Abstract
Indoleamine-2,3-dioxygenase (IDO) and tryptophanyl-tRNA-synthetase (TTS) are interferon-gamma (IFN-gamma)-inducible enzymes that are responsible for tryptophan degradation and for its use in protein synthesis, respectively. IFN-gamma-induced IDO has immunomodulatory properties in murine and human models. A concomitant increase of TTS has been postulated to protect the IDO-expressing cells from tryptophan catabolism. IDO can be induced in dendritic cells (DCs) by recombinant soluble cytotoxic T lymphocyte antigen-4 (CTLA-4-Fc). We investigated the effects of CTLA-4-Fc on IDO and TTS mRNA expression in human peripheral blood mononuclear cells (PBMCs) and isolated leukocyte subsets. CTLA-4-Fc exposure induced increased IDO and TTS expression in unseparated PBMCs, as well as in monocyte-derived mature DCs. CD4(+) T cells isolated from CTLA-4-Fc-treated PBMCs showed increased IDO and TTS compared with untreated cells. CD8(+) T cells from CTLA-4-Fc-treated PBMCs expressed increased levels of TTS but not IDO. Pretreatment of PBMCs with CTLA-4-Fc inhibited the activation of CD4(+) T cells induced by influenza A virus (Flu) or phytohemagglutinin A (PHA), but had no effect on CD8(+) T cells. This is the first report of IDO and TTS regulation by the CTLA-4-B7 system in human CD4(+) and CD8(+) T cells, and raises the possibility that these 2 tryptophan-modulating enzymes provide an important mechanism for regulating immune responses.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Antigens, CD / metabolism
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B7-1 Antigen / metabolism
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B7-2 Antigen
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CD4-Positive T-Lymphocytes / enzymology*
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CD4-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / enzymology
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CD8-Positive T-Lymphocytes / immunology
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Cell Separation
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Cell-Free System / metabolism
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Cells, Cultured
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Dendritic Cells / enzymology
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Dendritic Cells / immunology
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Humans
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Immunoconjugates / metabolism
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Immunoconjugates / pharmacology*
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Immunosuppressive Agents / metabolism
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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-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Kynurenine / metabolism
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Leukocytes, Mononuclear / enzymology
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lymphocyte Activation / immunology
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Membrane Glycoproteins / metabolism
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Monocytes / enzymology
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Monocytes / immunology
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Protein Binding / immunology
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RNA, Messenger / biosynthesis
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Tryptophan / metabolism
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Tryptophan / physiology
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Tryptophan Oxygenase / biosynthesis
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Tryptophan Oxygenase / genetics
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Tryptophan Oxygenase / metabolism*
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Tryptophan-tRNA Ligase / biosynthesis
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Tryptophan-tRNA Ligase / genetics
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Tryptophan-tRNA Ligase / metabolism*
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Up-Regulation / immunology
Substances
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Antigens, CD
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B7-1 Antigen
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B7-2 Antigen
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CD86 protein, human
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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-2
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Membrane Glycoproteins
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RNA, Messenger
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Kynurenine
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Abatacept
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Interferon-gamma
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Tryptophan
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Tryptophan Oxygenase
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Tryptophan-tRNA Ligase