title: IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation.
abstract: IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice. No apparent defects were observed in Ido2 (-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2 (-/-) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.
authors.affiliation: New Link Genetics Corporation, Ames, IA 50010, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Metz
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Smith
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.affiliation: Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Chandler
authors.affiliation: Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: Lauren M F
authors.initials: LM
authors.lastname: Merlo
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pigott
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Keough
authors.affiliation: New Link Genetics Corporation, Ames, IA 50010, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Rust
authors.affiliation: Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Mandik-Nayak
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA Department of Pathology, Anatomy and Cell Biology, Jefferson Medical School, Thomas Jefferson University, Philadelphia, PA 19107, USA prendergast@limr.org.
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007737:Kynurenine; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives; D058408:Th1-Th2 Balance
chemical_list: D002273:Carcinogens; D016207:Cytokines; C583637:IDO1 protein, mouse; C586429:IDO2 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D015127:9,10-Dimethyl-1,2-benzanthracene; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D013755:Tetradecanoylphorbol Acetate
keywords: adaptive immunity; contact hypersensitivity; inflammation; tolerance