Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity.
Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity.
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DOI：
10.1038/mtm.2014.27
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发表时间：
2014
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影响因子：
--
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中科院分区：
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我们先前发现了一种特定的HLA-A*02：01突变体，与野生型HLA-A*02：01相比，该突变体在体外增强了肽特异性细胞毒性T淋巴细胞（CTL）识别。该突变体在位于肽结合沟中的位置74（H74 L）处包含从组氨酸到亮氨酸的单个氨基酸取代。为了研究H74 L突变对体内CTL引发的影响，我们利用HLA I类单链三聚体（SCT）技术，其中包括肽、β2微球蛋白和HLA I类重链的三个组分通过柔性接头连接在一起。我们制备了表达SCT的重组腺病毒，SCT包含A型流感病毒基质蛋白（FMP）衍生肽、β2微球蛋白和H74 L重链。用腺病毒免疫HLA-A*02：01转基因小鼠，观察其诱导的肽特异性CTL和抗肿瘤免疫。清楚地表明，H74 L突变使得HLA-A*02：01 SCT分子能够显著增强FMP特异性CTL的体内引发和针对表达FMP的肿瘤细胞的致死性攻击的保护。这些数据提供了第一个证据，证明SCT的HLA I类重链中的简单点突变有利于改善基于CTL的免疫治疗和预防以控制肿瘤。
We previously discovered one particular HLA-A*02:01 mutant that enhanced peptide-specific cytotoxic T lymphocyte (CTL) recognition in vitro compared to wild-type HLA-A*02:01. This mutant contains a single amino acid substitution from histidine to leucine at position 74 (H74L) that is located in the peptide-binding groove. To investigate the effect of the H74L mutation on the in vivo CTL priming, we took advantage of the technology of the HLA class I single-chain trimer (SCT) in which three components involving a peptide, β2 microglobulin and the HLA class I heavy chain are joined together via flexible linkers. We generated recombinant adenovirus expressing SCT comprised influenza A matrix protein (FMP)-derived peptide, β2 microglobulin and the H74L heavy chain. HLA-A*02:01 transgenic mice were immunized with the adenovirus, and the induction of peptide-specific CTLs and antitumor immunity was investigated. It was clearly shown that the H74L mutation enabled the HLA-A*02:01 SCT molecule to dramatically enhance both in vivo priming of FMP-specific CTLs and protection against a lethal challenge of tumor cells expressing FMP. These data present the first evidence that a simple point mutation in the HLA class I heavy chain of SCT is beneficial for improving CTL-based immunotherapy and prophylaxis to control tumors.
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影响因子：
64.8
作者：
POWIS, SJ;TOWNSEND, ARM;HOWARD, JC
通讯作者：
HOWARD, JC
影响因子：
5.5
作者：
Hung, Chien-Fu;Calizo, Roanne;Wu, T-C
通讯作者：
Wu, T-C
DOI：
10.4049/jimmunol.0903955
发表时间：
2010-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kim S;Li L;McMurtrey CP;Hildebrand WH;Weidanz JA;Gillanders WE;Diamond MS;Hansen TH
通讯作者：
Hansen TH
影响因子：
5.5
作者：
Li, Lijin;Herndon, John M.;Gillanders, William E.
通讯作者：
Gillanders, William E.
影响因子：
4.4
作者：
Palmowski, Michael J.;Parker, Mathew;Gould, Keith G.
通讯作者：
Gould, Keith G.