Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation.
Dendritic cells (DCs) play a key role in the activation and regulation of B and T lymphocytes. Production of indoleamine 2, 3-dioxygenase (IDO) by macrophages has recently been described to result in inhibition of T cell proliferation through tryptophan degradation. Since DCs can be derived from monocytes, we sought to determine whether DCs could produce IDO which could potentially regulate T cell proliferation. Northern blot analysis of RNA from cultured monocyte-derived human DC revealed that IDO mRNA was induced upon activation with CD40 ligand and IFN-gamma. IDO produced from activated DCs was functionally active and capable of metabolizing tryptophan to kynurenine. Activated T cells were also capable of inducing IDO production by DCs, which was inhibited by a neutralizing Ab against IFN-gamma. DC production of IDO resulted in inhibition of T cell proliferation, which could be prevented using the IDO inhibitor 1-methyl-dl -tryptophan. These results suggest that activation of DCs induces the production of functional IDO, which causes depletion of tryptophan and subsequent inhibition of T cell proliferation. This may represent a potential mechanism for DCs to regulate the immune response.
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Surgery Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
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Lapointe
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Taylor
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Young
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D023201:CD40 Ligand; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology*; D004338:Drug Combinations; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D007737:Kynurenine / Q000302:isolation & purification / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D023201:CD40 Ligand; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase