T cell apoptosis by tryptophan catabolism

Cell Death Differ. 2002 Oct;9(10):1069-77. doi: 10.1038/sj.cdd.4401073.

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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyanthranilic Acid / metabolism
  • 3-Hydroxyanthranilic Acid / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Autoimmune Diseases / immunology*
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cells, Cultured
  • Cytochrome c Group / drug effects
  • Cytochrome c Group / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Kynurenine / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Microscopy, Electron
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Quinolinic Acid / metabolism
  • Quinolinic Acid / pharmacology
  • Self Tolerance / immunology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / ultrastructure
  • Th1 Cells / drug effects
  • Th1 Cells / metabolism
  • Th1 Cells / ultrastructure
  • Thymus Gland / drug effects
  • Thymus Gland / metabolism
  • Thymus Gland / ultrastructure
  • Tryptophan / metabolism*
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Caspase Inhibitors
  • Cytochrome c Group
  • fas Receptor
  • 3-Hydroxyanthranilic Acid
  • Kynurenine
  • Tryptophan
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 8
  • Caspase 9
  • Caspases
  • Quinolinic Acid