T cell apoptosis by tryptophan catabolism.
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. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We show here 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 of 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 caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data suggest that the selective deletion of T lymphocytes may be a major mechanism whereby tryptophan metabolism affects immunity under physiopathologic conditions.
Fallarino
F
F
Department of Experimental Medicine, University of Perugia, Italy.
Grohmann
U
U
Vacca
C
C
Bianchi
R
R
Orabona
C
C
Spreca
A
A
Fioretti
M C
MC
Puccetti
P
P
D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007737:Kynurenine / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017378:Quinolinic Acid / Q000378:metabolism / Q000494:pharmacology; D017634:Self Tolerance / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014364:Tryptophan / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D019014:fas Receptor; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D014364:Tryptophan; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D017378:Quinolinic Acid