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標題: | CD8 T 細胞在宿主防禦組織胞漿菌感染的功能 Functions of CD8 T Cells in Protective Immune Response to Histoplasmosis |
作者: | Jr-Shiuan Lin 林志萱 |
指導教授: | 伍安怡(Betty A. Wu-Hsieh) |
關鍵字: | 組織胞漿菌,干擾素γ產生細胞,特異性 T 細胞反應,T 細胞受體 Vβ 使用,CD8 T 細胞,巨噬細胞,樹突狀細胞,細胞凋亡,交叉抗原呈獻, Histoplasma,IFNγ-producing cell,specific T cell response,TCR Vβ repertoire,CD8 T cell,macrophage,dendritic cell,apoptosis,cross-presentation, |
出版年 : | 2005 |
學位: | 博士 |
摘要: | CD4 T 細胞在對抗巨噬細胞內之非病毒性病原菌扮演重要角色。在人類免疫不全病毒感染中,CD4 T 細胞會逐漸喪失。受感染個體發展成後天免疫缺乏症候群並死於伺機性感染。故了解 CD8 T 細胞在 CD4 T 細胞缺少時之功能是重要的研究課題。
首先,我計算在組織胞漿菌感染後脾臟中對於宿主抵禦感染非常重要之特異性 T 細胞數目,並發現此種巨噬細胞胞內病源菌之感染可以活化 CD4 及CD8 T 細胞。CD8 T 細胞反應強度雖較CD4 T 細胞的反應強度弱,二種細胞反應之擴張與收縮的動力學則是相同的模式。產生干擾素γ與高量 CD44 表現之間的高度相關性不只在反應高峰期可觀察到,在整個感染過程均是如此。此外,廣大系列 Vβ族群均會對全身性以及肺部感染產生反應,代表在抵抗組織胞漿菌之初次免疫反應中並無使用特定T 細胞受體傾向。有趣的是,在高劑量感染或二次感染後功能性 T 細胞擁有較初次感染窄小範圍之T 細胞受體 Vβ 使用。 CD8 T 細胞對於宿主抵抗組織胞漿菌感染的貢獻,在 CD4 T 細胞完整之小鼠是較其次的,因若去除CD8 T 細胞只會延遲但並不影響病菌的清除。然而,CD8 T 細胞在缺乏功能性CD4 T 細胞之宿主是否具有保護能力仍然需要更進一步的探討。在我的研究中發現,MHC class II 基因缺陷小鼠在感染組織胞漿菌後能將病菌數量維持如同第一週之數目長達十六週,顯示CD8 T 細胞能夠限制病菌之複製,但無法清除。研究結果顯示,由組織胞漿菌感染之野生型小鼠體內取出之CD8 T 細胞胞內會表現干擾素γ。此外,CD8 T 細胞也具有細胞毒殺的功能。然而 MHC class II 基因缺陷小鼠的 CD8 T 細胞的功能卻有限制,以致於無法完全清除全身性及肺部感染。 在我的研究中亦發現,巨噬細胞除了擔任組織胞漿菌之宿主細胞及功能細胞外,吞噬組織胞漿菌而凋亡之巨噬細胞亦可作為樹突狀細胞的抗原提供者。呈獻外源性組織胞漿菌抗原之樹突狀細胞可透過直接吞噬酵母菌,或透過取得凋亡巨噬細胞內之真菌抗原,即所謂”交叉抗原呈獻” 可刺激組織胞漿菌特異性 CD8 T 細胞產生反應。根據這些研究,我們提出一個詳述在組織胞漿菌感染宿主中,細胞性免疫反應與真菌清除之前因後果的模式。 It is widely accepted that cellular immune response via the activation of CD4+ T cells plays an important role in the protection against endosomal intracellular non-viral pathogens of the macrophage. In HIV infection, the major complication of the disease is the progressive loss of CD4+ T cells. The infected individuals develop AIDS and succumb to opportunistic infections. It is, therefore, important to understand how CD8+ T cells function in the absence of CD4+ T cells. First of all, I enumerated antigen-specific functional T cells, which are critical to host defense against infection, in the infection of Histoplasma capsulatum, an intracellular pathogen of the macrophages. I found that not only CD4 but also CD8 T cells were activated. The magnitude of CD8 T cell response was lower than CD4 T cell, but the expansion and contraction of both cell types followed the same kinetics. Strong correlation between IFNγ production and CD44hi expression was observed not only at the peak of response but also throughout the course of infection. Moreover, a broad spectrum of Vβ populations responded to systemic as well as pulmonary infections, suggesting no obvious T cell receptor bias in primary immune response to histoplasmosis. Interestingly, after high dose challenge or secondary infection the functional T cells had a narrower TCR Vβ repertoire than do primary effector cells. The contribution of CD8 T cells in host defense against histoplasmosis is minor in the CD4 T cell-intact mouse, as it has been shown that depleting CD8 T cells delays but does not affect fungal clearance. However, it remains to be determined whether the CD8 T cells are protective in a host lacking functional CD4 T cells. I found that MHC class II-deficient mice infected with Histoplasma kept the fungus in check for up to 16 weeks, indicating CD8 T cells are able to limit fungal replication but unable to clear the fungus. Ex vivo studies showed that CD8 T cells from Histoplasma-infected wild type mice exhibit cytotoxic activity as well as IFNγ production. However, the CD8 T cells in IIKO mice had functional limitation to clear systemic as well as pulmonary histoplasmosis. It is also demonstrated in this study that the macrophage, being the primary host cell as well as the effector cell of Histoplasma, can also serve as antigen donor to dendritic cells. Histoplasma-specific CD8 T cells are stimulated by dendritic cells that present exogenous Histoplasma antigens, either through direct ingestion of yeasts or through uptake of apoptotic macrophage-associated fungal antigens, a process known as ‘cross-presentation’. Based on these results, I present a model detailing the possible sequence of events leading to a cell-mediated immune response and fungal clearance in Histoplasma-infected hosts. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/35301 |
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