title: Tryptophan hydroxylase-1 regulates immune tolerance and inflammation.
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.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Nowak
authors.forename: Victor C
authors.initials: VC
authors.lastname: de Vries
authors.forename: Anna
authors.initials: A
authors.lastname: Wasiuk
authors.forename: Cory
authors.initials: C
authors.lastname: Ahonen
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Bennett
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Mercier
authors.forename: Dae-Gon
authors.initials: DG
authors.lastname: Ha
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D014364:Tryptophan / Q000097:blood / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D014364:Tryptophan; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D058570:TOR Serine-Threonine Kinases