發(fā)布時(shí)間：2018-06-17 01:03

  本文選題：主要組織相容性復(fù)合體 + 抗原肽��； 參考：《大連理工大學(xué)》2008年碩士論文

【摘要】： T細(xì)胞是最重要的免疫細(xì)胞,它的主要功能是介導(dǎo)細(xì)胞免疫和調(diào)節(jié)機(jī)體的免疫功能。細(xì)胞毒性T細(xì)胞能夠直接對(duì)腫瘤細(xì)胞進(jìn)行特異性殺傷。要使T細(xì)胞發(fā)揮它的免疫功能,需要激活T細(xì)胞的免疫應(yīng)答,使T細(xì)胞活化、增殖、分化�？墒荰細(xì)胞不能直接識(shí)別天然抗原,它只能識(shí)別與主要組織相容性復(fù)合體MHC分子結(jié)合、并被主要組織相容性復(fù)合體MHC分子提呈的抗原肽。本文主要研究的是能夠激活細(xì)胞毒性T細(xì)胞的、在內(nèi)源性抗原加工提呈途徑中產(chǎn)生的、與主要組織相容性復(fù)合體MHCⅠ類分子結(jié)合的抗原肽。內(nèi)源性抗原肽產(chǎn)生過(guò)程為:在抗原提呈細(xì)胞APC內(nèi)部,內(nèi)源性抗原與泛素結(jié)合,并被泛素帶到蛋白酶體中。在蛋白酶體中,內(nèi)源性抗原被加工處理、降解為抗原肽;抗原肽經(jīng)過(guò)抗原相關(guān)轉(zhuǎn)運(yùn)蛋白TAP轉(zhuǎn)運(yùn)至內(nèi)質(zhì)網(wǎng)中;在內(nèi)質(zhì)網(wǎng)中,抗原肽與新生成的MHCⅠ類分子結(jié)合為抗原肽-MHC分子復(fù)合物;復(fù)合物經(jīng)過(guò)高爾基體被轉(zhuǎn)移至抗原提呈細(xì)胞表面,并與T細(xì)胞表面的T細(xì)胞抗原受體TCR結(jié)合,成為T(mén)CR-抗原肽-MHC分子三元體,激活T淋巴細(xì)胞免疫應(yīng)答的全過(guò)程。 由內(nèi)源性抗原肽產(chǎn)生過(guò)程可知,抗原肽-MHCⅠ類分子復(fù)合體對(duì)T細(xì)胞的激活起到直接作用。因此,研究什么樣的抗原肽與MHCⅠ類分子結(jié)合是十分重要的。MHCⅠ類分子是由α鏈(含α1、α2和α3三個(gè)結(jié)構(gòu)域)和β鏈(β2m)組成,其中α1和α2構(gòu)成Ⅰ類分子抗原結(jié)合槽。結(jié)合槽的兩端是封閉的,因此能夠與MHCⅠ類分子結(jié)合的抗原肽的長(zhǎng)度受到限制,一般為8～11。在α1和α2構(gòu)成的結(jié)合槽中,有6個(gè)由氨基酸殘基構(gòu)成的口袋(pocket A～F)。與MHCⅠ類分子結(jié)合的抗原肽相應(yīng)位置的側(cè)鏈會(huì)進(jìn)入到這6個(gè)pocket中。而MHCⅠ類分子的這種結(jié)構(gòu)就決定了什么樣的抗原肽能夠與之結(jié)合。不同的抗原肽與MHCⅠ類分子的結(jié)合力是不同的,在免疫學(xué)實(shí)驗(yàn)上用IC_(50)值(InhibitConcentration to achieve 50%bioeffectivity)來(lái)表示這種結(jié)合親和力的大小。 MHCⅠ類分子的結(jié)合槽的氨基酸序列是不變的,因此抗原肽的氨基酸序列將決定它能否與MHCⅠ類分子結(jié)合。也就是說(shuō),抗原肽是激活T細(xì)胞免疫應(yīng)答的關(guān)鍵,這些能夠激活T細(xì)胞免疫應(yīng)答的抗原肽又稱為T(mén)細(xì)胞表位。因此T細(xì)胞表位的鑒定在免疫學(xué)中有十分重要的意義。實(shí)驗(yàn)上鑒定T細(xì)胞表位的方法是采用先合成大量的交疊肽,再通過(guò)多肽結(jié)合實(shí)驗(yàn)或T殺傷效應(yīng)檢測(cè)進(jìn)行選取。這種實(shí)驗(yàn)方法費(fèi)時(shí)費(fèi)力效率低,因而有必要采用理論方法預(yù)測(cè)T細(xì)胞表位。 本文基于長(zhǎng)度為9(含有9個(gè)氨基酸)的抗原肽的模型,建立了抗原肽的二維定量構(gòu)效關(guān)系模型,并用偏最小二乘法PLS對(duì)該模型求解,得到了抗原肽與MHCⅠ類分子結(jié)合親和力預(yù)測(cè)模型。該模型的預(yù)測(cè)準(zhǔn)確率為66.8%。通過(guò)對(duì)本模型的研究將有助于人們對(duì)MHCⅠ類分子結(jié)合抗原肽加工提呈過(guò)程的深入了解,對(duì)人們進(jìn)行腫瘤疫苗設(shè)計(jì)和開(kāi)發(fā)都是具有一定指導(dǎo)意義的。
[Abstract]:T cell is the most important immune cell. Its main function is to mediate cellular immunity and regulate the immune function of organism. Cytotoxic T cells can kill tumor cells directly. In order to make T cell play its immune function, it is necessary to activate the immune response of T cell and to activate, proliferate and differentiate T cell. However, T cells can not recognize natural antigens directly. They can only recognize the antigen peptides proposed by MHC molecules, which bind to the major histocompatibility complex MHC molecules. In this paper, antigenic peptides that can activate cytotoxic T cells, which are produced in the endogenous antigen processing presentation pathway and bound to MHC class I molecules of the main histocompatibility complex, are studied in this paper. Endogenous antigenic peptides are produced by binding endogenous antigens to ubiquitin in APC cells and being carried into proteasome by ubiquitin. In the proteasome, endogenous antigens are processed and degraded into antigenic peptides; antigenic peptides are transported to the endoplasmic reticulum via the antigen-associated transporter tap; in the endoplasmic reticulum, The antigenic peptide binds to the newly formed MHC class I molecule to form an antigenic peptide -MHC complex, which is transferred to the surface of the antigen-presenting cell through Golgi body and binds to the T cell antigen receptor TCR on the T cell surface. TCR- antigenic peptide-MHC molecule ternary activates T lymphocyte immune response. From the process of endogenous antigenic peptide production, it can be seen that the antigen peptide -MHC class I molecular complex plays a direct role in the activation of T cells. Therefore, it is very important to study which antigenic peptides bind to MHC class 鈪，

本文編號(hào)：2028878