Binding of viral antigens to major histocompatibility complex class I H-2D(b) molecules is controlled by dominant negative elements at peptide non-anchor residues - Implications for peptide selection and presentation
Binding of viral antigens to major histocompatibility complex class I H-2D(b) molecules is controlled by dominant negative elements at peptide non-anchor residues - Implications for peptide selection and presentation
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DOI：
10.1074/jbc.271.30.17829
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发表时间：
1996-07-26
影响因子：
4.8
通讯作者：
Gairin, JE
中科院分区：
文献类型：
--
作者：
Hudrisier, D;Mazarguil, H;Gairin, JE
病毒抗原与主要组织相容性复合体（MHC）I类分子的结合是CD 8（+）细胞毒性T淋巴细胞活化过程中的关键步骤。在本研究中，我们使用淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染其天然宿主小鼠的模型，研究了肽-MHC相互作用中非锚定残基处的结构因子的影响。使用合成肽，显示CD 8（+）细胞毒性T淋巴细胞仅识别三个H-2D（B）限制性表位，GP氨基酸33-41/43、GP 276-286和NP 396-404。然而，LCMV NP和GP蛋白含有31个带有H-2D（B）基序的其它肽，合成了这34种LCMV肽和11种其它已知的H2-D-B-限制性肽，并检测了其MHC结合特性。尽管存在H-2D（B）结合基序，但大多数LCMV肽显示出对H-2D（B）的弱亲和力或没有亲和力，我们观察到位于非锚定位置的显性负性结构元件在肽-MHC相互作用中起着至关重要的作用，通过对强结合物和非结合物的比较序列分析，并利用分子模拟，我们描述了这些负性结构元件，并评估了它们对肽-MHC相互作用的影响，我们的发现通过显示阴性元件的已知病毒表位序列中有利的非锚定残基的单个突变导致抗原呈递特性的显著降低而得到验证，而相反地，在非结合物的序列中用一个阴性元件取代阳性元件，赋予肽现在结合MHC分子的能力。
Binding of viral antigens to major histocompatibility complex (MHC) class I molecules is a critical step in the activation process of CD8(+) cytotoxic T lymphocytes, In this study, we investigated the impact of structural factors at non-anchor residues in peptide-MHC interaction using the model of lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, Altering viral genes by making reassortants, recombinants, and using synthetic peptides, CD8(+) cytotoxic T lymphocytes were shown to recognize only three H-2D(b)-restricted epitopes, GP amino acids 33-41/43, GP 276-286, and NP 396-404, However, LCMV NP and GP proteins contain 31 other peptides bearing the H-2D(b) motif, These 34 LCMV peptides and 11 other known H2-D-b-restricted peptides were synthesized and examined for MHC binding properties, Despite the presence of the H-2D(b) binding motif, the majority of LCMV peptides showed weak or no affinity for H-2D(b), We observed that dominant negative structural elements located at non-anchor positions played a crucial role in peptide-MHC interaction, By comparative sequence analysis of strong versus non-binders and using molecular modeling, we delineated these negative elements and evaluated their impact on peptide-MHC interaction, Our findings were validated by showing that a single mutation of a favorable non-anchor residue in the sequence of known viral epitopes for a negative element resulted in dramatic reduction of antigen presentation properties, while conversely, substitution of one negative for a positive element in the sequence of a non-binder conferred to the peptide an ability to now bind to MHC molecules.