Current adoptive T cell therapies conducted in an autologous setting are costly, time-consuming, and depend on the quality of the patient's T cells, and thus it would be highly beneficial to develop an allogeneic strategy. To this aim, we have developed a method by which cytotoxic T lymphocytes (CTLs) are regenerated from induced pluripotent stem cells that are originally derived from T cells (T-iPSCs). In order to assess the feasibility of this strategy, we investigated the frequency of usable T-iPSC clones in terms of their T cell-generating capability and T cell receptor (TCR) affinity. We first established eight clones of T-iPSCs bearing different MART-1-specific TCRs from a healthy volunteer. Whereas all clones were able to give rise to mature CTLs, cell yield varied greatly, and five clones were considered to be usable. TCR affinity in the regenerated CTLs showed a large variance among the eight clones, but functional avidities measured by cytotoxic activity were almost equivalent among three selected clones representing high, medium, and low TCR affinity. In a total of 50 alloreactivity tests using five CTL clones versus ten target cells, alloreactivity was seen in only three cases. These findings collectively support the feasibility of this T-iPSC strategy.

中文翻译：

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T细胞衍生的iPSC克隆的高频生产，能够产生有效的细胞毒性T细胞。

当前在自体环境中进行的过继性T细胞疗法昂贵，费时且取决于患者T细胞的质量，因此开发同种异体策略将非常有益。为此，我们开发了一种方法，通过该方法从最初源自T细胞（T-iPSC）的诱导性多能干细胞中再生细胞毒性T淋巴细胞（CTL）。为了评估该策略的可行性，我们从可用的T-iPSC克隆的T细胞生成能力和T细胞受体（TCR）亲和力的角度研究了它们的频率。我们首先从一个健康志愿者那里建立了八个带有不同MART-1特异性TCR的T-iPSC克隆。尽管所有克隆都能够产生成熟的CTL，但细胞产量差异很大，并且认为有五个克隆可用。再生CTL中的TCR亲和力在8个克隆中显示出很大的差异，但是通过细胞毒性活性测得的功能亲和力在代表高，中和低TCR亲和力的三个选定克隆中几乎相等。使用五个CTL克隆对十个靶细胞进行的总共50次同种异体反应测试中，只有3种情况出现了同种异体反应。这些发现共同支持了这种T-iPSC策略的可行性。