Abstract
Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance. Here we report the novel finding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 deficiency breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation, respectively. All of these effects of Tph-1 deficiency are independent of its downstream product serotonin. Because mast cells (MCs) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect, these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Flow Cytometry
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Gene Expression
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Immune Tolerance / genetics
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Immune Tolerance / immunology*
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Inflammation / genetics
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Inflammation / immunology*
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Male
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Mast Cells / immunology*
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Mast Cells / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / pathology
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Reverse Transcriptase Polymerase Chain Reaction
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Skin Transplantation / immunology
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TOR Serine-Threonine Kinases / immunology
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TOR Serine-Threonine Kinases / metabolism
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Transplantation, Homologous
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Tryptophan / blood
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Tryptophan / metabolism
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Tryptophan Hydroxylase / deficiency
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Tryptophan Hydroxylase / genetics
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Tryptophan Hydroxylase / immunology*
Substances
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Tryptophan
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Tph1 protein, mouse
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Tryptophan Hydroxylase
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TOR Serine-Threonine Kinases