TY - JOUR
T1 - Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation
AU - Xia, Lei
AU - Komissarova, Anastasia
AU - Jacover, Arielle
AU - Shovman, Yehuda
AU - Arcila-Barrera, Sebastian
AU - Tornovsky-Babeay, Sharona
AU - Jaya Prakashan, Milsee Mol
AU - Nasereddin, Abdelmajeed
AU - Plaschkes, Inbar
AU - Nevo, Yuval
AU - Shiff, Idit
AU - Yosefov-Levi, Oshri
AU - Izhiman, Tamara
AU - Medvedev, Eleonora
AU - Eilon, Elad
AU - Wilensky, Asaf
AU - Yona, Simon
AU - Parnas, Oren
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/10/9
Y1 - 2023/10/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85173632022&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-41792-8
DO - 10.1038/s41467-023-41792-8
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C2 - 37813864
AN - SCOPUS:85173632022
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6295
ER -
