Abstract
Previous studies have shown that the Notch1 and TGF-beta signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-beta signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-beta signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-beta signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-beta-mediated effector function of Tregs.
MeSH terms
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Animals
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Calcium-Binding Proteins / biosynthesis
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Line
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Cell Line, Tumor
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Cells, Cultured
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Coculture Techniques
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Female
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Growth Inhibitors / antagonists & inhibitors
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Growth Inhibitors / biosynthesis
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Growth Inhibitors / immunology
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Growth Inhibitors / physiology
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HT29 Cells
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Humans
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Immune Sera / pharmacology
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Interleukin-2 Receptor alpha Subunit / biosynthesis
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Interleukin-2 Receptor alpha Subunit / metabolism
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Jagged-1 Protein
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Jurkat Cells
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Ligands
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mink
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Receptor, Notch1 / antagonists & inhibitors
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Receptor, Notch1 / biosynthesis
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Receptor, Notch1 / immunology
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Receptor, Notch1 / physiology*
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Serrate-Jagged Proteins
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Signal Transduction / immunology*
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism*
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / physiology
Substances
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Calcium-Binding Proteins
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Growth Inhibitors
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Immune Sera
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Intercellular Signaling Peptides and Proteins
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Interleukin-2 Receptor alpha Subunit
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Ligands
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Membrane Proteins
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Receptor, Notch1
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Serrate-Jagged Proteins
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Transforming Growth Factor beta