Abstract
Distinct Notch ligands possess a characteristic ability in terms of functional T cell differentiation. However, the precise role or the therapeutic potential of each Notch ligand in autoimmune diseases is largely unknown. In this study, we examined whether Jagged1 modulates a collagen-induced rheumatoid arthritis (CIA) model by altering T cell responses. The injection of a soluble Jagged1-encoding plasmid, sJag1-P, before or even after initial type II collagen (CII) immunization suppressed the disease severity of CIA. However, this treatment did not suppress CII-specific CD4(+) T cell proliferation and CII-specific Ab production. Depletion of either CD4(+) or CD8(+) T cells ameliorated CIA severity and sJag1-P further improved CIA in CD4(+) but not CD8(+) T cell-depleted mice. Injection of OVA and Jagged1-encoding plasmids inhibited proliferation of OVA-specific granzyme B-producing CD8(+) T cells, although Jagged1 could not directly inhibit CD8(+) T cell proliferation in vitro. The blockade of Jagged1 by an anti-Jagged1 Ab exacerbated CIA, whereas this effect was not observed in the absence of CD8(+) T cells. These data indicate that Jagged1 is able to deliver an indirect negative signal into CD8(+) T cells in vivo, which suggests its therapeutic potential in the treatment of CD8(+) T cell-mediated diseases, including rheumatoid arthritis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis, Experimental / immunology*
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Arthritis, Experimental / pathology
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Arthritis, Experimental / therapy*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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Calcium-Binding Proteins / administration & dosage
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / physiology*
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Calcium-Binding Proteins / therapeutic use*
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Cell Line
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Cells, Cultured
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Down-Regulation / genetics
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Down-Regulation / immunology
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology
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Growth Inhibitors / therapeutic use*
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Humans
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Intercellular Signaling Peptides and Proteins / administration & dosage
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / physiology*
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Intercellular Signaling Peptides and Proteins / therapeutic use*
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Jagged-1 Protein
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Jurkat Cells
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphocyte Depletion
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Male
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Membrane Proteins / administration & dosage
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Membrane Proteins / therapeutic use*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Plasmids / administration & dosage
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Plasmids / genetics
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Plasmids / therapeutic use
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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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Vaccines, DNA / administration & dosage
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Vaccines, DNA / genetics
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Vaccines, DNA / therapeutic use
Substances
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Calcium-Binding Proteins
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Growth Inhibitors
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Intercellular Signaling Peptides and Proteins
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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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Membrane Proteins
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Serrate-Jagged Proteins
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Vaccines, DNA