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

Citation

Metz R, Smith C, Duhadaway JB, Chandler P, Baban B, Merlo LM, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, J Muller A, Prendergast GC. IDO2 is critical for IDO1-mediated T cell regulation and exerts a non-redundant function in inflammation. Int Immunol. 2014 Jan 8. [Epub ahead of print] PMID:24402311.

 

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 naรฏve 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-ฮณ, TNFฮฑ, 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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Heather Hopkins

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Written by Heather Hopkins

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