Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells

Collins, Patrick L.; Cella, Marina; Porter, Sofia I.; Li, Shasha; Gurewitz, Greer L.; Hong, Henoch S.; Johnson, R. Paul; Oltz, Eugene M.; Colonna, Marco

doi:10.1016/j.cell.2018.11.045

Cited by 138 publications

(143 citation statements)

References 79 publications

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“…The global gene expression differences we identified between CD56 bright CD16 À and CD56 dim CD16 + NK cells were conserved in all sites, revealing subset-specific profiles consistent with previous studies of NK subsets from single sites (Collins et al, 2019;Koopman et al, 2003;Marquardt et al, 2019;Melsen et al, 2018). Genes upregulated in CD56 dim CD16 + NK cells include those associated with effector function (GZMB, GZMH, IFNG), killer cell immunoglobulin-like receptors (KIR), and tissue egress and circulation (S1PR5, S1PR1, CXCR1, CXCR2, and CX3CR1), while CD56 bright CD16 À NK cells express elevated levels of genes associated with immune regulation (CD27, TNFSF4, TNFSF8, TNFSF13, and TNFSF13B) and tissue homing (CCR7, SELL, CXCR3, and CCR5) ( Figure S3B).…”

Section: Whole Transcriptome Profiling Uncovers Subset-and Tissue-spesupporting

confidence: 87%

Tissue Determinants of Human NK Cell Development, Function, and Residence

Dogra

Rancan

Wei-hua

et al. 2020

Cell

279

291

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Section: Whole Transcriptome Profiling Uncovers Subset-and Tissue-spesupporting

confidence: 87%

Tissue Determinants of Human NK Cell Development, Function, and Residence

Dogra

Rancan

Wei-hua

et al. 2020

Cell

279

291

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“…Ultralow Input ChIP-Seq was performed as described previously (50). Briefly, aliquots of 10 5 cells were suspended in 20 l of EZ nuclei isolation buffer (Sigma) and digested using 20 l of MNase (NEB MNase buffer, 1 l of MNase, and 3 mM dithiothreitol) for 5 min at 37°C, which was quenched by adding 4.4 l of 100 mM EDTA and 4.4 l of 1% Triton X-100 and 1% deoxycholate.…”

Section: Methodsmentioning

confidence: 99%

Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response

Qian

Bambousková

et al. 2020

mBio

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Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, including Oas2, Rsad2 (viperin), Ifit1, and ISG15. The phenotype in Banf1-deficient cells occurred through a cGAS-, STING-, and IRF3-dependent signaling axis, was associated with reduced infection of RNA and DNA viruses, and was reversed in Banf1 complemented cells. Confocal microscopy and biochemical studies revealed that a loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline. Our study identifies an undescribed role for Banf1 in regulating the levels of cytoplasmic DNA and cGAS-dependent ISG homeostasis and suggests possible therapeutic directions for promoting or inhibiting cell-intrinsic innate immune responses. IMPORTANCE Although the interferon (IFN) signaling pathway is a key host mechanism to restrict infection of a diverse range of viral pathogens, its unrestrained activity either at baseline or in the context of an immune response can result in host cell damage and injury. Here, we used a genome-wide CRISPR-Cas9 screen and identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1) as a modulator of basal cell-intrinsic immunity. A loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline, which triggered IFN-stimulated gene expression via a cGAS-STING-IRF3 axis that did not require type I IFN or STAT1 signaling. Our experiments define a regulatory network in which Banf1 limits basal inflammation by preventing self DNA accumulation in the cytosol.

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“…Mouse studies identified critical roles for T-bet and Eomes in the transition from CD27b + CD11bto CD27 -CD11b + cells, but the intracellular signaling pathways leading to activation of these transcription factors are still not understood 10,11 . Collin et al, described transcriptional differences between three functional distinct human NK cell subsets (CD56 bright , CD57 -CD56 dim , CD57 + CD56 dim ) and identified subset specific transcriptional regulators which were shared with the T cell lineage and thus evolutionarily conserved 12 . However, the molecular programs involved in maintaining NK cell repertoire diversity under homeostatic conditions remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

Pfefferle

Jacobs

Ask

et al. 2019

Preprint

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One Sentence Summary: High-resolution flow cytometry combined with single-cell RNA sequencing reveal a role for intra-lineage plasticity and functional reprogramming in maintaining phenotypically and functionally diverse NK cell repertoires during IL-15-driven homeostatic proliferation. 2 Abstract Natural killer (NK) cell repertoires are made up of a vast number of phenotypically distinct subsets with different functional properties. The molecular programs involved in maintaining NK cell repertoire diversity under homeostatic conditions remains elusive. Here we show that subsetspecific NK cell proliferation kinetics correlate with mTOR activation, and that global repertoire diversity is maintained through a high degree of intra-lineage subset plasticity during IL-15-driven homeostatic proliferation in vitro. High-resolution flow cytometry and single cell RNA sequencing revealed that slowly cycling sorted KIR + CD56 dim NK cells with an induced CD57 phenotype display increased functional potential associated with inhibitory MHC interactions and activating DAP12 signaling. In contrast, rapidly cycling cells upregulate NKG2A and display a general loss of functionality associated with a transcriptional increase in RNA-binding metabolic enzymes and cytokine signaling pathways. These results shed new light on the role of intra-lineage plasticity during NK cell homeostasis and suggest that the functional fate of the cell is tightly linked to the acquired phenotype and determined by transcriptional reprogramming.

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Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells

Cited by 138 publications

References 79 publications

Tissue Determinants of Human NK Cell Development, Function, and Residence

Tissue Determinants of Human NK Cell Development, Function, and Residence

Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

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