Abstract
A growing body of literature indicates that the Notch pathway can influence the activation and differentiation of peripheral murine T cells, though comparatively little is known about the effects of Notch signaling in human T cells. In the present report we demonstrate that Jagged-1-induced Notch signaling (using immobilized Jagged-1 fusion protein) during stimulation of purified human CD4+ and CD8+ T cells potently inhibits T cell proliferation and effector function, including both Th1- and Th2-associated cytokines. Inhibition of T cell activation is not due to apoptosis or disruption of proximal TCR signaling, but is associated with up-regulation of GRAIL (gene related to anergy in lymphocytes) in CD4+ T cells, with modest effects on other E3 ubiquitin ligases such as c-Cbl and Itch. When evaluated for its effects on CD4+ T cell differentiation, Jagged-1-mediated signaling inhibits T cell cytokine secretion with no significant effect on proliferative responses. Collectively, these data demonstrate that Notch signaling in human T cells induced by Jagged-1 promotes a novel form of T cell hyporesponsiveness that differs from anergy, whereby primary T cell proliferation and cytokine secretion are potently inhibited, and effector function but not proliferative capacity are ameliorated upon secondary stimulation.
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Calcium-Binding Proteins / biosynthesis
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / physiology
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Cell Proliferation
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Clonal Anergy / genetics*
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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Cytokines / genetics
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Humans
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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 / physiology
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Jagged-1 Protein
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Rats
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Receptors, Notch / metabolism
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Receptors, Notch / physiology*
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Serrate-Jagged Proteins
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Ubiquitin-Protein Ligases / biosynthesis*
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Ubiquitin-Protein Ligases / genetics*
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Up-Regulation / genetics*
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Up-Regulation / immunology
Substances
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Calcium-Binding Proteins
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Cytokines
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, rat
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Jagged-1 Protein
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Membrane Proteins
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Receptors, Notch
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Serrate-Jagged Proteins
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RNF128 protein, human
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Ubiquitin-Protein Ligases