Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells
Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells
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DOI：
10.1016/j.clim.2005.12.009
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发表时间：
2006-05-01
影响因子：
8.6
通讯作者：
Hooijberg, E
中科院分区：
文献类型：
--
作者：
Scholten, KBJ;Kramer, D;Hooijberg, E
天然转基因T细胞受体在受体人T细胞中的表达通常不足以获得高反应性T细胞块。在这里，我们表明，密码子修饰的HPV 16 E7特异性T细胞受体（TCR），连同省略mRNA不稳定基序和（隐蔽）剪接位点，导致显着增加的表达水平的转基因TCR在人CD 8 + T细胞。已经在逆转录病毒载体LZRS中以三种不同的构型测试了密码子修饰的TCR：（1）TCR α-IRES-GFP与TCR β-IRES-NGFR的组合，（2）TCR α-IRES-TCR I，和（3）TCR α-2A-TCR β。携带密码子修饰的TCR的T细胞对负载有相关肽的靶细胞、表达特异性表位的模型肿瘤细胞以及宫颈癌细胞具有功能活性。我们在此报告的特异性人TCR功能表达的显著改善将有望加快基于TCR转移的免疫疗法的临床应用。(c)2005年爱思唯尔公司All rights reserved.
Expression of native transgenic T cell receptors in recipient human T cells is often insufficient to achieve highly reactive T cell bulks. Here we show that codon modification of an HPV16E7-specific T cell receptor (TCR), together with omission of mRNA instability motifs and (cryptic) splice sites, leads to a dramatic increase in the expression levels of the transgenic TCRs in human CD8+ T cells. The codon-modified TCRs have been tested in three different configurations in the retroviral vector LZRS: (1) TCR alpha-IRES-GFP in combination with TCR beta-IRES-NGFR, (2) TCR alpha-IRES-TCRI, and (3) TCR alpha-2A-TCR beta. T cells carrying the codon-modified TCRs are functionally active against target cells loaded with relevant peptide, model tumor cells expressing the specific epitope as well as cervical carcinoma cells. The significant improvements we report here in the functional expression of specific human TCRs wilt hopefully expedite clinical application of TCR transfer-based immunotherapy. (c) 2005 Elsevier Inc. All rights reserved.