期刊
NATURE IMMUNOLOGY
卷 21, 期 11, 页码 1456-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-020-0784-4
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资金
- Diabetes Research Center (NIH) [P30 DK063720]
- Juno Therapeutics
- NIH [DP3DK111914-01, P50GM082250, DP5OD023056]
- Keck Foundation
- National Multiple Sclerosis Society [CA 1074-A-21]
- Career Award for Medical Scientists from the Burroughs Wellcome Fund
- Lloyd Old STAR career award from the Cancer Research Institute
- Innovative Genomics Institute
- Parker Institute for Cancer Immunotherapy
- German Research Foundation (DFG)
- Hanns-Seidel-Stiftung
Human regulatory T (T-reg) cells are essential for immune homeostasis. The transcription factor FOXP3 maintains T-reg cell identity, yet the complete set of key transcription factors that control T-reg cell gene expression remains unknown. Here, we used pooled and arrayed Cas9 ribonucleoprotein screens to identify transcription factors that regulate critical proteins in primary human T-reg cells under basal and proinflammatory conditions. We then generated 54,424 single-cell transcriptomes from T-reg cells subjected to genetic perturbations and cytokine stimulation, which revealed distinct gene networks individually regulated by FOXP3 and PRDM1, in addition to a network coregulated by FOXO1 and IRF4. We also discovered that HIVEP2, to our knowledge not previously implicated in T(reg)cell function, coregulates another gene network with SATB1 and is important for T-reg cell-mediated immunosuppression. By integrating CRISPR screens and single-cell RNA-sequencing profiling, we have uncovered transcriptional regulators and downstream gene networks in human T-reg cells that could be targeted for immunotherapies.
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