摘要
呈递病毒表位的主要组织相容性复合体Ⅰ类分子(pMHC Ⅰ)被T细胞受体(TCR)和共受体分子CD8识别,激活细胞毒性T细胞(CTL),诱导机体产生针对特定病原的细胞性免疫应答,从而清除病毒感染的细胞。与人和鼠MHCⅠ分子的研究相比,牛MHC I(称为BoLA-Ⅰ)分子的研究较少且缺乏精细结构生物学方面的积累。近年来,随着牛传染病的不断爆发,如牛口蹄疫等疾病的爆发,不仅导致了牛养殖业的重大经济损失,而且直接威胁着人类健康。迄今为止,对牛细胞介导的抗病毒免疫应答的研究仍然十分缺少,尤其是牛BoLA-Ⅰ递呈病毒抗原多肽的机制以及CD8作为辅助受体在其CTL免疫应答中与MHC Ⅰ分子的相互作用机理尚不清楚。由此可见,深入研究牛BoLA-Ⅰ和CD8分子单体和复合体的精细结构,对于阐明牛CTL免疫应答机理以及控制牛源传染病都有着重要的意义。因此,本文采用了分子克隆与结构生物学技术,表达、纯化、结晶并解析了牛BoLA-Ⅰ分子(BoLA-2*02201)与源于口蹄疫病毒(FMDV)多肽的单体、牛CD8αα二聚体以及CD8αα/BoLA-2*02201复合体结构；并对上述晶体进行了精细结构分析；获得了牛CTL免疫应答相关的第一手免疫学数据。
BoLA-2*02201总体结构框架与已解析的人和鼠MHC Ⅰ类似,但是,BoLA-Ⅰ具有明显的牛种属特征。与已解析的两套牛BoLA-Ⅰ结构相比,BoLA-2*02201分子具有突出的结构特点,其具有更大的“开放”型A口袋,带负电荷的B口袋较大较深以及体积最大的F口袋。这些结果使得BoLA-2*02201可递呈多肽的特征为：1)P1位锚定残基可以是较大构象的氨基酸；2)P2可以是具有长侧链、带正电荷的氨基酸；3)P9位可以是具有较大芳香苯环的氨基酸。根据上述BoLA-2*02201抗原结合槽的结构特征本文推定了其表位多肽结合基序。
随后,对牛CD8αα基因进行了修饰,获得了高效表达且复性效果好的牛CD8αα同源二聚体蛋白,并结晶、解析了其结构。参照人和鼠CD8αα/pMHCⅠ复合体中CD8αα的数据分析,关键性的氨基酸：R6、N102和S103在牛CD8αα中保守,它们也可能是牛CD8αα与BoLA-Ⅰ相互作用的核心位点。
最后,分析了牛CD8αα/BoLA-2*02201复合体结构并揭示：1)牛CD8αα与BoLA-Ⅰ结合后并不改变BoLA-2*02201递呈多肽的构象；2)BoLA-2*02201与CD8αα结合后的变化是其α3CDloop发生了方向的偏移；3)CD8αα与BoLA-2*02201结合后的变化是其CDR like loop发生了偏移；4)与人和鼠CD8αα/pMHCⅠ复合体结构相比,牛CD8αα/BoLA-2*02201具有更小的接触面积和亲和力。牛CD8αα与BoLA-Ⅰ分子之间相互作用方式是“抗原-抗体”式结合方式。
综上所述,本文解析了pBoLA-Ⅰ (BoLA-2*02201)的晶体结构,阐述了BoLA-2*02201递呈多肽的特点,阐明了BoLA-2*02201递呈抗原多肽的主要机制,其结果为牛CTL表位疫苗的研发提供了结构生物学参数；解析了牛CD8αα晶体结构,阐述了其特征：解析了牛CD8αα/BoLA-Ⅰ复合体结构,结果显示,牛CD8αα与BoLA-2*02201的相互作用具有种属特征,在已发现的哺乳动物CD8αα/pMHCⅠ结构中其接触面和亲和力最小。
总之,本研究推进了牛细胞免疫学中CTL免疫应答相关的结构免疫学的研究。
The main histocompatibility complex class1molecule presents viral epitopes (pMHC1) and is recognized by T cell receptor (TCR) and the CD8co-receptor molecules, this formation of an immune synapse results in the proliferation of cytotoxic lymphocyte (CTL), induction cellular immune responses against specific pathogens, lyses and eventual clearance of the target cells. About the researching of MHC I molecules, compared with human and mouse, there is a few research in structural studies about bovine leukocyte antigen I (BoLA-I). These years, viral diseases and other infections have been caused by zoonosis of cattle, such as foot-and-mouth disease virus (FMDV) which brought great economic losses and post a threat to human health,. So far, there are a few studies of the bovine cellular immune response which mediated by viruses, especially the mechanism of BoLA-I presenting viral antigen peptides and CD8as the auxiliary receptor interaction with MHC I molecules in CTL immune response is not clear. Therefore, father studies of the refined crystal structures of the monomer and complex of bovine MHC I (BoLA-I) and CD8(bCD8) are essential in order to clarify the mechanism of immune response of CTL and overcome bovine-origin Zoonotic diseases. Here, with the methods of molecular cloning and structural biology, the crystal structure of BoLA (BoLA-2*02201) complexed with peptide derived from the FMDV virus was solved. Furthermore, we solved the bCD8aa homodimer structure. Finally, CD8aa/BoLA-I crystal structure was also determined. We first acquired immunological data of bovine CTL immune response.
The overall structure of bovine BoLA-I is similar with the structures of human and mouse MHC I which have been determined, but has the characteristic of particular species or genera. Compared the structure with other two BoLA-I molecules, there are some prominent structural features of BoLA-2*02201. It has a large "open" A pocket, negatively charged B pocket and deeply and the largest volume of the F pocket. The peptide which can be presented by BoLA-2*02201has such characteristics:1) the anchor residues of P1can be larger conformation amino acids;2) P2positively charged with long side chains of amino acid,3) the anchor residues of P9position should be with a larger aromatic rings. According to the results of structure analysis and peptide binding, we put forward the peptide binding motif of the BoLA-2*02201molecule.
After modification the gene of CD8aa, it can be expressed and folded as bovine CD8aa homodimer, and its structural was crystallized and determined. According to the residues of CD8aa which interact with MHC I in human and mouse CD8aa/pMHC I complexes, the three R6, N102and S103amino acids are relatively conservative in bovine CD8aa molecule, these may be the residues which mediated the interaction between bovine CD8αα and MHC I molecules.
Finally, the results of bovine CD8aa/BoLA-2*02201complex are as follows:1) Bovine CD8aa of CD8aa/BoLA-2*02201complex cannot change the conformation of the peptide;2) After contacted with bovine CD8αα, the main change of BoLA-2*02201is offset direction of α3CD loop;3) The change of bovine CD8αα is mainly about the offset direction of CDR like loops.4) Compared with human and mouse CD8aa/MHC I complexes, the bovine CD8aa/BoLA-2*02201complex has least contaction area and minimal interactions. Determinately, the interaction between bovine CD8αα and BoLA-I is in antigen-antibody contact manner.
In brief, we solved the crystal structure of BoLA-I (BoLA-2*02201) and illustrate the structure basis of BoLA-I presenting peptides, and further screened and identified some potential CTL epitopes of FMDV-VP1. In addition, the crystal structure of bCD8aa was also determined, and carified the structure characteristics of bCD8aa. Analysis of the crystal structure of bovine CD8aa/BoLA-2*02201complex, we found the species characteristics between bovine CD8aa and BoLA-2*02201interaction, and it has least contaction area and minimal interactions.
In conclusion, these results might promote the development of the structural immunology of CTL immune response in bovine cellular immunology.
引文
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