發(fā)布時間：2018-06-17 01:03

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

【摘要】： T細胞是最重要的免疫細胞,它的主要功能是介導細胞免疫和調(diào)節(jié)機體的免疫功能。細胞毒性T細胞能夠直接對腫瘤細胞進行特異性殺傷。要使T細胞發(fā)揮它的免疫功能,需要激活T細胞的免疫應答,使T細胞活化、增殖、分化�？墒荰細胞不能直接識別天然抗原,它只能識別與主要組織相容性復合體MHC分子結(jié)合、并被主要組織相容性復合體MHC分子提呈的抗原肽。本文主要研究的是能夠激活細胞毒性T細胞的、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合體MHCⅠ類分子結(jié)合的抗原肽。內(nèi)源性抗原肽產(chǎn)生過程為:在抗原提呈細胞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)過抗原相關轉(zhuǎn)運蛋白TAP轉(zhuǎn)運至內(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分子復合物;復合物經(jīng)過高爾基體被轉(zhuǎn)移至抗原提呈細胞表面,并與T細胞表面的T細胞抗原受體TCR結(jié)合,成為TCR-抗原肽-MHC分子三元體,激活T淋巴細胞免疫應答的全過程。 由內(nèi)源性抗原肽產(chǎn)生過程可知,抗原肽-MHCⅠ類分子復合體對T細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)合的抗原肽相應位置的側(cè)鏈會進入到這6個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,在免疫學實驗上用IC_(50)值(InhibitConcentration to achieve 50%bioeffectivity)來表示這種結(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,抗原肽是激活T細胞免疫應答的關鍵,這些能夠激活T細胞免疫應答的抗原肽又稱為T細胞表位。因此T細胞表位的鑒定在免疫學中有十分重要的意義。實驗上鑒定T細胞表位的方法是采用先合成大量的交疊肽,再通過多肽結(jié)合實驗或T殺傷效應檢測進行選取。這種實驗方法費時費力效率低,因而有必要采用理論方法預測T細胞表位。 本文基于長度為9(含有9個氨基酸)的抗原肽的模型,建立了抗原肽的二維定量構(gòu)效關系模型,并用偏最小二乘法PLS對該模型求解,得到了抗原肽與MHCⅠ類分子結(jié)合親和力預測模型。該模型的預測準確率為66.8%。通過對本模型的研究將有助于人們對MHCⅠ類分子結(jié)合抗原肽加工提呈過程的深入了解,對人們進行腫瘤疫苗設計和開發(fā)都是具有一定指導意義的。
[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：2028878