Abstract
Tryptophan catabolism is a tolerogenic effector system in regulatory T cell function, yet the general mechanisms whereby tryptophan catabolism affects T cell responses remain unclear. We provide evidence that the short-term, combined effects of tryptophan deprivation and tryptophan catabolites result in GCN2 kinase-dependent down-regulation of the TCR zeta-chain in murine CD8+ T cells. TCR zeta down-regulation can be demonstrated in vivo and is associated with an impaired cytotoxic effector function in vitro. The longer-term effects of tryptophan catabolism include the emergence of a regulatory phenotype in naive CD4+CD25- T cells via TGF-beta induction of the forkhead transcription factor Foxp3. Such converted cells appear to be CD25+, CD69-, CD45RBlow, CD62L+, CTLA-4+, BTLAlow and GITR+, and are capable of effective control of diabetogenic T cells when transferred in vivo. Thus, both tryptophan starvation and tryptophan catabolites contribute to establishing a regulatory environment affecting CD8+ as well as CD4+ T cell function, and not only is tryptophan catabolism an effector mechanism of tolerance, but it also results in GCN2-dependent generation of autoimmune-preventive regulatory T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD
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Antigens, Differentiation / physiology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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CTLA-4 Antigen
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Cells, Cultured
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Coculture Techniques
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Down-Regulation / immunology*
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Female
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Forkhead Transcription Factors / biosynthesis
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Forkhead Transcription Factors / metabolism
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Immunophenotyping*
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Interleukin-10 / physiology
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Kynurenine / metabolism
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Kynurenine / pharmacology
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / biosynthesis*
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Mice
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Mice, Inbred DBA
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Mice, Transgenic
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Protein Kinases / physiology
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Protein Serine-Threonine Kinases
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Receptors, Antigen, T-Cell / antagonists & inhibitors*
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Receptors, Antigen, T-Cell / biosynthesis*
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Interleukin-2 / metabolism
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Resting Phase, Cell Cycle / immunology*
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocyte Subsets / pathology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta / physiology
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Tryptophan / metabolism*
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Tryptophan / physiology
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Membrane Proteins
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Receptors, Antigen, T-Cell
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Receptors, Interleukin-2
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Transforming Growth Factor beta
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antigen T cell receptor, zeta chain
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Interleukin-10
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Kynurenine
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Tryptophan
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Protein Kinases
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Eif2ak4 protein, mouse
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Protein Serine-Threonine Kinases