CTLA-4-Ig regulates tryptophan catabolism in vivo

Nat Immunol. 2002 Nov;3(11):1097-101. doi: 10.1038/ni846. Epub 2002 Sep 30.

Abstract

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) plays a critical role in peripheral tolerance. However, regulatory pathways initiated by the interactions of CTLA-4 with B7 counterligands expressed on antigen-presenting cells are not completely understood. We show here that long-term survival of pancreatic islet allografts induced by the soluble fusion protein CTLA-4-immunoglobulin (CTLA-4-Ig) is contingent upon effective tryptophan catabolism in the host. In vitro, we show that CTLA-4-Ig regulates cytokine-dependent tryptophan catabolism in B7-expressing dendritic cells. These data suggest that modulation of tryptophan catabolism is a means by which CTLA-4 functions in vivo and that CTLA-4 acts as a ligand for B7 receptor molecules that transduce intracellular signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Antigen Presentation / drug effects
  • Antigens, CD
  • Antigens, Differentiation / physiology*
  • B7-1 Antigen / immunology
  • B7-1 Antigen / metabolism
  • CTLA-4 Antigen
  • Cells, Cultured / metabolism
  • DNA-Binding Proteins / physiology
  • Dendritic Cells / classification
  • Dendritic Cells / drug effects*
  • Dendritic Cells / metabolism
  • Diabetes Mellitus, Experimental / surgery
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Graft Enhancement, Immunologic*
  • Graft Survival / drug effects
  • Imidazoles / pharmacology
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology
  • Immunoconjugates / pharmacology*
  • Immunoconjugates / toxicity
  • Immunoglobulin G / pharmacology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / physiology
  • Islets of Langerhans Transplantation*
  • Isoantigens / immunology
  • Kynurenine / biosynthesis
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Peptides / pharmacology
  • Pyridines / pharmacology
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use
  • STAT1 Transcription Factor
  • Trans-Activators / physiology
  • Transplantation, Homologous / immunology
  • Tryptophan / metabolism*
  • Tryptophan Oxygenase / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Imidazoles
  • Immunoconjugates
  • Immunoglobulin G
  • Isoantigens
  • NF-kappa B
  • Peptides
  • Pyridines
  • Recombinant Fusion Proteins
  • SN50 peptide
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Kynurenine
  • Abatacept
  • Interferon-gamma
  • Tryptophan
  • Tryptophan Oxygenase
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole