Transgenic mice with a diverse human T cell antigen receptor repertoire
Transgenic mice with a diverse human T cell antigen receptor repertoire
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DOI：
10.1038/nm.2197
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发表时间：
2010-09-01
期刊：
影响因子：
82.9
通讯作者：
Blankenstein, Thomas
中科院分区：
文献类型：
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作者：
Li, Liang-Ping;Lampert, J. Christoph;Blankenstein, Thomas
由于耐受机制，很难鉴定针对自身（例如，肿瘤）抗原的高亲和力T细胞的T细胞受体（TCR）。可以在小鼠中鉴定对来自非耐受性T细胞库的外来人抗原具有特异性的TCR。此外，如果构建小鼠以表达人TCR库，则它们可用于分析针对人自身抗原的非偏斜库。在这里，我们产生了转基因小鼠与整个人类TCR α β基因位点（1.1和0.7 Mb），其T细胞表达不同的人类TCR库，以弥补小鼠TCR缺陷。与小鼠TCR相比，人主要组织相容性I类转基因增加了人CD 8（+）T细胞的产生。诱导了针对几种人类肿瘤抗原的功能性CD 8（+）T细胞，并且针对Melan-A黑素瘤抗原的功能性CD 8（+）T细胞使用与在来自自身免疫性白癜风或黑素瘤个体的T细胞克隆中检测到的TCR相似的TCR。这些小鼠将使研究人员能够识别致病性和治疗性人类TCR。
Because of tolerance mechanisms, it has been hard to identify the T cell receptors (TCRs) of high-avidity T cells against self (for example, tumor) antigens. TCRs that are specific for foreign human antigens from the nontolerant T cell repertoire can be identified in mice. Moreover, if mice are constructed to express the human TCR repertoire, they can be used to analyze the unskewed repertoire against human self antigens. Here we generated transgenic mice with the entire human TCR alpha beta gene loci (1.1 and 0.7 Mb), whose T cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency. A human major histocompatibility class I transgene increases the generation of CD8(+) T cells with human compared to mouse TCRs. Functional CD8(+) T cells against several human tumor antigens were induced, and those against the Melan-A melanoma antigen used similar TCRs to those that have been detected in T cell clones from individuals with autoimmune vitiligo or melanoma. These mice will allow researchers to identify pathogenic and therapeutic human TCRs.