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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許秉寧 | zh_TW |
| dc.contributor.advisor | Ping-Ning Hsu | en |
| dc.contributor.author | 陳怡心 | zh_TW |
| dc.contributor.author | Yi-Hsin Chen | en |
| dc.date.accessioned | 2025-09-22T16:06:54Z | - |
| dc.date.available | 2025-09-23 | - |
| dc.date.copyright | 2025-09-22 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-30 | - |
| dc.identifier.citation | 1. Jenne, C. N., Kubes, P. (2013). Immune surveillance by the liver. Nature Immunology, 14(10), 996-1006. https://doi.org/10.1038/ni.2691
2. Shetty, S., Lalor, P. F., Adams, D. H. (2018). Liver sinusoidal endothelial cells — gatekeepers of hepatic immunity. Nature Reviews Gastroenterology & Hepatology, 15(9), 555-567. https://doi.org/10.1038/s41575-018-0020-y 3. Fernandez-Ruiz, D., Ng, W. Y., Holz, L. E., Ma, J. Z., Zaid, A., Wong, Y. C., Lau, L. S., Mollard, V., Cozijnsen, A., Collins, N., Li, J., Davey, G. M., Kato, Y., Devi, S., Skandari, R., Pauley, M., Manton, J. H., Godfrey, D. I., Braun, A., Tay, S. S., Tan, P. S., Bowen, D. G., Koch-Nolte, F., Rissiek, B., Carbone, F. R., Crabb, B. S., Lahoud, M., Cockburn, I. A., Mueller, S. N., Bertolino, P., McFadden, G. I., Caminschi, I., Heath, W. R. (2016). Liver-Resident Memory CD8+ T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection. Immunity, 45(4), 889-902. https://doi.org/10.1016/j.immuni.2016.08.011 4. Robinson, M. W., Harmon, C., O’Farrelly, C. (2016). Liver immunology and its role in inflammation and homeostasis. Cellular & Molecular Immunology, 13(3), 267 276. https://doi.org/10.1038/cmi.2016.3 5. Mueller, S. N., Mackay, L. K. (2016). Tissue-resident memory T cells: local specialists in immune defence. Nature Reviews Immunology, 16(2), 79-89. https://doi.org/10.1038/nri.2015.3 6. Evrard, M., Becht, E., Fonseca, R., Obers, A., Park, S. L., Ghabdan-Zanluqui, N., Schroeder, J., Christo, S. N., Schienstock, D., Lai, J., Burn, T. N., Clatch, A., House, I. G., Beavis, P., Kallies, A., Ginhoux, F., Mueller, S. N., Gottardo, R., Newell, E. W., Mackay, L. K. Single-cell protein expression profiling resolves circulating and resident memory T cell diversity across tissues and infection contexts. (2023). Immunity, 56(7), 1664-1680. https://doi.org/10.1016/j.immuni.2023.06.005 7. Pallett, L. J., Maini, M. K. (2022). Liver-resident memory T cells: life in lockdown. Semin Immunopathol. Seminars in Immunopathology, 44(6), 813-825. https://doi.org/10.1007/s00281-022-00932-w 8. Bolte, F. J., Rehermann, B. (2017). Tissue-resident T cells in hepatitis b: A new target for cure? Journal of Experimental Medicine, 214(6), 1564-1566. https://doi.org/10.1084/jem.20170842 9. Stelma, F., de Niet, A., Sinnige, M. J., van Dort, K. A., van Gisbergen, K. P. J. M., Verheij, J., van Leeuwen, E. M. M., Kootstra, N. A., Reesink, H. W. (2017). Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity. Scientific Reports, 7(1), 6172. https://doi.org/10.1038/s41598-017-06352-3 10. Wang, T., Shen, Y., Luyten, S., Yang, Y., Jiang, X. (2020). Tissue-resident memory CD8+ T cells in cancer immunology and immunotherapy. Pharmacological Research, 159, 104876. https://doi.org/10.1016/j.phrs.2020.104876 11. Koda, Y., Teratani, T., Chu, P. S., Hagihara, Y., Mikami, Y., Harada, Y., Tsujikawa, H., Miyamoto, K., Suzuki, T., Taniki, N., Sujino, T., Sakamoto, M., Kanai, T., Nakamoto, N. (2021). CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nature Communications, 12(1), 4474. https://doi.org/10.1038/s41467-021-24734-0 12. Suttles, J., Schwarting, G. A., Stout, R. D. Flow cytometric analysis reveals the presence of asialo GM1 on the surface membrane of alloimmune cytotoxic T lymphocytes. (1986). The Journal of Immunology, 136(5), 1586-1591. https://doi.org/10.4049/jimmunol.136.5.1586 13. He, K., Kimura, T., Takeda, K., Hayakawa, Y. Characterization of anti-asialo-GM1 monoclonal antibody. (2025). Biochemical and Biophysical Research Communications, 743, 151197. https://doi.org/10.1016/j.bbrc.2024.151197 14. Moore, M. L., Chi, M. H., Goleniewska, K., Durbin, J. E., Peebles, R. S. Jr. (2008). Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection. Viral Immunology, 21(3), 327-339. https://doi.org/10.1089/vim.2008.0003 15. Kosaka, A., Wakita, D., Matsubara, N., Togashi, Y., Nishimura, S., Kitamura, H., Nishimura, T. (2007). AsialoGM1+CD8+ central memory-type T cells in unimmunized mice as novel immunomodulator of IFN-gamma-dependent type 1 immunity. International Immunology, 19(3), 249-256. https://doi.org/10.1093/intimm/dxl140 16. Hargrove, M. E., Ting, C. C. (1988). Asialo GM1 as an accessory molecule determining the function and reactivity of cytotoxic T lymphocytes. Cellular Immunology, 112(1), 123-134. https://doi.org/10.1016/0008-8749(88)90281-X 17. Satarkar, D., Patra, C. (2022). Evolution, Expression and Functional Analysis of CXCR3 in Neuronal and Cardiovascular Diseases: A Narrative Review. Frontiers in Cell and Developmental Biology, 10, 882017. https://doi.org/10.3389/fcell.2022.882017 18. Groom, J. R., Richmond J., Murooka, T. T., Sorensen, E. W., Sung, J. H., Bankert, K., von Andrian, U. H., Moon, J. J., Mempel, T. R., Luster, A. D. (2012). CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. Immunity, 37(6), 1091-1103. https://doi.org/10.1016/j.immuni.2012.08.016 19. Hickman, H. D., Reynoso, G. V., Ngudiankama, B. F., Cush, S. S., Gibbs, J., Bennink, J. R., Yewdell, J. W. (2015). CXCR3 chemokine receptor enables local CD8(+) T cell migration for the destruction of virus-infected cells. Immunity, 42(3), 524-537. https://doi.org/10.1016/j.immuni.2015.02.009 20. Wasmuth, H. E., Lammert, F., Zaldivar, M. M., Weiskirchen, R., Hellerbrand, C., Scholten, D., Berres, M. L., Zimmermann, H., Streetz, K. L., Tacke, F., Hillebrandt, S., Schmitz, P., Keppeler, H., Berg, T., Dahl, E., Gassler, N., Friedman, S. L., Trautwein, C. (2009). Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology, 137(1), 309-319. https://doi.org/10.1053/j.gastro.2009.03.053 21. Zhang, X., Han, J., Man, K., Li, X., Du, J., Chu, E. S. H., Go, M. Y. Y., Sung, J. J. Y., Yu, J. (2016). CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. Journal of Hepatology, 64(1), 160-170. https://doi.org/10.1016/j.jhep.2015.09.005 22. Ivashkiv, L. B. (2018). IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nature Reviews Immunology, 18(9), 545-558. https://doi.org/10.1038/s41577-018-0029-z 23. Hu, X., li, J., Fu, M., Zhao, X., Wang, W. (2021). The JAK/STAT signaling pathway: from bench to clinic. Signal Transduction and Targeted Therapy, 6(1), 402. https://doi.org/10.1038/s41392-021-00791-1 24. Wang, H., Luo, H., Wan, X., Fu, X., Mao, Q., Xiang, X., Zhou, Y., He, W., Zhang, J., Guo, Y., Tan, W., Deng, G. (2020). TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection. Journal of Hepatology, 72(1), 45-56. https://doi.org/10.1016/j.jhep.2019.08.024 25. Papaioannou, S., See, J. X., Jeong, M., De La Torre, C., Ast, V., Reiners-Koch, P. S., Sati, A., Mogler, C., Platten, M., Cerwenka, A., Stojanovic, A. (2023). Liver sinusoidal endothelial cells orchestrate NK cell recruitment and activation in acute inflammatory liver injury. Cell Reports, 42(8), 112836. https://doi.org/10.1016/j.celrep.2023.112836 26. Radaeva, S., Sun, R., Jaruga, B., Nguyen, V. T., Tian, Z., Gao, B. (2006). Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology, 130(2), 435-452. https://doi.org/10.1053/j.gastro.2005.10.055 27. Tiegs, G., Hentschel, J., Wendel, A. (1992). A T cell-dependent experimental liver injury in mice inducible by concanavalin A. Journal of Clinical Investigation, 90(1), 196-203. https://doi.org/10.1172/JCI115836 28. Trautwein, C., Rakemann, T., Brenner, D. A., Streetz, K., Licato, L., Manns, M. P., Tiegs, G. (1998). Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice. Gastroenterology, 114(5), 1035-1045. https://doi.org/10.1016/s0016-5085(98)70324-5 29. Küsters, S., Gantner, F., Künstle, G., Tiegs, G. Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. (1996). Gastroenterology, 111(2), 462-471. https://doi.org/10.1053/gast.1996.v111.pm8690213 30. Sung, C. C., Horng, J. H., Siao, S. H., Chyuan, I. T., Tsai, H. F., Chen, P. J., Hsu, P. N. (2021). Asialo GM1-positive liver-resident CD8 T cells that express CD44 and LFA-1 are essential for immune clearance of hepatitis B virus. Cellular & Molecular Immunology, 18(7), 1772-1782. https://doi.org/10.1038/s41423-020-0376-0 31. Jung, I. Y., Noguera-Ortega, E., Bartoszek, R., Collins, S. M., Williams, E., Davis, M., Jadlowsky, J. K., Plesa, G., Siegel, D. L., Chew, A., Levine, B. L., Berger, S. L., Moon, E. K., Albelda, S. M., Fraietta, J. A. (2023). Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors. Cell Reports Medicine, 4(6), 101053. https://doi.org/10.1016/j.xcrm.2023.101053 32. Li, G., Srinivasan, S., Wang, L., Ma, C., Guo, K., Xiao, W., Liao, W., Mishra, S., Zhang, X., Qiu, Y., Lu, Q., Liu, Y., Zhang, N. (2022). TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine. Nature Communications, 13(1), 6043. https://doi.org/10.1038/s41467-022-33768-x 33. Hombrink, P., Helbig, C., Backer, R. A., Piet, B., Oja, A. E., Stark, R., Brasser, G., Jongejan, A., Jonkers, R. E., Nota, B., Basak, O., Clevers, H. C., Moerland, P. D., Amsen, D., van Lier, R. A. (2016). Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. Nature Immunology, 17(12), 1467-1478. https://doi.org/10.1038/ni.3589 34. Bandura, D. R., Baranov, V. I., Ornatsky, O. I., Antonov, A., Kinach, R., Lou, X., Pavlov, S., Vorobiev, S., Dick, J. E., Tanner, S. D. (2009). Mass Cytometry: Technique for Real Time Single Cell Multitarget Immunoassay Based on Inductively Coupled Plasma Time-of-Flight Mass Spectrometry. Analytical Chemistry, 81(16), 6813-6822. https://doi.org/10.1021/ac901049w | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99950 | - |
| dc.description.abstract | 肝臟是人體最大的內臟器官，具有嚴格的免疫調節特性，在面對無害的抗原時能夠維持免疫耐受性，同時也保持對病原體入侵的免疫監控。在肝臟免疫中，組織駐留型記憶T細胞被認為是重要的發炎反應驅動者。在我們過去的研究中，發現一群表現無唾液酸神經節苷脂的肝臟CD8 T細胞群，這群細胞對於乙型肝炎病毒感染中的病毒清除以及ConA所誘導的急性肝炎模型都扮演重要的角色，並且這群細胞展現與其他文獻所記載之肝臟駐留型記憶T細胞相似的特徵，包括表現LFA-1以及CD69等肝臟駐留記憶T細胞的表面標誌，以及在細胞過繼實驗中展現回到肝臟的能力。然而ASGM1並未有過被用作肝臟駐留型記憶T細胞表面標誌的先例，因此我們認為這群肝臟ASGM1+ CD8 T細胞是由複雜的細胞群所組成，其中可能包含一群肝臟駐留型記憶T細胞，並且這群細胞對於引發肝炎扮演重要的角色。因此本研究旨在透過高維度的免疫特徵分析，以單細胞RNA定序針對這群肝臟ASGM1+ CD8 T細胞的基因表達進行分析，以揭示不同的細胞次群，並確認其中是否包含肝臟駐留型記憶T細胞。研究結果顯示，根據基因的表現情況可以將這群肝臟ASGM1+ CD8 T細胞細分為十個次群，其中有一群與我們過去所發現的細胞特徵最為相似，包括表現組織駐留型T細胞的表面標誌以及干擾素γ等的基因。我們也進一步透過流式細胞術初步分析並且確認這群ASGM1+ CD8 T細胞群當中存在部分細胞會表現肝臟駐留記憶T細胞的表面標誌。除此之外，我們也觀察到在ConA誘導急性肝炎模型中，這群具有肝臟駐留型記憶T細胞表型的ASGM1+ CD8 T細胞會快速被活化並且開始製造干擾素γ。綜合上述，我們結合高維度單細胞RNA定序與流式細胞術，揭示肝臟ASGM1⁺ CD8 T細胞族群中的表型異質性與潛在功能分化狀態，並鑑定出一群具有肝臟駐留表型特徵且可迅速活化的效應性T細胞，為後續深入探討其在肝臟免疫反應中的功能奠定基礎。 | zh_TW |
| dc.description.abstract | The liver is the largest internal organ in the human body, with distinct immune regulatory characteristics. When encountering harmless antigens, the liver maintains immune tolerance toward these antigens while simultaneously preserving immune surveillance against invading pathogens. Within the liver immune system, liver-resident memory T cells (liver TRM) serve as critical drivers of inflammation. In our previous study, we identified a distinct population of ASGM1+ CD8 T cells present within the intrahepatic lymphocyte population. These ASGM1+ CD8 T cells play a critical role in both the clearance of hepatitis B virus (HBV) and the pathogenesis of ConA-induced hepatitis mouse model. In addition, ASGM1+ CD8 T cells exhibit reported characteristics of liver TRM, including the expression of TRM surface markers such as LFA-1 and CD69, and the ability to home back to the liver in adoptive transfer experiments. However, ASGM1 itself is not considered a canonical surface marker for distinguishing liver TRM. Therefore, we hypothesize that intrahepatic ASGM1+ CD8 T cells consist of multiple subsets, including a subset of liver TRM, which may serve as key initiators of hepatitis. This study aims to investigate intrahepatic ASGM1+ CD8 T cells through high-dimensional immune profiling by analyzing their gene expression using single-cell RNA sequencing (scRNA-seq). We also aim to investigate whether liver TRM cells exist within the ASGM1+ CD8 T cell population. In our results, scRNA-seq analysis revealed that ASGM1+ CD8 T cells can be divided into ten distinct clusters based on differential gene expression. One of these clusters exhibits characteristics most similar to those described in our previous study, including the expression of genes encoding TRM surface markers and interferon-gamma. Given that gene expression does not always correspond directly to protein expression, we further conducted flow cytometry analysis to confirm that a subset of ASGM1+ CD8 T cells expresses well-established or recently identified surface markers characteristic of liver TRM. In addition, we observed that, in the ConA-induced hepatitis model, the ASGM1+ CD8 T cells with a liver TRM-like phenotype were rapidly activated and began producing interferon-γ (IFN-γ). Taken together, by integrating high-dimensional single-cell RNA sequencing with flow cytometry, we revealed the phenotypic heterogeneity and potential functional states within the intrahepatic ASGM1+ CD8 T cell population. This analysis led to the identification of a TRM-like T cell subset capable of rapid activation, laying a foundation for future studies to further investigate their role in liver immune responses. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-22T16:06:54Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-22T16:06:54Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 1
中文摘要 2 Abstract 3 1. Background 7 1.1 Liver immunity 7 1.2 Liver inflammation 9 1.3 Tissue-resident memory T cell (TRM) 10 1.4 Liver-resident memory T cell (Liver TRM) 11 1.5 Asialo-GM1 (ASGM1) 12 1.6 CXC motif chemokine receptor 3 (CXCR3) 13 1.7 Interferon gamma (IFN-γ) 14 1.8 Concanavalin A (ConA)-induced hepatitis 15 2. Specific aims 16 2.1 Use single-cell RNA sequencing (scRNA-seq) to identify distinct populations of ASGM1+ CD8 T cells 16 2.2 Validate the results of scRNA-seq at the protein level using flow cytometry 17 2.3 To investigate IFN-γ-secreting cells within intrahepatic ASGM1+ CD8 T cells subsets in ConA-induced hepatitis mouse model 17 3. Materials and methods 18 3.1 Materials 18 3.1.1 Mice 18 3.1.2 Kits 18 3.1.3 Antibodies 19 3.1.4 Chemicals and reagents 22 3.1.5 Buffer 23 3.2 Methods 25 3.2.1 Establishment of ConA-induced hepatitis mouse model 25 3.2.2 Isolation of intrahepatic lymphocytes and splenocytes 25 3.2.3 Flow cytometry 26 3.2.4 Statistical analysis 27 4. Results 29 4.1 Single-cell RNA sequencing (scRNA-seq) analysis of intrahepatic ASGM1+ CD8 T cells 29 4.2 Intrahepatic ASGM1+ CD8 T cells exhibit phenotypic characteristics of liver TRM cells 30 4.3 The ASGM1+ CD8 T cell subset with TRM phenotypic characteristics becomes rapidly activated and produces IFN-γ one hour after ConA treatment 32 5. Figures 33 6. Discussion 47 7. References 52 | - |
| dc.language.iso | en | - |
| dc.subject | 肝臟駐留型記憶 T 細胞 | zh_TW |
| dc.subject | 高維度免疫特徵分析 | zh_TW |
| dc.subject | 干擾素γ | zh_TW |
| dc.subject | ConA 誘導急性肝炎模型 | zh_TW |
| dc.subject | 無唾液酸神經節苷脂 | zh_TW |
| dc.subject | Asialo-GM1 | en |
| dc.subject | ConA-induced hepatitis model | en |
| dc.subject | Interferon-γ | en |
| dc.subject | Liver-resident CD8 T cell | en |
| dc.subject | High-dimensional profiling | en |
| dc.title | 透過高維度分析揭示肝臟內不同ASGM1+ CD8 T細胞群的表型特徵 | zh_TW |
| dc.title | Phenotypic characteristics of distinct intrahepatic ASGM1+ CD8 T cell populations revealed by high-dimensional profiling | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 廖秀蓉;王維樂;楊宏志;柯俊榮 | zh_TW |
| dc.contributor.oralexamcommittee | Hsiu-Jung Liao;Wei-Le Wang;Hung-Chih Yang;Chun-Jung Ko | en |
| dc.subject.keyword | 高維度免疫特徵分析,肝臟駐留型記憶 T 細胞,無唾液酸神經節苷脂,ConA 誘導急性肝炎模型,干擾素γ, | zh_TW |
| dc.subject.keyword | High-dimensional profiling,Liver-resident CD8 T cell,Asialo-GM1,ConA-induced hepatitis model,Interferon-γ, | en |
| dc.relation.page | 59 | - |
| dc.identifier.doi | 10.6342/NTU202502859 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-07-31 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 免疫學研究所 | - |
| dc.date.embargo-lift | 2030-07-29 | - |
| 顯示於系所單位： | 免疫學研究所 | |
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