Abstract
CTLA-4-Ig and CD28-Ig are both agonist ligands of B7 coreceptor molecules on mouse dendritic cells (DCs), yet they bias the downstream response in opposite directions, and CTLA-4-Ig promotes tolerance, whereas CD28-Ig favors the onset of immunity. Although B7 engagement by either ligand leads to a mixed cytokine response, a dominant IL-6 production in response to CD28-Ig prevents the IFN-gamma-driven induction of immunosuppressive tryptophan catabolism mediated by IDO. In the present study, we show that silencing the expression of suppressor of cytokine signaling 3 (SOCS3) in DCs by RNA interference renders CD28-Ig capable of activating IDO, likely as a result of unrestrained IFN-gamma signaling and IFN-gamma-like actions of IL-6. Thus, in the absence of SOCS3, CD28-Ig becomes immunosuppressive and mimics the action of CTLA-4-Ig on tryptophan catabolism.
MeSH terms
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Abatacept
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Adjuvants, Immunologic / physiology*
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Animals
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Antigen Presentation / immunology
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CD28 Antigens / pharmacology*
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CD8 Antigens / biosynthesis
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DNA-Binding Proteins / metabolism
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Dendritic Cells / enzymology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Female
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Gene Silencing* / immunology
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Immunoconjugates / pharmacology
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Immunosuppressive Agents* / pharmacology
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Interferon-gamma / physiology
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Interleukin-6 / pharmacology
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Mice
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Mice, Inbred DBA
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Phosphorylation
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics*
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STAT3 Transcription Factor
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency
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Transcription Factors / genetics*
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Tryptophan / metabolism
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Tryptophan Oxygenase / biosynthesis
Substances
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Adjuvants, Immunologic
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CD28 Antigens
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CD8 Antigens
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DNA-Binding Proteins
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Immunoconjugates
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Immunosuppressive Agents
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Interleukin-6
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Repressor Proteins
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Abatacept
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Interferon-gamma
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Tryptophan
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Tryptophan Oxygenase