Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells.
In: Cell Reports, Jg. 42 (2023-03-28), Heft 3, S. N.PAG
academicJournal
Zugriff:
Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs. [Display omitted] • Tonic CAR signaling diverts T cell differentiation to the ILC lineage from hPSCs • CAR activation during early lymphoid development enriches for ILC2 precursors • Antigen-mediated CAR activation during development enhances NK/ILC1 output • Lower tonic signaling of 41BBζ-based CARs enables normal CAR-T cell differentiation Li et al. show that tonic CAR activation during early lymphoid development from pluripotent stem cells (PSCs) diverts T cell development to innate lymphoid cell lineages. They show that tuning CAR tonic signaling via alternative costimulatory domains enables preservation of conventional CAR-T cell differentiation from PSCs. [ABSTRACT FROM AUTHOR]
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Titel: |
Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells.
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Autor/in / Beteiligte Person: | Li, Suwen ; Wang, Chloe S. ; Montel-Hagen, Amélie ; Chen, Ho-Chung ; Lopez, Shawn ; Zhou, Olivia ; Dai, Kristy ; Tsai, Steven ; Satyadi, William ; Botero, Carlos ; Wong, Claudia ; Casero, David ; Crooks, Gay M. ; Seet, Christopher S. |
Zeitschrift: | Cell Reports, Jg. 42 (2023-03-28), Heft 3, S. N.PAG |
Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
ISSN: | 2639-1856 (print) |
DOI: | 10.1016/j.celrep.2023.112241 |
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