本文選題：樹突狀細(xì)胞　切入點(diǎn)：HVEM　出處：《蘇州大學(xué)》2009年碩士論文　論文類型：學(xué)位論文

【摘要】： 啟動T細(xì)胞免疫應(yīng)答需要雙信號的參與:T細(xì)胞抗原受體TCR和抗原遞呈細(xì)胞(antigen presenting cell, APC)上MHC/抗原肽復(fù)合物結(jié)合產(chǎn)生的第一信號;T細(xì)胞與APC表面的共刺激分子相互作用產(chǎn)生的第二信號。樹突狀細(xì)胞(DC)是已知體內(nèi)最強(qiáng)的APC,在腫瘤免疫、抗感染免疫、自身免疫和移植免疫中發(fā)揮著巨大作用。 共刺激分子主要分為兩類:腫瘤壞死因子受體超家族(TNFRSF)和免疫球蛋白超家族(IgSF)。HVEM(herpes virus-entry mediator)是TNFRSF成員,BTLA屬于IgSF。過去一直認(rèn)為,所有的IgSF成員只與B7分子家族成員相互作用;而TNFRSF成員只與TNF家族成員相互作用。而BTLA與HVEM的結(jié)合改變了傳統(tǒng)的看法。這兩個分子的結(jié)合將兩大家族直接聯(lián)系了起來,也是目前唯一的一對。 近年來的研究表明,HVEM既可作為受體與LIGHT作用傳遞正性協(xié)同刺激信號,又能作為配體作用于BTLA介導(dǎo)負(fù)性協(xié)同抑制信號。HVEM可與BTLA結(jié)合并誘導(dǎo)其酪氨酸磷酸化,發(fā)揮抑制功能,降低T細(xì)胞的增殖能力,BTLA缺陷的T細(xì)胞增殖能力增強(qiáng)。HVEM與BTLA結(jié)合,發(fā)揮負(fù)性調(diào)節(jié)作用,HVEM-BTLA代表了一對新的負(fù)性協(xié)同刺激分子。 本文第一部分采用小鼠骨髓來源的DC(BMDC),就影響HVEM分子在DC表達(dá)的因素作些探討研究。將促DC成熟活化因子LPS、TNF-α、4-1BB分子激發(fā)型抗體(2A)、CD40激發(fā)型抗體(1c10)和免疫負(fù)性調(diào)節(jié)因子IL-10加入到各組BMDC中,觀察BMDC上HVEM表達(dá)的變化。結(jié)果顯示,加入促成熟活化因子的各組BMDC上HVEM表達(dá)與對照組相比有顯著下調(diào)(P0.05),而加入免疫負(fù)性調(diào)節(jié)因子的BMDC上HVEM表達(dá)與對照組相比有顯著上調(diào)(P0.05),提示LPS、TNF-α、2A抗體、1c10抗體可能通過下調(diào)DC上HVEM分子的表達(dá),從而在與T細(xì)胞相互作用時降低T細(xì)胞活化的閾值。反之,IL-10抑制DC免疫功能的另一個可能機(jī)制,即上調(diào)DC上HVEM分子的表達(dá),抬高T細(xì)胞活化的閾值,減弱T細(xì)胞的免疫應(yīng)答。 本文第二部分研究C57BL/6 BMDC上HVEM被抗HVEM抗體封閉后,作用于BALB/c小鼠脾臟T細(xì)胞,對T細(xì)胞活化尤其是早期活化的影響,以及白細(xì)胞介素2(IL-2)的分泌情況。檢測表明,無論是混合培養(yǎng)的早期(0-48h)還是晚期(48-96h),加抗HVEM抗體封閉的實(shí)驗(yàn)組的T細(xì)胞增殖效應(yīng)明顯強(qiáng)于對照組。同時IL-2的分泌也高于對照組。說明了HVEM-BTLA傳遞的信號對T細(xì)胞的活化起抑制作用。特別是,在T細(xì)胞與DC混合培養(yǎng)早期(0-48h),BTLA即有抑制T細(xì)胞活化的作用,這與傳統(tǒng)認(rèn)為T細(xì)胞活化后誘導(dǎo)表達(dá)負(fù)性分子的負(fù)反饋調(diào)節(jié)理論是相矛盾的,提示免疫細(xì)胞可能存在多種負(fù)性調(diào)節(jié)方式。 綜上所述,本研究表明促成熟活化因子LPS、TNF-α、2A抗體、1c10抗體能下調(diào)DC上HVEM分子的表達(dá),免疫負(fù)性調(diào)節(jié)因子IL-10能上調(diào)DC上HVEM分子的表達(dá)。經(jīng)抗HVEM抗體封閉后的DC刺激T細(xì)胞活化的效應(yīng)增強(qiáng),與T細(xì)胞反應(yīng)早期(0-48h)和晚期(48-96h)都存在這個現(xiàn)象,尤其在T細(xì)胞與DC混合培養(yǎng)早期(0-48h)。BTLA的抑制T細(xì)胞活化作用提示免疫細(xì)胞除了負(fù)反饋調(diào)節(jié)機(jī)制外,可能還存在其它負(fù)性調(diào)節(jié)方式。
[Abstract]:Start the T cell immune response involves two signals: T cell antigen receptor TCR and antigen presenting cells (antigen presenting cell, APC) MHC/ antigen peptide complex with the first signal generated by T and APC; cell surface costimulatory molecules produced by the interaction of the second signal. Dendritic cells (DC) are known the most powerful APC in tumor immunity, infection and immunity, play a huge role in autoimmune and transplantation.
Costimulatory molecules are divided into two categories: tumor necrosis factor receptor superfamily (TNFRSF) and immunoglobulin superfamily (IgSF).HVEM (herpes virus-entry mediator) is a member of TNFRSF, BTLA and IgSF. belong to the past has been that all members of IgSF and only members of the B7 family of molecules interaction; while TNFRSF and TNF family members only members interact with each other. And the combination of BTLA and HVEM changed the traditional view. The combination of these two molecules will directly link up the two families, is currently the only one.
Recent studies show that HVEM can be used as receptor and LIGHT functions to transfer positive costimulatory signal, and can be used as ligands acting on BTLA mediated negative synergistic inhibitory signal.HVEM can combine with BTLA and its induced tyrosine phosphorylation, play inhibitory function, reduce the proliferation of T cells, T cell proliferation ability of BTLA defects the enhanced.HVEM and BTLA combination, play a negative regulatory role, HVEM-BTLA represents a new pair of negative costimulatory molecules.
The first part of this paper using mouse bone marrow-derived DC (BMDC), factors affecting the expression of HVEM molecules in DC are discussed in this paper. The research will promote DC maturation and activation of factor LPS, TNF- alpha, stimulate antibody 4-1BB molecule (2A), CD40 antibody (1c10) and stimulate the immune negative regulation factor IL-10 into groups in BMDC, expression of HVEM was observed on BMDC. The results showed that adding maturation promoting activating factor BMDC on the expression of HVEM in each group compared with the control group were significantly reduced (P0.05), and adding negative immuno regulatory factor BMDC on the expression of HVEM compared with the control group were significantly increased (P0.05), LPS, TNF- alpha, 2A antibody, 1c10 antibody by down-regulation of HVEM expression on DC, thereby reducing the threshold for activation of T cells in interactions with T cells. On the contrary, another possible mechanism of IL-10 inhibiting DC immune function, namely the upregulation of DC expression of HVEM molecules, elevation of T cell activation The threshold, which weakens the immune response of T cells.
The second part of this paper studies C57BL/6 BMDC HVEM by anti HVEM antibody is closed, in the role of BALB/c in mouse spleen T cells, activation of T cells especially the early activation effect, and interleukin 2 (IL-2) secretion. Test showed that both the early mixed culture (0-48h) or late (48-96h) T cell proliferation, anti HVEM antibody closed in the experimental group was significantly stronger than the control group. At the same time, the secretion of IL-2 is higher than that of the control group. The signal transmission of HVEM-BTLA activation of T cells inhibited. In particular, raising early in T cells and DC mixed culture (0-48h), BTLA inhibition the activation of T cells, the expression of negative thought and traditional molecular induced T cell activation after the negative feedback theory is contradictory, suggesting that immune cells may have many negative ways. Regulation
In summary, this study shows that maturation promoting factor LPS activation, TNF- alpha, 2A antibody, 1c10 antibody can decrease the expression of HVEM molecule on DC, immune negative regulator of IL-10 expression of HVEM upregulated by DC. The enhancement effect of anti HVEM antibody after the closure of DC stimulated the activation of T cells, T cells and early response (0-48h) and late (48-96h) the existence of this phenomenon, especially in the early stage of culture T cells mixed with DC (0-48h) activation suggesting that immune cells in addition to negative feedback mechanism of.BTLA inhibition of T cell, there may be other negative regulation.

【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2009
【分類號】：R392

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本文編號：1625106