culture of colonic tissue and cytokine detection 29 2.6 Culture of Th2 cells 29 2.7 Asthma model 30 2.7.1 OVA-induced allergic asthma and adoptive transfer 30 2.7.2 Evaluation of airway function 30 2.7.3 Detection of anti-OVA-specific antibodies 30 2.7.4 Bronchoalveolar lavage fluid (BALF) collection and analysis 31 2.7.5 Detection of pro-inflammatory cytokines in lung tissue 31 2.7.6 Histopathology evaluation 31 2.8 Statistical analysis 32 Chapter 3. Results 33 Section 1. Characterization of CD8+ Treg-of-B cells 34 1.1 The generation of CD8+ Treg-of-B cells 34 1.2 The phenotypical characterization of CD8+ Treg-of-B cells 34 1.3 Cytokine production by CD8+ Treg-of-B cells 35 1.4 Cytotoxic factor expression in CD8+ Treg-of-B cells 35 1.5 The suppressive capacity of CD8+ Treg-of-B cells 36 1.6 CD8+ Treg-of-B cells exerted the suppressive function through a cell-cell contact manner 36 1.7 The function of surface molecules in CD8+ Treg-of-B cells-mediated suppression 37 Section 2. The immunomodulatory function of CD8+ Treg-of-B cells in IBD 38 2.1 DSS-induced colitis model 38 2.1.1 Adoptive transfer of CD8+ Treg-of-B cells slightly alleviated weight loss 38 2.1.2 Adoptive transfer of CD8+ Treg-of-B cells reduced pro-inflammatory cytokines in the colonic tissue of DSS-induced colitis mice 38 2.1.3 Adoptive transfer of CD8+ Treg-of-B cells alleviated DSS-induced colitis 39 2.2 T cell transfer colitis model 39 2.2.1 CD8+ Treg-of-B cells suppressed CD4+CD45RBhi T cell proliferation in vitro 39 2.2.2 Adoptive transfer of CD8+ Treg-of-B cells in T cell transfer colitis 40 2.2.3 Adoptive transfer of CD8+ Treg-of-B cells reduced pro-inflammatory cytokines in the colonic tissue of T cell transfer colitis 41 2.2.4 Adoptive transfer of CD8+ Treg-of-B cells did not alleviate histologic changes in T cell transfer colitis 41 Section 3. The immunomodulatory function of CD8+ Treg-of-B cells in asthma 42 3.1 CD8+ Treg-of-B cells suppressed Th2 proliferation and cytokine secretion in vitro 42 3.2 CD8+ Treg-of-B cells regulated airway hyperresponsiveness 43 3.3 Adoptive transfer of CD8+ Treg-of-B cells did not alter OVA-specific antibody levels in the asthma model 43 3.4 CD8+ Treg-of-B cells decreased eosinophil accumulations in BALF 44 3.5 The impact of CD8+ Treg-of-B cells on inflammatory cytokines in the asthma model 45 3.6 Adoptive transfer of CD8+ Treg-of-B cells could not alleviate pulmonary inflammation 45 Section 4. Identification of CD8+ Treg-of-B cells and natural CD8+ Tregs 46 4.1 CD8+ Treg-of-B cells expressed CD122 46 4.2 The transcriptional levels of CD8+ Treg-related genes in CD8+CD122+ cells and CD8+ Treg-of-B cells 46 Chapter 4. Discussion 48 Chapter 5. Perspectives 59 Chapter 6. References 62 Chapter 7. Figures 81 Chapter 8. Tables 109 | - |
| dc.language.iso | en | - |
| dc.subject | B細胞誘導調節性T細胞 | zh_TW |
| dc.subject | CD8+調節性T細胞 | zh_TW |
| dc.subject | 細胞治療 | zh_TW |
| dc.subject | 氣喘 | zh_TW |
| dc.subject | 發炎性腸道疾病 | zh_TW |
| dc.subject | inflammatory bowel disease | en |
| dc.subject | asthma | en |
| dc.subject | cell therapy | en |
| dc.subject | Treg-of-B cells | en |
| dc.subject | CD8+ Tregs | en |
| dc.title | 研究B細胞誘導的調節性CD8+ T細胞特徵及其在小鼠發炎疾病模型中的免疫調節功能 | zh_TW |
| dc.title | Characterization of CD8+ Treg-of-B Cells and Their Modulatory Effect in Murine Inflammatory Disease Models | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 王弘毅;沈家瑞;楊皇煜;樹金忠 | zh_TW |
| dc.contributor.oralexamcommittee | Hurng-Yi Wang;Chia-Rui Shen;Huang-Yu Yang;Chin-Chung Shu | en |
| dc.subject.keyword | CD8+調節性T細胞,B細胞誘導調節性T細胞,發炎性腸道疾病,氣喘,細胞治療, | zh_TW |
| dc.subject.keyword | CD8+ Tregs,Treg-of-B cells,inflammatory bowel disease,asthma,cell therapy, | en |
| dc.relation.page | 114 | - |
| dc.identifier.doi | 10.6342/NTU202501552 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-07-09 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 臨床醫學研究所 | - |
| dc.date.embargo-lift | 2030-07-03 | - |
| 顯示於系所單位： | 臨床醫學研究所 | |
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