Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: Implications for vaccine design
Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: Implications for vaccine design
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DOI：
10.4049/jimmunol.174.8.4812
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发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Baker, BM
中科院分区：
文献类型：
--
作者：
Borbulevych, OY;Baxter, TK;Baker, BM
“锚定”改变的肽配体的使用在癌症和传染病治疗性疫苗的开发中引起了相当大的兴趣，但成功改变的肽配体引起免疫增强的机制尚不清楚。在这项研究中，我们已经确定了与HLA-A*0201（HLA-A2）分子复合的主要肿瘤排斥Ag，gp 100（209-217）的晶体结构，以及在位置2（T2 M; gp 100（211- 2 M））用甲硫氨酸取代苏氨酸的肽的修饰形式的结构。T2 M修饰的肽在体外和体内更具免疫原性，在生理温度下以相似的9倍更大的亲和力结合HLA-A2，并具有相似的7倍更慢的解离速率。在晶体学数据的限度内，T2 M取代不改变肽/HLA-A2复合物的结构。与这一发现一致，在95名人类受试者的外周血中，我们无法鉴定出对天然或修饰肽具有特异性的更高频率的T细胞。这些数据强烈支持gp 100（201- 2 M）肽的更大免疫原性是由于肽/MHC复合物的稳定性增强的结论，验证了用于产生治疗性疫苗候选物的锚定固定方法。热力学数据表明，T2 M修饰的肽/HLA-A2复合物的增强的稳定性可归因于修饰的肽的疏水性增加，但是由于疏水性的增益被天然肽与HLA-A2分子形成的氢键的损失相当大地抵消。我们的研究结果对优化当前疫苗设计策略具有广泛的意义。
The use of "anchor-fixed" altered peptide ligands is of considerable interest in the development of therapeutic vaccines for cancer and infectious diseases, but the mechanism by which successful altered peptide ligands elicit enhanced immunity is unclear. In this study, we have determined the crystallographic structure of a major tumor rejection Ag, gp100(209-217), in complex with the HLA-A*0201 (HLA-A2) molecule, as well as the structure of a modified version of the peptide which substitutes methionine for threonine at position 2 (T2M; gp100(211-2M)). The T2M-modified peptide, which is more immunogenic in vitro and in vivo, binds HLA-A2 with a similar to 9-fold greater affinity and has a similar to 7-fold slower dissociation rate at physiological temperature. Within the limit of the crystallographic data, the T2M substitution does not alter the structure of the peptide/HLA-A2 complex. Consistent with this finding, in peripheral blood from 95 human subjects, we were unable to identify higher frequencies of T cells specific for either the native or modified peptide. These data strongly support the conclusion that the greater immunogenicity of the gp100(201-2M) peptide is due to the enhanced stability of the peptide/MHC complex, validating the anchor-fixing approach for generating therapeutic vaccine candidates. Thermodynamic data suggest that the enhanced stability of the T2M-modified peptide/HLA-A2 complex is attributable to the increased hydrophobicity of the modified peptide, but the gain due to hydrophobicity is offset considerably by the loss of a hydrogen bond made by the native peptide to the HLA-A2 molecule. Our findings have broad implications for the optimization of current vaccine-design strategies.