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| Home > Institute Collections > W500 > Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation. |
| Home > Institute Collections > W500 > Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation. |
| Journal Article | DKFZ-2025-02474 |
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2023
Springer Nature
[London]
Abstract: Genetic engineering of immune cells has opened new avenues for improving their functionality but it remains a challenge to pinpoint which genes or combination of genes are the most beneficial to target. Here, we conduct High Multiplicity of Perturbations and Cellular Indexing of Transcriptomes and Epitopes (HMPCITE-seq) to find combinations of genes whose joint targeting improves antigen-presenting cell activity and enhances their ability to activate T cells. Specifically, we perform two genome-wide CRISPR screens in bone marrow dendritic cells and identify negative regulators of CD86, that participate in the co-stimulation programs, including Chd4, Stat5b, Egr2, Med12, and positive regulators of PD-L1, that participate in the co-inhibitory programs, including Sptlc2, Nckap1l, and Pi4kb. To identify the genetic interactions between top-ranked genes and find superior combinations to target, we perform high-order Perturb-Seq experiments and we show that targeting both Cebpb and Med12 results in a better phenotype compared to the single perturbations or other combinations of perturbations.
Keyword(s): T-Lymphocytes (MeSH) ; Lymphocyte Activation: genetics (MeSH) ; Transcription Factors (MeSH) ; Transcriptome: genetics (MeSH) ; Immunity, Innate: genetics (MeSH) ; Transcription Factors
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