Secondary anchor substitutions in an HLA-A*0201-restricted T-cell epitope derived from Her-2/neu.
Secondary anchor substitutions in an HLA-A*0201-restricted T-cell epitope derived from Her-2/neu.
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源自 Her-2/neu 的 HLA-A*0201 限制性 T 细胞表位中的二级锚定取代。
DOI：
10.1016/j.molimm.2006.02.027
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发表时间：
2007
影响因子：
3.6
通讯作者：
Meng,WilsonS
中科院分区：
文献类型：
--
作者：
Joseph,MatthewA;Mitchell,MeganL;Evanseck,JeffreyD;Kovacs,JeffreyR;Jia,Liang;Shen,Hongmei;Meng,WilsonS
我们研究了GP 2（IISAVGIL）的类似物，GP 2是一种HLA-A*0201限制性T细胞表位，来源于肿瘤相关抗原（TAA）Her-2/neu中的残基654-662。GP 2的一个限制因素是其对HLA-A*0201的亲和力差。构象分析显示GP 2中的P5-P7区域似乎与P9侧链与MHC分子相互作用的稳定性有关。为了鉴定对HLA-A*0201具有增强呈递的GP 2变体，我们测试了V6 S、V6 T、V6 Q、G7 P、G7 F、T6 F7和Q6 F7稳定细胞表面HLA-A*0201分子的能力。在单取代的变体中，与GP 2相比，V6 Q和G7 F表现出上级稳定性。分子动力学模拟表明，结合的改善可以归因于肽的中心和C-末端区域的协同运动。这些数据支持HLA-A*0201表位中的氨基酸可能相互依赖的观点。用G7 F负载的同基因树突状细胞引发HLA-A*0201转基因小鼠刺激小鼠T细胞产生比用GP 2免疫的小鼠更高水平的INFγ。
We investigated analogues of GP2 (IISAVVGIL), an HLA-A*0201-restricted T-cell epitope derived from residues 654–662 in the tumor-associated antigen (TAA) Her-2/neu. One limiting factor of GP2 is its poor affinity for HLA-A*0201. Conformational analysis revealed the P5–P7 region in GP2 appears to be linked to the stability of P9 side chain interaction with the MHC molecule. To identify variants of GP2 with enhanced presentation to HLA-A*0201, we tested V6S, V6T, V6Q, G7P, G7F, T6F7, and Q6F7 for their capacity to stabilize cell surface HLA-A*0201 molecules. Of the mono-substituted variants, V6Q and G7F exhibited superior stabilization as compared to GP2. Molecular dynamics simulations suggest the improved binding can be attributed to concerted motions in the central and C-terminal regions of the peptide. These data support the notion that amino acids in HLA-A*0201 epitopes may be inter-dependent. Priming HLA-A*0201 transgenic mice with G7F-loaded syngeneic dendritic cells stimulated mouse T cells to produce a higher level of INFγ than mice immunized with GP2.