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首页> 外文期刊>Journal of Molecular Biology >Plasticity in the contribution of T cell receptor variable region residues to binding of peptide-HLA-A2 complexes
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Plasticity in the contribution of T cell receptor variable region residues to binding of peptide-HLA-A2 complexes

机译：T细胞受体可变区残基对肽-HLA-A2复合物结合的贡献的可塑性

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One hypothesis accounting for major histocompatibility complex (MHC) restriction by T cell receptors (TCRs) holds that there are several evolutionary conserved residues in TCR variable regions that contact MHC. While this "germline codon" hypothesis is supported by various lines of evidence, it has been difficult to test. The difficulty stems in part from the fact that TCRs exhibit low affinities for pep/MHC, thus limiting the range of binding energies that can be assigned to these key interactions using mutational analyses. To measure the magnitude of binding energies involved, here we used high-affinity TCRs engineered by mutagenesis of CDR3. The TCRs included a high-affinity, MART-1/HLA-A2-specific single-chain TCR and two other high-affinity TCRs that all contain the same Vα region and recognize the same MHC allele (HLA-A2), with different peptides and Vβ regions. Mutational analysis of residues in CDR1 and CDR2 of the three Vα2 regions showed the importance of the key germline codon residue Y51. However, two other proposed key residues showed significant differences among the TCRs in their relative contributions to binding. With the use of single-position, yeast-display libraries in two of the key residues, MART-1/HLA-A2 selections also revealed strong preferences for wild-type germline codon residues, but several alternative residues could also accommodate binding and, hence, MHC restriction. Thus, although a single residue (Y51) could account for a proportion of the energy associated with positive selection (i.e., MHC restriction), there is significant plasticity in requirements for particular side chains in CDR1 and CDR2 and in their relative binding contributions among different TCRs.
机译：一种假设解释了T细胞受体（TCR）对主要组织相容性复合物（MHC）的限制，认为在接触MHC的TCR可变区中存在几个进化保守的残基。尽管“种系密码子”假说得到各种证据的支持，但很难进行检验。困难部分源于这样的事实，即TCR对pep / MHC的亲和力很低，因此限制了使用突变分析可以分配给这些关键相互作用的结合能的范围。为了测量涉及的结合能的大小，在这里我们使用了通过诱变CDR3设计的高亲和力TCR。 TCR包括一个高亲和力的MART-1 / HLA-A2特异性单链TCR和两个其他高亲和力TCR，它们都包含相同的Vα区域并识别相同的MHC等位基因（HLA-A2），并具有不同的肽和Vβ区。对三个Vα2区CDR1和CDR2中残基的突变分析表明，关键种系密码子残基Y51的重要性。但是，另外两个提议的关键残基在TCR之间对结合的相对贡献方面显示出显着差异。通过在两个关键残基中使用单位置酵母展示文库，MART-1 / HLA-A2选择也显示出对野生型种系密码子残基的强烈偏好，但是一些替代残基也可以适应结合，因此，MHC限制。因此，尽管单个残基（Y51）可以占与阳性选择相关的能量的一部分（即，MHC限制），但对CDR1和CDR2中特定侧链的要求以及它们在不同位置之间的相对结合贡献具有明显的可塑性TCR。

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