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Analysis of peptide binding patterns in different major histocompatibility complex/T cell receptor complexes using pigeon cytochrome c-specific T cell hybridomas. Evidence that a single peptide binds major histocompatibility complex in different conformations

机译:使用鸽子细胞色素c特异性T细胞杂交瘤分析不同主要组织相容性复合物/ T细胞受体复合物中的肽结合模式。单个肽以不同构象结合主要组织相容性复合物的证据

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摘要

The interaction of TCR, antigen, and MHC complex has been analyzed using synthetic peptide antigens and a series of single amino acid- substituted analogues. Two similar antigens, mouse cytochrome c (mcyt c) and pigeon cytochrome c (pcyt c), elicit T cell responses in strains of mice bearing MHC class II Ek beta Ek alpha (B10.A), Eb beta Ek alpha [B10.A(5R)], and Es beta Ek alpha [B10.S(9R)]. The immunogenic regions of these antigens are located in the peptide sequence p88-104 for pcyt c and m88-103 for mcyt c. The limited T cell repertoire for these antigens is comprised of four groups of T cell phenotypes that have very few differences in their TCR gene make up. In this paper, we examine the diversity in their fine specificity for each of the antigens, m88-103 and p88-104, complexed with each of the I-Ek haplotypes. Epitopes, i.e., residues that interact with the TCR, and agretopes, i.e., residues in the MHC-binding site, were assigned for the two peptide antigens in the presence of APC bearing E beta kEk alpha, Eb beta Ek alpha, or Eb beta Ek alpha using T cell hybridomas of the phenotypes I, IIIa, and IV. From our results, we conclude that first, the substitution of any residue between 95 and 104 of the cytochrome c peptide changed the antigenic potency of the peptide for at least one of the hybridomas. Second, each T cell type has a different recognition pattern of epitopes and agretopes for a particular antigen-MHC complex, thus, ruling out a static model of T cell recognition, which assigns certain, invariant agretopic residues to the peptide by which it interacts with the MHC molecule independently of the TCR. Third, the same T cell hybridoma responded to the antigens differently when presented on various MHC molecules, implying that overall changes in the MHC groove, as displayed by the three haplotypes, may affect the efficiency in binding the peptide. Fourth, since most of the residues are used as epitopes by at least one of the T cell specificities, the peptide appears to be recognized in a different conformation by each T cell hybridoma phenotype; and, finally, the epitopic and agretopic residues do not segregate, for any one of the T cell specificities, in such a way that suggests they are recognized in a helical conformation. In summary, our results suggest that a single peptide may generate diversity in the T cell response by virtue of its conformational flexibility within the TCR-MHC-antigen complex.
机译:已使用合成肽抗原和一系列单个氨基酸取代的类似物分析了TCR,抗原和MHC复合物的相互作用。两种相似的抗原,小鼠细胞色素c(mcyt c)和鸽子细胞色素c(pcyt c),在带有MHC II类Ek beta Ek alpha(B10.A),Eb beta Ek alpha [B10.A]的小鼠品系中引发T细胞反应。 (5R)]和Es beta Ek alpha [B10.S(9R)]。这些抗原的免疫原性区域位于pcyt c的肽序列p88-104和mcyt c的m88-103中。这些抗原的有限T细胞库由四组T细胞表型组成,它们的TCR基因组成几乎没有差异。在本文中,我们检查了与每种I-Ek单倍体复合的每种抗原m88-103和p88-104的精细特异性多样性。在带有E beta kEk alpha,Eb beta Ek alpha或Eb beta的APC存在下,将抗原决定簇(即与TCR相互作用的残基)和抗原决定簇(即MHC结合位点中的残基)分配给了两种肽抗原使用I型,IIIa型和IV型T细胞杂交瘤进行Ek alpha处理。根据我们的结果,我们得出结论,首先,细胞色素c肽的95至104之间的任何残基取代都会改变该肽对至少一种杂交瘤的抗原效力。其次,每种T细胞类型对特定抗原-MHC复合物的抗原决定簇和抗原决定簇具有不同的识别模式,因此,排除了T细胞识别的静态模型,该模型为与之相互作用的肽分配了某些不变的蛋白结合残基。 MHC分子独立于TCR。第三,同一T细胞杂交瘤在呈递给各种MHC分子时对抗原的反应不同,这意味着如三个单体型所显示的,MHC沟的整体变化可能会影响结合肽的效率。第四,由于大多数残基被至少一种T细胞特异性用作表位,因此该肽似乎被每种T细胞杂交瘤表型以不同的构象识别。最后,对于任何一种T细胞特异性,抗原决定簇和总抗原残基都不分离,表明它们以螺旋构象被识别。总而言之,我们的结果表明,单个肽可能由于其在TCR-MHC-抗原复合物中的构象灵活性而在T细胞反应中产生多样性。

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