T细胞受体
生物
细胞生物学
主要组织相容性复合体
诱导多能干细胞
间质细胞
抗原
T细胞
干细胞
链霉菌
抗原提呈细胞
分子生物学
免疫学
癌症研究
免疫系统
胚胎干细胞
遗传学
基因
作者
Peter Chang,Xuegang Yuan,Alexandre Zampieri,Cindy Towns,Sang Pil Yoo,Caron M. Engstrom,Shau‐Wei Tsai,Christopher R. Robles,Yuhua Zhu,S. R. Lopez,Amélie Montel‐Hagen,Christopher S. Seet,Gay M. Crooks
标识
DOI:10.1038/s41551-023-01146-7
摘要
Abstract Pluripotent stem cells (PSCs) are a promising source of allogeneic T cells for off-the-shelf immunotherapies. However, the process of differentiating genetically engineered PSCs to generate mature T cells requires that the same molecular elements that are crucial for the selection of these cells be removed to prevent alloreactivity. Here we show that antigen-restricted mature T cells can be generated in vitro from PSCs edited via CRISPR to lack endogenous T cell receptors (TCRs) and class I major histocompatibility complexes. Specifically, we used T cell precursors from RAG1 −/− RAG2 − /− B2M − /− human PSCs expressing a single TCR, and a murine stromal cell line providing the cognate human major histocompatibility complex molecule and other critical signals for T cell maturation. Possibly owing to the absence of TCR mispairing, the generated T cells showed substantially better tumour control in mice than T cells with an intact endogenous TCR. Introducing the T cell selection components into the stromal microenvironment of the PSCs overcomes inherent biological challenges associated with the development of T cell immunotherapies from allogeneic PSCs.
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