ArticleJournal of immunology (Baltimore, Md. : 1950)2016
The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation.
Article in Journal of immunology (Baltimore, Md. : 1950), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- Notch signaling in the tumor microenvironment: recent advances and targeted therapeutics.Molecular cancer · 2026Review
- Identification of distinct cDC2 subpopulations that direct microbiota-specific T cell differentiation.bioRxiv : the preprint server for biology · 2025Article
- Promoting ER stress in a plasmacytoid dendritic cell line drives fibroblast activation.Cell communication and signaling : CCS · 2025Article
- Notch signalling in T cells: bridging tumour immunity and intratumoral cellular crosstalk.Frontiers in immunology · 2025Review
- Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies?Cancer cell international · 2024Review
- Inhibition of DLL4/Notch Signaling Pathway Promotes M2 Polarization and Cell Proliferation in Pulmonary Arterial Hypertension.ACS omega · 2024Article
- Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis.Frontiers in immunology · 2024Review
- The Notch signaling pathway: a potential target for cancer immunotherapy.Journal of hematology & oncology · 2023Review
- Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy.Frontiers in molecular biosciences · 2023Review
- The role of the Notch signalling pathway in the pathogenesis of ulcerative colitis: from the perspective of intestinal mucosal barrier.Frontiers in medicine · 2023Review
- The protective and pathogenic role of Th17 cell plasticity and function in the tumor microenvironment.Frontiers in immunology · 2023Review
- Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn's disease.Communications biology · 2022Article
- Migrating Type 2 Dendritic Cells Prime Mucosal Th17 Cells Specific to Small Intestinal Commensal Bacteria.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation.Nature communications · 2022Article
- Article
- Intravenous Immunoglobulin Therapy Restores the Quantity and Phenotype of Circulating Dendritic Cells and CD4Frontiers in immunology · 2022Article
- hsa-miR-518-5p/hsa-miR-3135b Regulates the REL/SOD2 Pathway in Ischemic Cerebral Infarction.Frontiers in neurology · 2022Article
- Alloantigen-activated (AAA) CD4Journal of experimental & clinical cancer research : CR · 2021Article
- Sepsis Inflammation Impairs the Generation of Functional Dendritic Cells by Targeting Their Progenitors.Frontiers in immunology · 2021Article
- CD28 Signaling Drives Notch Ligand Expression on CD4 T Cells.Frontiers in immunology · 2020Article
Corrections and comments
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Authors and funding
19 authors at 10 institutions in 4 countries.
Funding
Abstract
Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor-derived CD1c(+) DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Th1 and Th17 cells. Both NF-κB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.
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