title: Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines.
abstract: Production of indoleamine 2,3-dioxygenase (IDO) by tumor cells, leading to tryptophan depletion and production of immunosuppressive metabolites, may facilitate immune tolerance of cancer. IDO gene is also expressed in dendritic cells (DC) upon maturation induced by lipopolysaccarides or IFN. We investigated IDO gene expression in melanoma cell lines and clinical specimens as compared to mature DC (mDC). Furthermore, we explored effects of L-kynurenine (L-kyn) and 3-hydroxyanthranilic acid (3-HAA) on survival and antigen-dependent and independent proliferation of CD8(+) cells. We observed that IDO gene expression in cultured tumor cells and freshly excised samples is orders of magnitude lower than in mDC, providing highly efficient antigen presentation to CD8(+) T cells. Non toxic concentrations of L-kyn or 3-HAA did not significantly inhibit antigen-specific CTL responses. However, 3-HAA, but not L-kyn markedly inhibited antigen-independent proliferation of CD8(+) T cells induced by common receptor gamma-chain cytokines IL-2, -7 and -15. Our data suggest that CD8(+) T cell activation induced by antigenic stimulation, a function exquisitely fulfilled by mDC, is unaffected by tryptophan metabolites. Instead, in the absence of effective T cell receptor triggering, 3-HAA profoundly affects homeostatic proliferation of CD8(+) T cells.
authors.affiliation: Institut für Chirurgische Forschung und Spitalmanagement and Department Forschung, University of Basel, Basel, Switzerland.
authors.forename: Walter P
authors.initials: WP
authors.lastname: Weber
authors.forename: Chantal
authors.initials: C
authors.lastname: Feder-Mengus
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
authors.forename: Rachel
authors.initials: R
authors.lastname: Rosenthal
authors.forename: Anca
authors.initials: A
authors.lastname: Reschner
authors.forename: Reto
authors.initials: R
authors.lastname: Schumacher
authors.forename: Paul
authors.initials: P
authors.lastname: Zajac
authors.forename: Heidi
authors.initials: H
authors.lastname: Misteli
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Frey
authors.forename: Daniel
authors.initials: D
authors.lastname: Oertli
authors.forename: Michael
authors.initials: M
authors.lastname: Heberer
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D016166:Free Radical Scavengers / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D016166:Free Radical Scavengers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D014364:Tryptophan