The CD8 T cell response to the HLA-A2-restricted epitope LLWNGPMAV (LLW) of the non-structural protein 4b of Yellow Fever Virus (YFV) is remarkably immunodominant, highly prevalent and powerful in YFV-vaccinated humans. Here we used a combinatorial peptide library screening in the context of an A2/LLW-specific CD8 T cell clone to identify a superagonist that features a methionine to isoleucine substitution at position 7. Based on in silico modeling, the functional enhancement of this LLW-7I mutation was associated with alterations in the structural dynamics of the peptide in the major histocompatibility complex (pMHC) binding with the T cell receptor (TCR). While the TCR off-rate of LLW-7I pMHC is comparable to the wild type peptide, the rigidity of the 7I peptide seems to confer less entropy loss upon TCR binding. This LLW-7I superagonist is an example of improved functionality in human CD8 T cells associated with optimized ligand rigidity for TCR binding and not with changes in TCR:pMHC off-rate kinetics.

对黄热病病毒（YFV）非结构蛋白4b的HLA-A2限制性表位LLWNGPMAV（LLW）的CD8 T细胞反应在接种YFV的人类中具有显着的免疫优势，高度流行和强大的能力。在这里，我们使用的组合肽文库在A2 / LLW特异性CD8 T细胞克隆的上下文中筛选以鉴定一个超激动剂，基于在位置7设有一个甲硫氨酸到异亮氨酸取代，在硅片在模型上，该LLW-7I突变的功能增强与与T细胞受体（TCR）结合的主要组织相容性复合体（pMHC）中肽的结构动力学变化有关。虽然LLW-7I pMHC的TCR失活率与野生型肽相当，但7I肽的刚性似乎使TCR结合时的熵损失较小。这款LLW-7I超激动剂是人类CD8 T细胞中功能改善的一个示例，该功能与针对TCR结合的优化配体刚性相关，而与TCR：pMHC脱速率动力学的变化无关。