Engineering superior DNA vaccines: MHC class I single chain trimers bypass antigen processing and enhance the immune response to low affinity antigens
Engineering superior DNA vaccines: MHC class I single chain trimers bypass antigen processing and enhance the immune response to low affinity antigens
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DOI：
10.1016/j.vaccine.2009.10.096
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发表时间：
2010-02-23
期刊：
影响因子：
5.5
通讯作者：
Gillanders, William E.
中科院分区：
文献类型：
--
作者：
Li, Lijin;Herndon, John M.;Gillanders, William E.
通常认为，将抗原递送到I类抗原呈递途径中是DNA疫苗临床转化的限制因素。这在癌症疫苗开发的背景下是特别令人关注的，因为许多源自自身肿瘤抗原的免疫显性肽不能被有效地加工和呈递。为了解决这一局限性，我们设计了完全组装的肽/MHC I类复合物，其中所有三种组分（I类重链、β（2）m和肽）通过柔性接头连接并表达为单个多肽（单链三聚体或SCT）。在这项研究中，我们测试了连续几代SCT DNA疫苗的效力，这些疫苗被设计为（1）增强肽结合，（2）增强与CD 8辅助受体的相互作用，和/或（3）激活CD 4（+）辅助T细胞。二硫阱SCT（dtSCT）已被工程化以改善肽结合，突变设计为在I类重链和肽接头之间产生二硫键。如通过ELISPOT分析和肿瘤攻击所测量的，dtSCT DNA疫苗显著增强对模型低亲和力抗原的免疫应答。设计用于增强与CD 8辅助受体相互作用的SCT对TCR/CD 8复合物具有更高的亲和力，并且与疫苗接种后更稳健的CD 8（+）T细胞应答相关。最后，共表达通用辅助表位PADRE的SCT构建体显著增强CD 8（+）T细胞应答。综上所述，我们的数据表明，共表达通用CD 4表位的dtSCT DNA疫苗在产生对不良加工和呈递的癌抗原的免疫应答方面非常有效。(C)2009爱思唯尔有限公司保留所有权利。
It is commonly believed that delivery of antigen into the class I antigen presentation pathway is a limiting factor in the clinical translation of DNA vaccines. This is of particular concern in the context of cancer vaccine development as many immunodominant peptides derived from self tumor antigens are not processed and presented efficiently. To address this limitation, we have engineered completely assembled peptide/MHC class I complexes whereby all three components (class I heavy chain, beta(2)m, and peptide) are attached by flexible linkers and expressed as a single polypeptide (single chain trimers or SCT). In this study, we tested the efficacy of progressive generations of SCT DNA vaccines engineered to (I) enhance peptide binding, (2) enhance interaction with the CD8 coreceptor, and/or (3) activate CD4(+) helper T cells. Disulfide trap SCT (dtSCT) have been engineered to improve peptide binding, with mutations designed to create a disulfide bond between the class I heavy chain and the peptide linker. dtSCT DNA vaccines dramatically enhance the immune response to model low affinity antigens as measured by ELISPOT analysis and tumor challenge. SCT engineered to enhance interaction with the CD8 coreceptor have a higher affinity for the TCR/CD8 complex, and are associated with more robust CD8(+) T cell responses following vaccination. Finally, SCT constructs that coexpress a universal helper epitope PADRE, dramatically enhance CD8(+)T cell responses. Taken together, our data demonstrate that dtSCT DNA vaccines coexpressing a universal CD4 epitope are highly effective in generating immune responses to poorly processed and presented cancer antigens. (C) 2009 Elsevier Ltd. All rights reserved.