Transcription Factor PU.1 Promotes Conventional Dendritic Cell Identity and Function via Induction of Transcriptional Regulator DC-SCRIPT

Chopin, Michaël; Lun, Aaron T. L.; Zhan, Yifan; Schreuder, Jaring; Coughlan, Hannah D.; D’Amico, Angela; Mielke, Lisa A.; Almeida, Francisca F.; Kueh, Andrew J.; Dickins, Ross A.; Belz, Gabrielle T.; Naik, Shalin H.; Lew, Andrew M.; Bouillet, Phillipe; Herold, Marco J.; Smyth, Gordon K.; Corcoran, Lynn M.; Nutt, Stephen L.

doi:10.1016/j.immuni.2018.11.010

Cited by 67 publications

(61 citation statements)

References 64 publications

(74 reference statements)

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“…They also found that the pioneer factors Cebpb and Hif1 were involved in inflammatory gene expression (TNF and ROS), whereas PU.1 led to their downregulation (96). The latter result was consistent with the recent finding by Chopin et al that PU.1 is involved in conventional dendritic-cell development (102). Next, they confirmed the known roles of Stat1/2 in the activation of the antiviral response and the roles of Rel, Irf2, and Atf3 in its suppression.…”

Section: Single-cell Screens With Crisprsupporting

confidence: 86%

Genome editing of immune cells using CRISPR/Cas9

et al. 2021

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The ability to read, write, and edit genomic information in living organisms can have a profound impact on research, health, economic, and environmental issues. The CRISPR/Cas system, recently discovered as an adaptive immune system in prokaryotes, has revolutionized the ease and throughput of genome editing in mammalian cells and has proved itself indispensable to the engineering of immune cells and identification of novel immune mechanisms. In this review, we summarize the CRISPR/Cas9 system and the history of its discovery and optimization. We then focus on engineering T cells and other types of immune cells, with emphasis on therapeutic applications. Last, we describe the different modifications of Cas9 and their recent applications in the genome-wide screening of immune cells.

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Section: Single-cell Screens With Crisprsupporting

confidence: 86%

Genome editing of immune cells using CRISPR/Cas9

et al. 2021

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“…Irf8 are expressed in cells that are further differentiated (36,37). This suggests that Flt3 high MPPs are less differentiation-prone than Flt3 mod MPPs.…”

Section: Resultsmentioning

confidence: 99%

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

Tian¹,

Meng²,

Wang³

et al. 2021

Journal of Clinical Investigation

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Graft-versus-host disease (GVHD) causes failed reconstitution of donor plasmacytoid dendritic cells (pDCs) that are critical for immune protection and tolerance. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type-I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-γ. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD. Figure 2. GVHD causes loss of DC progenitors. (A-B) B6 TCD-BM (5 × 10 6) was transplanted with or without CD4 + T cells (5 × 10), into lethally irradiated BALB/C mice to induce GVHD. (A) Percentages and number of MPPs and CDPs in the BM from normal, TCD-BM and T cell recipients, each group contained 4 to 10 mice pooled from at least independent three experiments. (B) MPPs and CDPs were FACS-sorted from normal and GVHD mice (CD45.2 +) and cultured with feeder cells (BM from B6/SJL mice, CD45.1 +) in the presence of Flt3L+SCF. MPPs and CDPs were cultured for 9 days and 3 days, respectively. Percentages and numbers of pDCs were measured. (C-D) BM cells were obtained from HD and allo-HSCT patients. (C) Plots show pDC and cDC gating strategy. Plots show phenotypes of human CD34 + HSPCs from HD (n=12), grades 0-I GVHD patients (n=7) and grades II-IV GVHD patients (n=8), (D) Graphs show the percentages of human MPPs and CDPs from healthy donors (HD) (n=12), grades 0-I GVHD patients (n=8) and grades II-IV GVHD patients (n=9). Multiple comparisons by One-way ANOVA with Boferroni's multiple comparisons test (A), two group comparisons by unpaired t test (two-tailed) (B), and multiple comparisons by Kruskal-Wallis test with Dunne's multiple comparison test (D). Data shown are mean ± SD. Results shown in A and B are representative of three independent experiments.

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“…2c , d ). Other factors impacting DC development such as Bcl11a, Spi1, Klf4 , and Notch2 29 , 30 , 31 , 32 were not differentially expressed across the CDP, perhaps suggesting that specification of cDC2s and pDCs occurs after the CDP ( Fig. 2d , Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development

et al. 2019

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Classical type 1 dendritic cells (cDC1s) are required for anti-viral and anti-tumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E protein–dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor IRF8 (+41 kb Irf8 enhancer) but its maturation instead requires the BATF3-dependent +32 kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 , and Zeb2 . Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2 hi and Id2 lo CDPs to Zeb2 lo and Id2 hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E protein activity to exclude plasmacytoid DC potential and explains the switch in Irf8 enhancer usage during cDC1 development.

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Transcription Factor PU.1 Promotes Conventional Dendritic Cell Identity and Function via Induction of Transcriptional Regulator DC-SCRIPT

Cited by 67 publications

References 64 publications

Genome editing of immune cells using CRISPR/Cas9

Genome editing of immune cells using CRISPR/Cas9

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development

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