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IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation

Lookup NU author(s): Emeritus Professor Andrew MellorORCiD

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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.

Publication metadata

Author(s): Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LMF, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC

Publication type: Article

Publication status: Published

Journal: International Immunology

Year: 2014

Volume: 26

Issue: 7

Pages: 357-367

Print publication date: 07/07/2014

Online publication date: 08/01/2014

Acceptance date: 16/12/2013

ISSN (print): 0953-8178

ISSN (electronic): 1460-2377

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/intimm/dxt073

DOI: 10.1093/intimm/dxt073

PubMed id: 24402311

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