%0 Journal Article
%A Xia, Lei
%A Komissarova, Anastasia
%A Jacover, Arielle
%A Shovman, Yehuda
%A Arcila-Barrera, Sebastian
%A Tornovsky-Babeay, Sharona
%A Jaya Prakashan, Milsee Mol
%A Nasereddin, Abdelmajeed
%A Plaschkes, Inbar
%A Nevo, Yuval
%A Shiff, Idit
%A Yosefov-Levi, Oshri
%A Izhiman, Tamara
%A Medvedev, Eleonora
%A Eilon, Elad
%A Wilensky, Asaf
%A Yona, Simon
%A Parnas, Oren
%T Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation.
%J Nature Communications
%V 14
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-02474
%P 6295
%D 2023
%Z #DKFZ-MOST-Ca197#
%X 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.
%K T-Lymphocytes
%K Lymphocyte Activation: genetics
%K Transcription Factors
%K Transcriptome: genetics
%K Immunity, Innate: genetics
%K Transcription Factors (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37813864
%2 pmc:PMC10562403
%R 10.1038/s41467-023-41792-8
%U https://inrepo02.dkfz.de/record/306245