Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells.

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-18 DOI:10.1016/j.celrep.2024.114994

Jessie M Barra, Rob A Robino, Roberto Castro-Gutierrez, James Proia, Holger A Russ, Leonardo M R Ferreira

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Abstract

Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation.

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通过嵌合抗原受体调节性 T 细胞对干细胞衍生的 beta 细胞进行免疫保护的组合基因工程策略。

再生医学是一个迅速发展的领域，它利用人体多能干细胞（hPSC）衍生的细胞和组织治疗多种疾病，包括1型糖尿病。然而，移植物免疫保护仍是一项关键挑战。嵌合抗原受体（CAR）技术为效应T细胞和免疫抑制调节性T细胞（Tregs）赋予了新的特异性。CAR设计面临的一个挑战是确定相关细胞特有的靶分子。在这里，我们采用组合基因工程，将CAR-Treg介导的局部免疫保护赋予干细胞衍生细胞。引人注目的是，CAR-Tregs抑制了体外先天性和适应性免疫反应，并防止了EGFRt-hPSC衍生的胰腺β样细胞（sBC[干细胞衍生β细胞]）在体内的移植物免疫破坏。总之，我们提供了一个概念证明：hPSCs 和 Tregs 可以共同设计，以保护 hPSC 衍生细胞在移植时免受免疫排斥。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.