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Int Immunol. 2014 Jul;26(7):357-67. doi: 10.1093/intimm/dxt073. Epub 2014 Jan 8.

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

Author information

1
New Link Genetics Corporation, Ames, IA 50010, USA.
2
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
3
Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA.
4
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
5
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
6
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.

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.

KEYWORDS:

adaptive immunity; contact hypersensitivity; inflammation; tolerance

PMID:
24402311
PMCID:
PMC4432394
DOI:
10.1093/intimm/dxt073
[Indexed for MEDLINE]
Free PMC Article

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