Organoid-Induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells
Organoid-Induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells
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DOI：
10.1016/j.stem.2018.12.011
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发表时间：
2019-03-07
期刊：
影响因子：
23.9
通讯作者：
Crooks, Gay M.
中科院分区：
文献类型：
--
作者：
Montel-Hagen, Amelie;Seet, Christopher S.;Crooks, Gay M.
从多能干细胞（PSC）产生T细胞的能力有可能通过促进通用的现成细胞产品来改变自体T细胞免疫疗法。然而，用现有方法将人PSC分化成成熟的常规T细胞一直是具有挑战性的。我们报道了一个连续的3D类器官系统通过造血特化和有效的终末分化诱导PSC来源的胚胎中胚层有序的定向和分化序列，从而分化为具有不同T细胞受体（TCR）库的幼稚CD 3（+）CD 8 α β（+）和CD 3（+）CD 4（+）常规T细胞。在PSC中引入MHC I类限制性TCR产生了初始的抗原特异性CD 8 α β（+）T细胞，其缺乏内源性TCR表达并在体外和体内显示出抗肿瘤功效。功能测定和RNA测序将PSC衍生的T细胞与原代幼稚CD 8（+）T细胞比对。本文提出的PSC-人工胸腺类器官（ATO）系统是从人PSC产生功能性成熟T细胞的有效平台。
The ability to generate T cells from pluripotent stem cells (PSCs) has the potential to transform autologous T cell immunotherapy by facilitating universal, off-the-shelf cell products. However, differentiation of human PSCs into mature, conventional T cells has been challenging with existing methods. We report that a continuous 3D organoid system induced an orderly sequence of commitment and differentiation from PSC-derived embryonic mesoderm through hematopoietic specification and efficient terminal differentiation to naive CD3(+) CD8 alpha beta(+) and CD3(+) CD4(+) conventional T cells with a diverse T cell receptor (TCR) repertoire. Introduction of an MHC class I-restricted TCR in PSCs produced naive, antigen-specific CD8 alpha beta(+) T cells that lacked endogenous TCR expression and showed anti-tumor efficacy in vitro and in vivo. Functional assays and RNA sequencing aligned PSC-derived T cells with primary naive CD8(+) T cells. The PSC-artificial thymic organoid (ATO) system presented here is an efficient platform for generating functional, mature T cells from human PSCs.