ArticleNature immunology2024
Optimization of the Irf8 +32-kb enhancer disrupts dendritic cell lineage segregation.
Article in Nature immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed.
- ID2 secures cDC1 specification by antagonizing E proteins at a pleiotropic Zeb2 enhancer.Nature immunology · 2026Article
- Biomimetic nanodecoys remodel the mechano-immune microenvironment to potentiate checkpoint blockade in colorectal cancer.Journal of nanobiotechnology · 2026Article
- A proposed convergent molecular chain linking senescence, cancer, and chronic infection to a correctable failure of dendritic cell instruction.Frontiers in immunology · 2026Review
- Glycolysis in the tumor microenvironment shapes dendritic cell function and antitumor immunity.Frontiers in immunology · 2026Review
- ID2 secures cDC1 specification by antagonizing E proteins at a pleiotropicResearch square · 2025Article
- Rewriting the dendritic cell code in cancer-from subset identity to immunotherapeutic design.FEBS letters · 2025Review
- C/EBPα activatesScience immunology · 2025Article
- Evolving Rel.Nature immunology · 2025Article
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
Autoactivation of lineage-determining transcription factors mediates bistable expression, generating distinct cell phenotypes essential for complex body plans. Classical type 1 dendritic cell (cDC1) and type 2 dendritic cell (cDC2) subsets provide nonredundant functions for defense against distinct immune challenges. Interferon regulatory factor 8 (IRF8), the cDC1 lineage-determining transcription factor, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32-kb enhancer, responsible for IRF8 autoactivation, is naturally suboptimized with low-affinity IRF8 binding sites. Introducing multiple high-affinity IRF8 sites into the Irf8 +32-kb enhancer causes a gain-of-function effect, leading to erroneous IRF8 autoactivation in specified cDC2 progenitors, redirecting them toward cDC1 and a novel hybrid DC subset with mixed-lineage phenotypes. Further, this also causes a loss-of-function effect, reducing Irf8 expression in cDC1s. These developmental alterations critically impair both cDC1-dependent and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of cDCs required for normal immune function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.