CTL recognition of a bulged viral peptide involves biased TCR selection
CTL recognition of a bulged viral peptide involves biased TCR selection
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DOI：
10.4049/jimmunol.175.6.3826
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发表时间：
2005-09-15
影响因子：
4.4
通讯作者：
McCluskey, J
中科院分区：
文献类型：
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作者：
Miles, JJ;Elhassen, D;McCluskey, J
MHC I类分子通常呈现8-10 aa长的肽，在HLA间隙中形成延伸的卷曲。虽然较长的肽也可以结合I类分子，但它们倾向于从裂缝中凸出，并且不知道TCR库是否具有足够的可塑性以在抗病毒CTL应答期间识别这些决定簇。在这项研究中，我们发现，感染EBV的无关个体产生一个显着的CTL反应，针对HLA-B*3501限制性，11聚体表位从BZLF 1抗原。11-mer决定簇采用高度凸出的构象，其中7个肽侧链暴露于溶剂中并可用于TCR相互作用。这样的复合物潜在地对HLA-B*3501和肽Ag两者的TCR共识别产生结构挑战。令人惊讶的是，识别11聚体的不相关的B*3501供体使用相同或密切相关的α β TCR序列，其共享特定的CDR 3基序。在观察到的少数优势CTL克隆型中，每个克隆型对肽的暴露侧链残基具有离散的精细特异性。数据显示，膨胀的病毒肽确实是免疫原性的，但表明高度限制的TCR库反映了对一些不寻常的MHC肽配体响应时TCR多样性的限制。
MHC class I molecules generally present peptides of 8-10 aa long, forming an extended coil in the HLA cleft. Although longer peptides can also bind to class I molecules, they tend to bulge from the cleft and it is not known whether the TCR repertoire has sufficient plasticity to recognize these determinants during the antiviral CTL response. In this study, we show that unrelated individuals infected with EBV generate a significant CTL response directed toward an HLA-B*3501-restricted, 11-mer epitope from the BZLF1 Ag. The 11-mer determinant adopts a highly bulged conformation with seven of the peptide side chains being solvent-exposed and available for TCR interaction. Such a complex potentially creates a structural challenge for TCR corecognition of both HLA-B*3501 and the peptide Ag. Surprisingly, unrelated B*3501 donors recognizing the 11-mer use identical or closely related alpha beta TCR sequences that share particular CDR3 motifs. Within the small number of dominant CTL clonotypes observed, each has discrete fine specificity for the exposed-side chain residues of the peptide. The data show that bulged viral peptides are indeed immunogenic but suggest that the highly constrained TCR repertoire reflects a limit to TCR diversity when responding to some unusual MHC peptide ligands.