title: Modulation of invariant natural killer T cell cytokine responses by indoleamine 2,3-dioxygenase.
abstract: The intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which degrades the rare and essential amino acid tryptophan and converts it into a series of biologically active catabolites, has been linked to the regulation of immune tolerance by specific dendritic cell subsets, and to the downmodulation of exacerbated immune responses. Although the immunoregulatory effects of IDO may be in part due to generalized suppression of cell proliferation caused by tryptophan starvation, there is also evidence that tryptophan catabolites could be directly responsible for some of the observed effects. In this report, we investigated the consequences of IDO activity, particularly with regard to the effects of tryptophan-derived catabolites, on the cytokine responses of activated invariant natural killer T (iNKT) cells, a specialized T cell subset known to have immunoregulatory properties. Our results showed that pharmacologic inhibition of IDO skewed cytokine responses of iNKT cells towards a Th1 profile. In contrast, the presence at low micromolar concentrations of the tryptophan catabolites l-kynurenine, 3-hydroxy-kynurenine, or 3-hydroxy-anthranilic acid shifted the cytokine balance towards a Th2 pattern. These findings have implications for our current understanding of immunoregulation, and the mechanisms by which iNKT cells participate in the modulation of immune responses.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Molano
authors.forename: Petr A
authors.initials: PA
authors.lastname: Illarionov
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017635:Clonal Anergy; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D007737:Kynurenine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D005699:Galactosylceramides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C493154:alpha-galactosylceramide; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan