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

Metz R1, Smith C2, DuHadaway JB2, Chandler P3, Baban B3, Merlo LM2, Pigott E2, Keough MP2, Rust S1, Mellor AL3, Mandik-Nayak L4, Muller AJ5,Prendergast GC6.

Int Immunol. 2014;26(7):357-67.

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1New Link Genetics Corporation, Ames, IA 50010, USA.and

2Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.and

3Immunotherapy Center, Georgia Regents University, Augusta, GA 30912, USA.and

4Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

5Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

6Lankenau 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. [email protected]

 

 

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 inIdo2 (-/-) 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-{Gamma}, TNF-{Alpha}, 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.

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IDO2 is critical for IDO1-mediated T-cell regulation - Global Medical Discovery