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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Generation and characterization of transgenic mice expressing a T-cell receptor specific for the tumour-associated antigen MDM2.
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Generation and characterization of transgenic mice expressing a T-cell receptor specific for the tumour-associated antigen MDM2.

机译：表达特定于肿瘤相关抗原MDM2的T细胞受体的转基因小鼠的产生和表征。

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T-cell-based antigen-specific immunotherapy targeting tumour-associated antigens offers the potential for cancer immunotherapy. However, the majority of identified tumour-associated antigens are also expressed at low levels in normal tissues and mechanisms of tolerance induction are likely to affect the quality of T-cell responses to such antigens. In this study a T-cell receptor transgenic model was developed to determine the magnitude of T-cell tolerance to the tumour-associated antigen murine double minute-2 (MDM2), a widely expressed protein that is found at elevated levels in many tumours. The analysis of transgenic mice showed that thymic deletion was responsible for purging large numbers of MDM2-specific T cells from the repertoire. However, some T cells with specificity for MDM2 were able to escape thymic deletion and persisted in the peripheral T-cell pool. Functional analysis revealed that these T cells displayed defects in antigen-driven expansion. This functional impairment of the MDM2-specific T cells was maintained following adoptive transfer of the T cells into hosts that were unable to present the T-cell-receptor-recognized antigen. This study demonstrates that thymic deletion and the functional impairment of T cells present in the periphery both operate to establish T-cell tolerance to the tumour-associated antigen MDM2. Furthermore, the tolerant phenotype was stable and did not require continuous MDM2 peptide presentation in normal tissues.
机译：针对肿瘤相关抗原的基于T细胞的抗原特异性免疫疗法为癌症免疫疗法提供了潜力。然而，大多数鉴定出的与肿瘤相关的抗原也在正常组织中以低水平表达，并且耐受诱导的机制可能影响对此类抗原的T细胞应答的质量。在这项研究中，开发了一种T细胞受体转基因模型来确定T细胞对与肿瘤相关的抗原鼠类double minutes-2（MDM2）的耐受性的大小，MDM2是一种广泛表达的蛋白，在许多肿瘤中均以升高的水平被发现。对转基因小鼠的分析表明，胸腺缺失是导致从库中清除大量MDM2特异性T细胞的原因。但是，一些对MDM2具有特异性的T细胞能够逃避胸腺的缺失，并持续存在于外周T细胞库中。功能分析表明，这些T细胞在抗原驱动的扩增中显示出缺陷。在将T细胞过继转移至无法呈递T细胞受体识别抗原的宿主后，MDM2特异性T细胞的功能受损得以维持。这项研究表明，胸腺的缺失和周围T细胞的功能受损都可以建立对肿瘤相关抗原MDM2的T细胞耐受性。此外，耐受表型是稳定的，不需要在正常组织中连续呈递MDM2肽。

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