https://scholars.lib.ntu.edu.tw/handle/123456789/160649
Title: | 缺乏作用的記憶型 CD8 T 淋巴球在肝臟中增殖並形成週邊記憶型 CD8 T 淋巴球 Effector function-deficient memory CD8+ T cells clonally expand in the liver and give rise to peripheral memory CD8+ T cells |
Authors: | 蘇裕家 Su, Yu-Chia |
Keywords: | 記憶型 CD8 T 淋巴球;肝臟;memory CD8+ T cells;liver | Issue Date: | 2010 | Abstract: | 未觸碰到抗原的 CD8+ T 細胞 (naïve CD8+ T cells) 在體外 (in vitro) 同時接受 T 細胞受器 (T cell receptor) 與第四介白素 (interleukin-4) 的活化後,可以在抗原相容 (histocompatible) 小鼠體內,長期存活成為記憶型 CD8+ T 細胞 (memory CD8+ T cells)。 在含有這些記憶型 CD8+ T 細胞移植的小鼠,有一獨特亞群的記憶型 CD8+ T 細胞在肝臟中 (TLM) 被發現。 但在缺乏第十五介白素甲型受體 (interleukin-15 receptor alpha) 的小鼠肝臟中,這些 TLM 細胞明顯減少。 TLM 細胞表現 CD62LlowCCR7-相似於作用記憶型 CD8+ T 細胞 (effector memory CD8+ T cells; TEM),但丙型干擾素 (IFN-gamma) 的誘發能力、細胞毒殺功能 (cytotoxicity) 及 T 細胞受器刺激所誘發的細胞增生則明顯比 TEM 細胞低落。 利用 CFSE 試劑 (carboxyfluorescein diacetate succinimidyl ester) 檢測 TEM 細胞在體內 (in vivo) 的恆定性增生 (homeostatic proliferation),發現 TLM 細胞的增生需依賴肝臟所表現的第十五介白素甲型受體。 免疫螢光染色 (immunofluorescent staining) 的結果發現 TLM 細胞形成的細胞簇 (cell cluster) 大量散布在野生型 (wildtype) 小鼠肝臟,但在缺乏第十五介白素甲型受體的肝臟不存在。 利用同時刺激 T 細胞受體與第四介白素受體,在體外活化表現 Vbeta5+ 與 Vbeta8+ T 細胞受體的 CD8+ T 細胞後,移植等量的 Vbeta5+ 與 Vbeta8+ T 細胞受體 CD8+ T 細胞到抗原相容小鼠,在肝臟所形成的每一個 CD8+ T 細胞簇僅表現單一的 Vbeta5+ 與 Vbeta8+ T 細胞受體,由此證實肝臟中 CD8+ T 細胞簇是由單一的 TLM 細胞無性增生所形成。 當小鼠耐受李斯特菌 (Listeria monocytogenes) 感染後,其肝臟亦可觀察到由單一的 TLM 細胞無性增生所形成的細胞簇。 TLM 細胞簇局限在肝血竇 (sinusoid) 之外,與肝臟星狀細胞 (hepatic stellate cells) 相接近,且與表現第十五介白素及第十五介白素甲型受體的樹突樣構造 (dendrite-like processes) 並存。 CD62Llow TLM 細胞自肝臟中純化後再被移植到未受刺激的小鼠中,會轉移到脾臟與淋巴節中並增加 CD62L 表現如核心記憶型 CD8+ T 細胞 (central memory CD8+ cells; TCM)。 不同於以往,我們的這個發現指出肝臟對刺激記憶型 CD8+ T 細胞的生長與維持其恆定扮演重要的腳色。 一般認為肝生檢 (biopsy) 樣本中出現局部淋巴球增生即為病理現象,但我們的發現結果揭示了記憶型 CD8+ T 細胞在肝臟無性增生是正常生理現象而非病理特徵。 Upon adoptive transfer into congenic histocompatible hosts, naïve CD8+ T cells stimulated ex vivo by TCR in the presence of IL-4 persist in the hosts and become long-lived memory cells. A unique subset of memory CD8+ T cells resides in the liver (TLM) and this subset is highly reduced in the IL-15Ralpha-knockout (ko) liver. TLM cells are similar to effector memory (TEM) cells in that they are both CD62LlowCCR7-, but are unlike TEM cells in that they express reduced IFN-gamma inducibility, cytolytic activity and TCR-induced proliferation. CFSE dilution assay results indicate that TLM cells undergo IL-15Ralpha-dependent proliferation. Immunofluorescent staining revealed that the TLM cells form a large number of cell clusters in the liver of WT but not IL-15Ralpha-ko mice. TLM cells form clusters through clonal expansion because adoptive transfer of an admixture of TCR+ IL-4-activated Vbeta8+ and Vbeta5+ CD8+ T cells results in clusters composed exclusively of Vbeta5+ or Vbeta8+ cells. Clonal expansion of CD8+ T cells is also found in the liver of Listeria monocytogenes-immune mice. TLM cell clusters in the liver are located around the sinusoid, closely associate with hepatic stellate cells, and are in close association with IL-15+ and IL-15Ralpha+ dendrite-like processes. Sorted CD62Llow TLM cells can migrate to other organs after re-transfer and display increased CD62L expression and become phenotypically similar to central memory (TCM) cells. Our results bring to light a previously unappreciated role of the liver in the growth and maintenance of memory CD8+ T cells. These results also indicate that clonal growth of memory CD8+ T cells in the liver is a normal physiological process and that caution should be exercised in interpreting focal lymphoid growth in clinical liver biopsy specimens as pathology and not normal physiology. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/248024 |
Appears in Collections: | 免疫學研究所 |
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ntu-99-D89449002-1.pdf | 23.32 kB | Adobe PDF | View/Open |
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