title: T cell apoptosis by kynurenines.
abstract: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. The discovery that inhibition of IDO activity reduces the survival of MHC-mismatched fetuses in mice and that the risk of fetal allograft rejection correlates with the degree of parental tissue incompatibility has led to the hypothesis that IDO activity protects fetal allografts from maternal T cell-mediated immunity. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We have found that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions and was associated with the activation of casapase-8 and the release of cytochrome c from mitochondria. In vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data may represent the first experimental evidence for the involvement of tryptophan catabolism in the regulation of T cell apoptosis and maintenance of peripheral T cell tolerance.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Italy. fllfnc@tin.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.forename: Antonio
authors.initials: A
authors.lastname: Spreca
authors.forename: Maria C
authors.initials: MC
authors.lastname: Fioretti
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007737:Kynurenine / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D017634:Self Tolerance / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007737:Kynurenine; D014364:Tryptophan