» Articles » PMID: 39561045

Combinatorial Genetic Engineering Strategy for Immune Protection of Stem Cell-derived Beta Cells by Chimeric Antigen Receptor Regulatory T cells

Overview
Journal Cell Rep
Publisher Cell Press
Date 2024 Nov 19
PMID 39561045
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Expanding the engineered Treg multiverse.

Cochrane R, Allen E, Ferreira L Mol Ther. 2025; 33(3):833-836.

PMID: 39986268 PMC: 11897745. DOI: 10.1016/j.ymthe.2025.02.007.

References
1.
Siegel E, Wollheim C, Kikuchi M, Renold A, SHARP G . Dependency of cyclic AMP-induced insulin release on intra- and extracellular calcium in rat islets of Langerhans. J Clin Invest. 1980; 65(2):233-41. PMC: 371360. DOI: 10.1172/JCI109665. View

2.
Schmidt A, Oberle N, Krammer P . Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012; 3:51. PMC: 3341960. DOI: 10.3389/fimmu.2012.00051. View

3.
Rezania A, Bruin J, Arora P, Rubin A, Batushansky I, Asadi A . Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014; 32(11):1121-33. DOI: 10.1038/nbt.3033. View

4.
Muller Y, Ferreira L, Ronin E, Ho P, Nguyen V, Faleo G . Precision Engineering of an Anti-HLA-A2 Chimeric Antigen Receptor in Regulatory T Cells for Transplant Immune Tolerance. Front Immunol. 2021; 12:686439. PMC: 8488356. DOI: 10.3389/fimmu.2021.686439. View

5.
Fiorentino D, Zlotnik A, Mosmann T, Howard M, OGarra A . IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991; 147(11):3815-22. View