Department of Chemistry & Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA.
Immunity. 2009 Dec 18;31(6):885-96. doi: 10.1016/j.immuni.2009.11.003.
T cell-mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The alphabeta TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were attributable to peptide and MHC molecular motion present in Tel1p-HLA-A2 but absent in Tax-HLA-A2. Differential "tuning" of the dynamic properties of HLA-A2 by the Tax and Tel1p peptides thus facilitates cross-recognition and impacts how structural diversity can be presented to and accommodated by receptors of the immune system.
T 细胞介导的免疫需要 T 细胞受体 (TCR) 的交叉反应性，但其背后的机制仍不完全清楚。alphabeta TCR A6 识别由人类 I 类 MHC 分子 HLA-A2 呈递的 Tax（LLFGYPVYV）和 Tel1p（MLWGYLQYV）肽。在这里，我们发现尽管这两个配体是理想的结构模拟物，但它们与 A6 形成了截然不同的界面，在肽、TCR 中存在构象差异，出乎意料的是，在 MHC 分子中也存在构象差异。Tax 和 Tel1p 三元复合物之间的差异无法从游离肽-MHC 结构中预测，也与传统的诱导契合机制不一致。相反，这些差异归因于 Tel1p-HLA-A2 中存在而 Tax-HLA-A2 中不存在的肽和 MHC 分子运动。Tax 和 Tel1p 肽对 HLA-A2 动态特性的差异“调谐”，从而促进了交叉识别，并影响了免疫系统受体如何呈现和容纳结构多样性。
