本文關鍵詞：人脾臟基質(zhì)細胞誘導新型調(diào)節(jié)性樹突狀細胞亞群的產(chǎn)生及其相關機制研究　出處：《第二軍醫(yī)大學》2010年碩士論文　論文類型：學位論文

  更多相關文章： 人調(diào)節(jié)性樹突狀細胞 基質(zhì)細胞 人脾臟 免疫調(diào)節(jié) 免疫微環(huán)境

【摘要】： 樹突狀細胞(Dendritic cell, DC)被認為是目前已知的功能最強大的專職抗原提呈細胞(antigen presenting cells, APC),能夠感知、整合一系列的外來病原體信號并將其傳遞給淋巴細胞,啟動適度的免疫應答反應以清除入侵機體的病原體。未成熟DC在微生物感染或移植后識別、吞噬外源性抗原,可快速成熟。DC成熟后吞噬能力減弱,但細胞表面共刺激分子和粘附分子的表達上調(diào),并分泌促炎癥細胞因子,啟動初始的T細胞介導的免疫應答反應。近年來,越來越多的研究表明DC是一種異質(zhì)性的細胞群體,分布于不同的解剖部位,含有不同的細胞亞群,處于不同的成熟階段,表達不同的表型和細胞因子,其功能也是多樣性的。其中,具有負向免疫調(diào)控作用的DC亞群的發(fā)現(xiàn)及其功能特點與作用機制的研究是該領域近年來的重要進展之一,此類具有負向免疫調(diào)控作用的DC亞群被稱為調(diào)節(jié)性DC(Regulatroy DC).目前認為,調(diào)節(jié)性DC主要通過選擇性的誘導Th2型的免疫應答或促使初始CD4+和CD8+T細胞分化為分泌IL-10的調(diào)節(jié)性T細胞來負向調(diào)控免疫應答。 在前期的研究中,以小鼠為實驗對象,我們發(fā)現(xiàn)以往被認為終末分化細胞的成熟DC,與小鼠脾臟基質(zhì)細胞共培養(yǎng)后能夠進一步增殖并分化為一類能夠通過分泌NO而抑制T細胞增殖的新型調(diào)節(jié)性樹突狀細胞,我們將之命名為“分化樣樹突狀細胞”(Differentiated dendritic cell, diffDC),從而提出了成熟DC并非均為終末分化細胞的觀點,其在完成了抗原遞呈任務之后,在次級淋巴器官微環(huán)境的作用下,仍能夠進一步增殖分化,從而被賦予了新的生命與功能。在不同的生理或病理情況下,diffDC與周圍很多免疫細胞存在相互作用,彼此精密調(diào)節(jié),例如可以通過分泌IL-10活化NK細胞而促進其殺傷能力,并通過分泌IP-10選擇性地趨化Thl細胞并抑制其增殖,從而維持機體的穩(wěn)態(tài)。然而,上述觀點都是來自于針對小鼠的實驗結(jié)果,在人體內(nèi)成熟樹突狀細胞與脾臟基質(zhì)微環(huán)境又是如何作用的呢?是否會產(chǎn)生像小鼠diffDC那樣的具有負向調(diào)節(jié)功能的人樹突狀細胞亞群呢?如果真有這樣一種人DC亞群,其生物學意義及其相關的作用機制又是什么呢? 鑒于本課題本質(zhì)為兩種細胞的相互作用,我們在本研究中分為三部分內(nèi)容,分別圍繞脾臟基質(zhì)細胞系的建立、新型人調(diào)節(jié)性樹突狀細胞亞群的特點與功能以及該細胞亞群的人體內(nèi)驗證三方面進行探討。 一、人脾臟基質(zhì)細胞系HESSCs的建立與鑒定 首先,我們分離4-6月引產(chǎn)胎兒新鮮脾臟,用組織培養(yǎng)法培養(yǎng)脾臟基質(zhì)細胞。大約一個月左右,貼壁生長的基質(zhì)細胞鋪滿培養(yǎng)板,消化傳代后形成最初的脾臟基質(zhì)細胞系。此時的脾臟基質(zhì)細胞系在鏡下觀察可見由數(shù)種形態(tài)、大小不一的細胞組成,純度不佳。隨著進一步的培養(yǎng),逐步純化為主要由內(nèi)皮狀細胞組成的基質(zhì)細胞系,細胞生長速度趨于穩(wěn)定,如此經(jīng)過大約2-3月的培養(yǎng)后,形成穩(wěn)定的脾臟基質(zhì)細胞系。 接下來,我們對所建的人類脾臟基質(zhì)細胞系進行了初步鑒定,通過流式檢測分析發(fā)現(xiàn)該細胞系主要是由CD105+的內(nèi)皮細胞組成,不表達CD11c、CDllb等髓系細胞標志。mRNA分析表明該基質(zhì)細胞系以內(nèi)皮型細胞為主,檢測通過ELISA檢測發(fā)現(xiàn)該細胞系分泌較高的TGF-p,提示該細胞系可能具有一定的誘導分化能力,因此我們構(gòu)建的脾臟基質(zhì)細胞系是一群主要由內(nèi)皮細胞構(gòu)成的具有潛在誘導分化能力的基質(zhì)細胞系,我們稱其為HESSCs (Human Endothelial-like Spleen Stromal Cells) 二、HESSCs誘導產(chǎn)生的新型人調(diào)節(jié)性樹突狀細胞亞群的特點與功能 在本部分實驗中,我們著重研究了由人脾臟基質(zhì)細胞系HESSCs誘導的,從人外周血單核細胞來源的成熟樹突狀細胞分化而來的CD11bhiCTLA-4+新型人調(diào)節(jié)性樹突狀細胞亞群的特點與功能。 首先,我們從正常人外周血樣本分離得到人外周血單個核細胞(PBMC),進一步純化為CD14+單核細胞,用GM-CSF及IL-4聯(lián)合誘導其分化為典型的未成熟樹突狀細胞(imDC),再用TLR配體LPS刺激其分化為成熟樹突狀細胞(maDC)后,將該maDC與之前建立的脾臟基質(zhì)細胞系HESSC混合培養(yǎng),觀察二者之間的相互作用。實驗發(fā)現(xiàn),去除誘導性細胞因子GM-CSF及IL-4后,對照培養(yǎng)基中的maDC大部分在1-2周內(nèi)凋亡或死亡,而大部分與HESSCs混合培養(yǎng)的樹突狀細胞依舊存活,說明HESSCs支持單核細胞來源的maDC的存活。 基于上述現(xiàn)象,我們選定與HESSC共培養(yǎng)1-2周后的maDC作為研究對象,進行表型與功能方面的檢測。經(jīng)流式分析發(fā)現(xiàn)這些細胞相對于maDC主要表現(xiàn)為CD11clow、CD11bhi、HLA-DRlow、CD80low、CD83low、CD86low及CTLA-4+,同時細胞因子檢測證實該群細胞高分泌PGE2、TGF-p,然而目前尚未發(fā)現(xiàn)該群細胞能夠分泌較高的IL-10、NO等負向調(diào)節(jié)因子。令人感興趣的是,該群細胞表達抑制性受體CTLA-4,加之其又能分泌高水平的PGE2、TGF-p等負向調(diào)節(jié)細胞因子,提示該群新型樹突狀細胞亞群可能發(fā)揮著一定的免疫抑制功能。通過對maDC及該新型樹突狀細胞亞群的mRNA進行分析對比,驗證了該群新型樹突狀細胞亞群TGF-β、CTLA-4的mRNA表達水平都明顯高于maDC,同時尚未發(fā)現(xiàn)該樹突狀細胞亞群的IL-10、PD-1、PDL-1、PDL-2等重要分子的mRNA水平有明顯增高。 樹突狀細胞作為最主要的抗原提呈細胞,在炎癥的發(fā)生發(fā)展過程中發(fā)揮著重要的調(diào)控作用,那么我們這群新型的樹突狀細胞亞群在炎癥狀態(tài)下又有怎樣的反應呢?實驗證明,該新型樹突狀細胞亞群與maDC相比在TLR4配體LPS刺激后,能夠分泌高水平的炎性細胞因子,包括IL-10、TNF-α、PGE2、TGF-β等。這一結(jié)果提示我們該新型樹突狀細胞亞群可能在炎癥狀態(tài)下發(fā)揮著更大的免疫調(diào)節(jié)作用。 由HESSCs誘導的這群新型調(diào)節(jié)性樹突狀細胞表達CTLA-4,而CTLA-4作為重要的負向調(diào)節(jié)分子,在抑制T細胞免疫應答過程中發(fā)揮重要作用,因此我們推測該新型樹突狀細胞亞群可能具有免疫抑制的功能。通過體外混合淋巴反應實驗,我們發(fā)現(xiàn)該新型DC亞群確實能夠顯著抑制maDC刺激后異體CD4+T細胞的增殖,具體的機制還有待于進一步研究。 眾所周知,DC在未成熟狀態(tài)下具有極強的吞噬能力,當其遇到刺激或吞噬抗原分化成熟后吞噬能力就基本喪失。而由成熟DC分化而來的該新型DC亞群的吞噬能力卻又大大增強,這一現(xiàn)象為我們對其功能的深入研究探討提供了極大的想象空間。 總之通過上述實驗,發(fā)現(xiàn)脾臟基質(zhì)細胞系HESSCs可以誘導外周血單核細胞來源的maDC分化為一種高分泌PGE2、TGF-β等調(diào)節(jié)性因子的具有獨特表型CD1 1bhiCTLA-4+的新型人調(diào)節(jié)性樹突狀細胞亞群。我們初步將其命名為CD11bhiCTLA-4+DCreg。 三、人體內(nèi)新型調(diào)節(jié)性樹突狀細胞亞群的鑒定 在本部分研究工作中,我們著重在人體脾臟內(nèi)尋找并初步驗證了這類新型調(diào)節(jié)性樹突狀細胞的存在。 為了驗證該新型DC亞群是否真的存在于體內(nèi),我們在人脾臟中尋找該DC亞群。我們首先用該新型DC亞群的特異性表面標志(CD11c+CD11bhiCTLA-4+)將表型相同的細胞分選出來,再通過檢測它的細胞因子分泌情況及其抑制功能來判斷人體內(nèi)是否存在這樣一群還未被人們發(fā)現(xiàn)的DC亞群。 我們用流式分選儀將人體脾臟內(nèi)CD11c+細胞分選為CD11chiHLA-DRhiCD11blow、CD11chiHLA-DRhiCD11bhi和CD11cintHLA-DRlowCD11bhi三個細胞亞群來研究,經(jīng)過對細胞表型、混合淋巴反應、細胞因子分泌及吞噬能力多個方面進行檢測對比,證實人體脾臟內(nèi)存在一群CD11chiHLA-DRhiCD11bhi的細胞表達CTLA-4,且分泌大量的PGE2、TGF-β、IL-10等細胞因子,具有較強的吞噬能力,在所占比例較大的情況下可以有效抑制體外maDC誘導的異體CD4+T淋巴細胞的增殖。因此我們初步判斷人脾臟內(nèi)CD11chiHLA-DRhiCD11bhi細胞與體外脾臟基質(zhì)細胞系HESSCs誘導分化的CD11bhiCTLA-4+DCreg具有相似的特點與功能。 綜上所述,我們通過實驗發(fā)現(xiàn),人脾臟基質(zhì)細胞系HESSCs可以誘導人外周血單核細胞來源的成熟DC分化為一群具有負向免疫調(diào)節(jié)作用的新型人樹突狀細胞亞群。該細胞亞群具有獨特的細胞表型CD11bhiCTLA-4+,高分泌PGE2、TGF-β等負向調(diào)節(jié)性因子,能夠有效抑制CD4+T淋巴細胞的增殖,并初步驗證了其在人體(脾臟)內(nèi)的存在。這些實驗結(jié)果豐富了對免疫微環(huán)境負向調(diào)控免疫應答多細胞網(wǎng)絡的認識,為今后進一步研究樹突狀細胞參與免疫負向調(diào)控的機制提供了新的方向和一定的實驗基礎,為探索腫瘤、自身耐受和自身免疫性疾病等的發(fā)生機制及免疫治療的應用提供了新的研究途徑。
[Abstract]:Dendritic cells (Dendritic cell DC) is considered to be a professional antigen known as the most powerful antigen-presenting cells (antigen, presenting, cells, APC) is able to perceive the integration of a wide array of incoming signals and delivers them to lymphocytes, start an immune response reaction free moderate to eliminate invading pathogens of immature DC. In the recognition of microbial infection or after transplantation, phagocytosis of exogenous antigen,.DC can quickly mature mature phagocytic ability is abate, but cell surface costimulatory molecules and up-regulated the expression of adhesion molecules, and proinflammatory cytokines, start the immune response of primary T cell-mediated. In recent years, more and more studies show that DC is a heterogeneous cell population distribution in different anatomic sites, containing different subpopulations of cells in different stages of maturity, and the phenotypic expression of different cytokines, its function It is also diversity. Among them, the research has a negative effect to the immune regulation of DC subgroup discovery and function characteristics and mechanism of action is one of the important progress in recent years in the field, this has a negative effect to the immune regulation of DC subsets called regulatory DC (Regulatroy DC). At present, regulation DC mainly through the immune response induced by Th2 selective or to the initial CD4+ and CD8+T cells to secrete IL-10 regulatory T cells to negatively regulate immune response.
In a previous study, mice as experimental subjects, we found previously considered mature DC cell terminal differentiation, coculture with mouse splenic stromal cells can further proliferate and differentiate into a class could inhibit the proliferation of T cells by secreting NO and new regulatory dendritic cells, which we named "the differentiation of dendritic cells" (Differentiated dendritic cell, diffDC), which made the DC are not mature view of terminally differentiated cells, the antigen presentation after the completion of the task, as the micro environment in secondary lymphoid organs by, still can further proliferation and differentiation, which was given new life and function in different physiological or pathological conditions, diffDC interacts with each other around a lot of immune cells, the precise regulation for IL-10 secreted by activated NK cells and promote its ability to kill, and A selective chemoattractant IP-10 secretion of Thl cells and inhibit its proliferation, thereby maintaining the homeostasis. However, these views are from the experimental results in mice, the micro environment is how the role of the dendritic cells and splenic stroma in the human body will produce mature? Like mice like diffDC with negative regulation the function of human dendritic cell subsets? If there is such a DC subgroup, and what is the biological significance and the related mechanism?
In view of this topic is the interaction of the two kinds of cells, in this study we divided into three parts, respectively set up around the splenic stromal cells, the new regulation of human authentication three aspects the features and functions of dendritic cell subsets and cell subsets in the human body.
Establishment and identification of human spleen stromal cell line HESSCs
First, we isolated 4-6 month fetus fresh spleen, splenic stromal cells cultured by tissue. About a month or so, with stromal cells adherent culture plates were digested after the formation of splenic stromal cells. The initial splenic stromal cells that can be observed in a form of composition cell sizes, purity poor. With further training, gradually purified to stromal cells mainly by endothelial cell composition, cell growth rate tends to be stable, so after about 2-3 months of training, the formation of splenic stromal cell line stably.
Next, we conducted a preliminary identification of the human splenic stromal cells by flow cytometry analysis showed that the cell line is mainly composed of CD105+ endothelial cells, the expression of CD11c, CDllb and other myeloid cell marker.MRNA analysis showed that the cells within the skin type stromal cell line, detect detection by ELISA secretion the higher the TGF-p cell lines, suggesting that the cells may have certain differentiation ability, so we construct the splenic stromal cells is mainly composed of a group of endothelial cells composed of stromal cells with potential differentiation ability, which we call HESSCs (Human Endothelial-like Spleen Stromal Cells)
Two, the characteristics and functions of a new human regulated dendritic cell subgroup induced by HESSCs
In this part of the experiment, we focused on the characteristics and functions of CD11bhiCTLA-4+ novel human regulatory dendritic cell subsets differentiated from human peripheral blood monocyte derived mature dendritic cells induced by human spleen HESSCs.
First, we isolated human peripheral blood mononuclear cells from normal human peripheral blood samples (PBMC), for further purification of mononuclear cells of CD14+, GM-CSF and IL-4 combined with differentiation into immature dendritic cells (imDC), and the typical TLR ligand LPS to stimulate the differentiation of mature dendritic cells (maDC) after splenic stromal cells, the maDC and HESSC mixed culture will be built before, to investigate the interaction between the two. It was found that the removal of induced cytokines GM-CSF and IL-4, most of the control in 1-2 weeks of apoptosis or death of maDC medium, and most mixed with HESSCs cultured dendritic cells are still alive. That HESSCs supports the survival of monocyte derived maDC.
Based on the above phenomenon, we selected were co cultured with HESSC 1-2 weeks after maDC as the research object, detect the phenotype and function. The flow cytometry analysis showed that these cells relative to maDC mainly for CD11clow, CD11bhi, HLA-DRlow, CD80low, CD83low, CD86low and CTLA-4+, and cytokine assay confirmed that the cells secrete PGE2. TGF-p, however, has not yet found the group of cells can secrete higher IL-10, NO and other negative regulatory factor. Interestingly, the expression of inhibitory receptor CTLA-4, and it can produce high levels of PGE2, TGF-p and other negative regulation of cytokines, suggesting that the new group of dendritic cell subsets may some play immunesuppression. According to the analysis and comparison of mRNA maDC and the new type of dendritic cell subsets, verify the group TGF- beta model of dendritic cell subsets, the expression of mRNA in water CTLA-4 The level of IL-10, PD-1, PDL-1, PDL-2 and other important molecules of the dendritic cell subgroup were significantly higher than that of maDC.
Dendritic cells are the most important antigen-presenting cells, play an important role in the development of inflammation, so our group of new dendritic cell subsets in the inflammatory state and how to respond? Experiments show that the model of dendritic cell subsets compared with maDC in TLR4 ligand after LPS stimulation that inflammatory cytokines can secrete high levels of IL-10, TNF- alpha, PGE2 beta, TGF-. This result suggests that the new type of dendritic cell subsets in inflammatory conditions may play immunomodulatory effects even more.
HESSCs induced by this group of new regulatory dendritic cells and the expression of CTLA-4, CTLA-4 as an important negative regulator, play an important role in the inhibition of T cells during the immune response, so we speculate that the new type of dendritic cell subsets may have immunosuppressive function. Mixed lymphocyte reaction by in vitro experiments, we found that the new DC subsets can indeed significantly inhibited maDC stimulated allogeneic CD4+T cell proliferation, the specific mechanism needs further study.
As everyone knows, DC has a strong ability of phagocytosis in the immature state, when they encounter stimulation or differentiation after phagocytosis of phagocytic antigen basically lost. The phagocytic capacity of the new DC subsets by mature DC differentiation and is greatly enhanced, provide a great imagination on this phenomenon, we discuss deeply the study of its function.
In conclusion through the above experiment, found the maDC differentiation of splenic stromal cells HESSCs induced peripheral blood mononuclear cells from a high PGE2 people have a unique phenotype of CD1 model, 1bhiCTLA-4+ TGF- beta regulatory factor regulatory dendritic cell subsets. We named it CD11bhiCTLA-4+DCreg.
Three, identification of a new regulatory dendritic cell subgroup in the human body
In this part, we focus on finding and preliminarily verifying the existence of this new type of regulatory dendritic cells in the human spleen.
In order to verify the new DC subsets really exist in the body, we are looking for the people in the spleen of DC subgroup. We first used the new DC subgroup specific surface markers (CD11c+CD11bhiCTLA-4+) will be the same phenotype of cell sorting out, through the detection of cytokine secretion and inhibit its function to judge the human body if there is such a group of people have not been found in DC subsets.
We use the flow cytometry instrument of human spleen CD11c+ cell sorting for CD11chiHLA-DRhiCD11blow, CD11chiHLA-DRhiCD11bhi and CD11cintHLA-DRlowCD11bhi three cell subsets of the cell phenotype, mixed lymphocyte reaction, cytokine secretion and phagocytosis were detected compared to many aspects, confirmed the expression of CTLA-4 CD11chiHLA-DRhiCD11bhi memory in a group of human spleen cells, and secretion a large number of PGE2, TGF- beta, IL-10 and other cytokines, has strong phagocytic ability, can effectively inhibit the in vitro induced by maDC in a larger proportion of the cases of allogeneic CD4+T lymphocytes proliferation. So we determine the initial human spleen CD11chiHLA-DRhiCD11bhi cells in vitro and splenic stromal cell line HESSCs induced differentiation of CD11bhiCTLA-4+DCreg with features and functions similar.
In summary, we found through experiments, mature DC differentiation of human splenic stromal cells HESSCs induced human peripheral blood monocyte derived as a group has a negative regulatory role of immune model of human dendritic cell subsets. The cell subsets with CD11bhiCTLA-4+ cell phenotype, unique hypersecretion PGE2, a negative regulator of TGF- P factor, can effectively inhibit the proliferation of CD4+T lymphocytes, and verified the human (spleen) in existence. These results enrich the immune microenvironment to recognize negative regulation of immune response multicellular networks, for the further study of dendritic cells in the immune negative regulation mechanism provides a new direction and some the experimental basis for exploring tumor, provides a new way to study the self tolerance and autoimmune diseases such as the application of pathogenesis and immunotherapy.

【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2010
【分類號】：R392

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