Abstract
Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Animals
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Proliferation
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Clonal Anergy
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Dendritic Cells / immunology
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Enzyme Activation
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In Vitro Techniques
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Lymphocyte Culture Test, Mixed
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Protein Kinases / deficiency
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases
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Signal Transduction
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T-Lymphocytes / cytology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology
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Transcription Factor CHOP
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tryptophan / pharmacology
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Tryptophan Oxygenase / genetics
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Tryptophan Oxygenase / metabolism*
Substances
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CCAAT-Enhancer-Binding Proteins
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Ddit3 protein, mouse
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Transcription Factors
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Transcription Factor CHOP
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Tryptophan
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Tryptophan Oxygenase
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Protein Kinases
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Eif2ak4 protein, mouse
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Protein Serine-Threonine Kinases