High Frequency Production of T Cell-Derived iPSC Clones Capable of Generating Potent Cytotoxic T Cells
High Frequency Production of T Cell-Derived iPSC Clones Capable of Generating Potent Cytotoxic T Cells
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DOI：
10.1016/j.omtm.2019.12.006
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发表时间：
2020-03-13
影响因子：
4.7
通讯作者：
Kawamoto, Hiroshi
中科院分区：
文献类型：
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作者：
Nagano, Seiji;Maeda, Takuya;Kawamoto, Hiroshi
目前在自体环境中进行的过继性T细胞疗法是昂贵的、耗时的，并且取决于患者的T细胞的质量，因此开发同种异体策略将是非常有益的。为此，我们开发了一种方法，通过该方法，细胞毒性T淋巴细胞（CTL）从最初来源于T细胞的诱导多能干细胞（T-iPSC）再生。为了评估这种策略的可行性，我们研究了可用的T-iPSC克隆在其T细胞生成能力和T细胞受体（TCR）亲和力方面的频率。我们首先从健康志愿者中建立了8个携带不同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，但细胞产率变化很大，并且认为5个克隆是可用的。再生的CTL中的TCR亲和力在8个克隆中显示出较大的差异，但通过细胞毒性活性测量的功能亲合力在代表高、中和低TCR亲和力的3个选定克隆中几乎相等。在总共50个同种异体反应性测试中，使用5个CTL克隆对10个靶细胞，同种异体反应性仅见于3例。这些发现共同支持了这种T-iPSC策略的可行性。
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.