PLS方法在T细胞表位预测中的应用

发布时间：2018-03-20 06:09

本文选题：T细胞表位　切入点：抗原加工提呈途径　出处：《大连理工大学》2009年博士论文　论文类型：学位论文

【摘要】： T细胞表位能够激活T细胞的免疫应答,在特异性免疫应答中发挥重要的作用。而T细胞表位的产生依赖于抗原加工提呈过程。细胞毒性T细胞(cytotoxicy T lymphocyte,CTL)表位的产生需要经过内源性抗原蛋白被蛋白酶体裂解产生内源性抗原肽、抗原肽被与抗原提呈相关的转运蛋白(transporter associated with antigen processing,TAP)转运至内质网(endoplasmic reticulum,ER)中、抗原肽与主要组织相容性复合体(majorhistocompatibility complex,MHC)Ⅰ类分子结合形成抗原肽-MHCⅠ类分子复合物、复合物被提呈至抗原提呈细胞(antigen presenting cells,APC)表面,与T细胞表面抗原受体(T cell receptor,TCR)结合激活CTL细胞这些主要过程。而辅助性T细胞(helperT cell,Th)表位的产生需要经过外源性抗原蛋白在内体/溶酶体(endosome/lysosome)中被裂解产生外源性抗原肽、抗原肽与MHCⅡ类分子结合形成抗原肽-MHCⅡ类分子复合物、复合物被提呈至APC表面,与TCR结合激活Th细胞这些主要过程。因此,抗原的加工提呈过程对T细胞表位的产生起到决定性作用。为了深入了解抗原的加工提呈机制,本文应用定量构效关系(quantitative structure activity relationships,QSAR)方法对抗原加工提呈途径中三个重要的选择性阶段进行了理论预测研究。 1.在内源性抗原的加工提呈途径中,抗原肽-MHCⅠ类分子复合物起到激活CTL细胞免疫应答的关键作用。而MHCⅠ类分子只能与特定的抗原肽结合,那么深入研究哪些抗原肽能够与MHCⅠ类分子结合,准确预测抗原肽与MHCⅠ类分子的结合亲和力将有助于深入了解抗原肽与MHCⅠ类分子结合的生物机理,有助于揭示CTL表位的产生机制。为了研究抗原肽与MHCⅠ类分子的结合特异性,本文建立了三种MHCⅠ类配体的QSAR模型,并采用偏最小二乘法(partial least squares,PLS)方法求解。通过比较各个模型的预测性能可知,在建立MHCⅠ类配体的QSAR模型时需要考虑氨基酸残基之间的相互作用。另外,本文通过分析抗原肽中不同位置氨基酸对结合MHCⅠ类分子形成的权重系数,获得了抗原肽与MHCⅠ类分子的结合特异性。 2.在内源性抗原的加工提呈途径中,真核细胞中的泛素—蛋白酶体系统对内源性抗原蛋白发挥着重要的降解功能。本文建立了蛋白酶体裂解内源性抗原蛋白的QSAR模型来研究蛋白酶体对抗原蛋白裂解的特异性,并采用PLS方法求解模型。得到模型的预测准确度为82.8%。在相同的检验集下与同领域其他模型比较可知,本文模型的预测性能最优。本文通过分析预测模型中不同位置上氨基酸对裂解位点形成的权重系数,发现裂解位点“｜”及其近邻位置氨基酸具有明显的特异性。研究结果表明蛋白酶体对抗原蛋白的酶切处理不是随机的,而是有一定模式和选择性的。 3.在外源性抗原的加工提呈途径中,抗原肽与MHCⅡ类分子复合物起到激活Th细胞免疫应答的关键作用。MHCⅡ类分子只能与特定的抗原肽结合,为了研究抗原肽与MHCⅡ类分子的结合特异性,本文分别建立了四种基于9-mer核心结合序列的MHCⅡ类配体QSAR模型和四种基于13-mer扩展核心结合序列的MHCⅡ类配体QSAR模型,采用CV-ISC-PLS方法进行求解。通过比较各个模型预测性能可知建立模型时需要考虑核心结合序列两侧的扩展位置并应采用合适的氨基酸描述符对氨基酸进行描述。另外,本文以HLA DRB1*0101为例,通过分析抗原肽中不同位置氨基酸对结合MHCⅡ类分子形成的权重系数,获取了抗原肽与MHCⅡ类分子的结合特异性。所得结果表明抗原肽的氨基酸特异性与实验结果基本一致。
[Abstract]:T cell epitope can activate T cell immune response, play an important role in specific immune response. The production of T cell epitopes depends on the antigen processing and presentation process. Cytotoxic T cells (cytotoxicy T lymphocyte, CTL) epitopes generated by endogenous antigen protein by the proteasome cleavage to produce endogenous antigen peptide antigen peptide is associated with the transporter protein and antigen (transporter associated with antigen processing, TAP) transport to the endoplasmic reticulum (endoplasmic reticulum, ER), and antigen peptide major histocompatibility complex (majorhistocompatibility complex, MHC) with class I molecules to form antigen peptide -MHC class I molecule complex. The complex is presented to antigen-presenting cells (antigen presenting cells, APC) surface with T cell surface antigen receptor (T cell receptor, TCR) combined with activated CTL cells of the main process. The helper T cells (helperT cell Th) epitopes generated by exogenous antigen protein, body / lysosome (endosome/lysosome) was cracking to produce exogenous antigen peptide, peptide binding MHC class II molecules to form antigen peptide -MHC class II molecule complexes, complexes were presented to the surface of APC the main process of activation of Th cells combined with TCR. Therefore, antigen processing and presenting a decisive role in the production of T cell epitopes. In order to understand the mechanism of antigen processing and presentation, the quantitative structure-activity relationship (quantitative structure activity relationships, QSAR) method of antigen processing and presentation of three important selective phase pathway were studied. Theoretical prediction
1. presenting pathway in the endogenous antigen processing and antigen peptide -MHC class I molecule complexes play a key role in the activation of CTL cell immune response. MHC class I molecules bind only to specific antigenic peptide, then further study which peptides could bind to MHC molecules, accurately predict peptide binding the affinity of MHC class I molecules will help to deeply understand the mechanism of biological antigen peptide and MHC class I molecules, helps to reveal the mechanism of the CTL table. In order to study binding antigen peptide and the specificity of MHC class I molecule, this paper establishes a QSAR model for three MHC class I ligands, and the use of partial least squares (partial least, squares, PLS) method. Through compare the predictive performance of each model that takes into account the interaction between amino acid residues are required in the QSAR model of MHC class I ligands. In addition, this article through the analysis The binding specificity of antigenic peptides and MHC class I molecules is obtained by the weight coefficients of different amino acids in the antigen peptide binding to the MHC class I molecules.
2. presenting pathway in the endogenous antigen processing in eukaryotic cells in the ubiquitin proteasome system of endogenous antigen proteins play important function degradation. This paper establishes a model of QSAR proteasome cleaving antigen protein to study the proteasome cleavage specificity of antigen protein solutions, and PLS method is used to solve the model. The predictive accuracy of the model is 82.8%. in the same test set with the same domain model comparison, the optimal performance prediction model in this paper. Through the analysis of forecast weight coefficient of amino acids in different positions in the model on the cleavage site formation, found that the cleavage site of "1" and its neighboring amino acid position has obvious specificity. The results show that the proteasome protein enzyme treatment is not random, but selectively.
3. presentation pathway in the exogenous antigen processing and antigen peptide and MHC class II molecules complexes play a key role in.MHC class II molecules can activate Th cell immune response with specific antigenic peptide, in order to study binding antigen peptide and MHC class II molecules specific, this paper establishes four kinds of combination the sequence of MHC class II ligand QSAR model and four kinds of extended core binding MHC class II ligand QSAR model based on the sequence of 13-mer based on 9-mer core is solved by using the CV-ISC-PLS method. Through the comparison of various models to predict the performance that models need to consider the core position with the extended sequence on both sides and should adopt appropriate amino acid descriptors to describe amino acid. In addition, this paper takes HLA DRB1*0101 as an example, through the analysis of the weight coefficient in combination with MHC class II molecules formed in different positions in the amino acid peptide, peptide and The binding specificity of MHC class II molecules shows that the amino acid specificity of the antigen peptide is basically consistent with the experimental results.

【学位授予单位】：大连理工大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392

【引证文献】