Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells.

Autor: Dawson NAJ; Department of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada., Rosado-Sánchez I; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Novakovsky GE; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Fung VCW; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Huang Q; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., McIver E; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Sun G; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Gillies J; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Speck M; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Orban PC; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Mojibian M; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada., Levings MK; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada. mlevings@bcchr.ca.; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2020 Aug 19; Vol. 12 (557).
DOI: 10.1126/scitranslmed.aaz3866
Abstrakt: Antigen-specific regulatory T cells (T regs ) engineered with chimeric antigen receptors (CARs) are a potent immunosuppressive cellular therapy in multiple disease models and could overcome shortcomings of polyclonal T reg therapy. CAR therapy was initially developed with conventional T cells, which have different signaling requirements than do T regs To date, most of the CAR T reg studies used second-generation CARs, encoding a CD28 or 4-1BB co-receptor signaling domain and CD3ζ, but it was not known if this CAR design was optimal for T regs Using a human leukocyte antigen-A2-specific CAR platform and human T regs , we compared 10 CARs with different co-receptor signaling domains and systematically tested their function and CAR-stimulated gene expression profile. T regs expressing a CAR encoding CD28wt were markedly superior to all other CARs tested in an in vivo model of graft-versus-host disease. In vitro assays revealed stable expression of Helios and an ability to suppress CD80 expression on dendritic cells as key in vitro predictors of in vivo function. This comprehensive study of CAR signaling domain variants in T regs can be leveraged to optimize CAR design for use in antigen-specific T reg therapy.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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