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CRISPR activation and interference screens decode stimulation responses in primary human T cells.

ABSTRACT: Regulation of cytokine production in stimulated T cells can be disrupted in autoimmunity, immunodeficiencies, and cancer. Systematic discovery of stimulation-dependent cytokine regulators requires both loss-of-function and gain-of-function studies, which have been challenging in primary human cells. We now report genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells to identify gene networks controlling interleukin-2 (IL-2) and interferon-γ (IFN-γ) production. Arrayed CRISPRa confirmed key hits and enabled multiplexed secretome characterization, revealing reshaped cytokine responses. Coupling CRISPRa screening with single-cell RNA sequencing enabled deep molecular characterization of screen hits, revealing how perturbations tuned T cell activation and promoted cell states characterized by distinct cytokine expression profiles. These screens reveal genes that reprogram critical immune cell functions, which could inform the design of immunotherapies.

SUBMITTER: Schmidt R 

PROVIDER: S-EPMC9307090 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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CRISPR activation and interference screens decode stimulation responses in primary human T cells.

Schmidt Ralf R   Steinhart Zachary Z   Layeghi Madeline M   Freimer Jacob W JW   Bueno Raymund R   Nguyen Vinh Q VQ   Blaeschke Franziska F   Ye Chun Jimmie CJ   Marson Alexander A  

Science (New York, N.Y.) 20220204 6580

Regulation of cytokine production in stimulated T cells can be disrupted in autoimmunity, immunodeficiencies, and cancer. Systematic discovery of stimulation-dependent cytokine regulators requires both loss-of-function and gain-of-function studies, which have been challenging in primary human cells. We now report genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells to identify gene networks controlling interleukin-2 (IL-2) and interferon-γ (IFN-γ) p  ...[more]

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