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Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells

ABSTRACT: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. A detailed understanding of the effects of CARs on T cell differentiation from PSCs is important to 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 ILC2 lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages which share certain developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during early lymphoid development was evident in ILC2-primed lymphoid precursors. We applied this understanding to rationally modulate CAR signaling strength through changes to CAR expression level, structure, or expression of cognate antigen and demonstrate that the T-versus-ILC lineage decision can be controlled in either direction, providing a framework for achieving normal CAR-T cell development from PSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224964 | GEO | 2023/03/16

REPOSITORIES: GEO

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Systemic human ILC precursors provide a substrate for tissue ILC differentiation

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Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses - WT ILC2

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