CTLA-4-Ig regulates tryptophan catabolism in vivo.
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.
D000069594:Abatacept; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002478:Cells, Cultured / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D003713:Dendritic Cells / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology* / Q000633:toxicity; D007074:Immunoglobulin G / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D007519:Isoantigens / Q000276:immunology; D007737:Kynurenine / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007519:Isoantigens; D016328:NF-kappa B; D010455:Peptides; D011725:Pyridines; D011993:Recombinant Fusion Proteins; C118258:SN50 peptide; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007737:Kynurenine; D000069594:Abatacept; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole