Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation

Author:

Xia LeiORCID,Komissarova AnastasiaORCID,Jacover ArielleORCID,Shovman YehudaORCID,Arcila-Barrera Sebastian,Tornovsky-Babeay Sharona,Jaya Prakashan Milsee Mol,Nasereddin AbdelmajeedORCID,Plaschkes Inbar,Nevo Yuval,Shiff IditORCID,Yosefov-Levi Oshri,Izhiman Tamara,Medvedev Eleonora,Eilon Elad,Wilensky Asaf,Yona SimonORCID,Parnas OrenORCID

Abstract

AbstractGenetic 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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