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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE160341 | GEO | 2021/02/25

REPOSITORIES: GEO

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8<sup>+</sup> T cell fate decisions.

Project description:How early events in effector T cell (TEFF) subsets tune memory T cell (TMEM) responses remains incompletely understood. Here, we systematically investigated metabolic factors in fate determination of TEFF and TMEM cells using in vivo pooled CRISPR screening, focusing on negative regulators of TMEM responses. We found that amino acid transporters Slc7a1 and Slc38a2 dampened the magnitude of TMEM differentiation, in part through modulating mTORC1 signaling. By integrating genetic and systems approaches, we identified cellular and metabolic heterogeneity among TEFF cells, with terminal effector differentiation associated with establishment of metabolic quiescence and exit from the cell cycle. Importantly, Pofut1 (protein-O-fucosyltransferase-1) linked GDP-fucose availability to downstream Notch-Rbpj signaling, and perturbation of this nutrient signaling axis blocked terminal effector differentiation but drove context-dependent TEFF proliferation and TMEM development. Our study establishes that nutrient uptake and signaling are key determinants of T cell fate and shape the quantity and quality of TMEM responses.

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [Pofut1_microarray]

Project description:The role of nutrient signaling processes in the fate decision of CD8 is incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [NICD_microarray]

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [microarray_dataset1]

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [scRNA-seq]

Project description:The role of nutrient signaling processes in the fate decision of CD8 T cells are incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [Pofut1 ATAC-seq]

Project description:The role of nutrient signaling processes in the fate decision of CD8 are incompletely understood. By performing in vivo pooled CRISPR-Cas9 screening, we uncovered nutrient signaling processes underpinning the dynamics and heterogeneity of CD8 T cell fate decisions.

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions

Project description:In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [microarray_dataset1]

Project description:In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [microarray_dataset1]

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [NICD_microarray]

Project description:In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [NICD_microarray]

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In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [Pofut1_microarray]

Project description:In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions [Pofut1_microarray]