Department of Hematology, Leiden University Medical Center, The Netherlands.
J Immunother. 2011 Mar;34(2):165-74. doi: 10.1097/CJI.0b013e318206a10c.
To broaden the applicability of cellular immunotherapy, adoptive transfer of T-cell receptor (TCR) transferred T cells may be an attractive strategy. Using this approach, high numbers of defined antigen-specific T cells can be engineered. As the introduced TCR has to compete for cell surface expression with the endogenous TCR, the introduced TCR chains are under control of a strong viral promotor, which, in contrast to the endogenous promotor, is constitutively active. We examined whether this difference in regulation would result in differences in TCR internalization and re-expression of the introduced and endogenous TCR on dual TCR engineered T cells and the antigen-responsiveness of both the TCRs. We showed comparable TCR downregulation of TCRs expressed under regulation of a retroviral promotor or the endogenous promotor. However, the introduced TCRs were rapidly re-expressed on the cell surface after TCR stimulation. Despite rapid re-expression of the introduced TCR, T cells exerted similar antigen-sensitivity compared with control T cells, showing that cell mechanisms other than TCR cell surface expression are involved in antigen-sensitivity directly after antigen-specific stimulation. These results showed that TCR transduced T cells are functionally not different from nontransduced T cells and can potentially be used as an effective treatment strategy.
为了拓宽细胞免疫治疗的应用范围，过继转移 T 细胞受体（TCR）转导的 T 细胞可能是一种有吸引力的策略。使用这种方法，可以设计出大量的定义明确的抗原特异性 T 细胞。由于引入的 TCR 必须与内源性 TCR 竞争细胞表面表达，因此引入的 TCR 链受强病毒启动子的控制，与内源性启动子相反，该启动子是组成性激活的。我们研究了这种调节上的差异是否会导致双 TCR 工程化 T 细胞上引入的和内源性 TCR 的 TCR 内化和再表达以及两种 TCR 的抗原反应性的差异。我们表明，在逆转录病毒启动子或内源性启动子调节下表达的 TCR 的 TCR 下调具有可比性。然而，在 TCR 刺激后，引入的 TCR 迅速在细胞表面重新表达。尽管引入的 TCR 迅速重新表达，但与对照 T 细胞相比，T 细胞表现出相似的抗原敏感性，表明在抗原特异性刺激后，涉及 TCR 细胞表面表达的其他细胞机制参与了抗原敏感性。这些结果表明，转导 TCR 的 T 细胞在功能上与未转导的 T 细胞没有区别，并且可以作为一种有效的治疗策略。
