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

Richard Metz, Courtney Smith, James B. DuHadaway, Phillip Chandler, Babak Baban, Lauren M F Merlo, Elizabeth Pigott, Martin P. Keough, Sonja Rust, Andrew L. Mellor, Laura Mandik-Nayak, Alexander J. Muller, George C. Prendergast

Research output: Contribution to journalArticle

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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 nonredundant contributions to inflammation.

Original languageEnglish (US)
Pages (from-to)357-367
Number of pages11
JournalInternational Immunology
Volume26
Issue number7
DOIs
StatePublished - Jan 1 2014

Fingerprint

Inflammation
T-Lymphocytes
Kynurenine
Peritoneum
Contact Dermatitis
Skin Neoplasms
Granulocyte Colony-Stimulating Factor
Regulatory T-Lymphocytes
Granulocyte-Macrophage Colony-Stimulating Factor
Tryptophan
Thymus Gland
Embryonic Development
Immunity
Interleukin-6
Spleen
Lymph Nodes
Bone Marrow
Macrophages
Cytokines
Skin

Keywords

  • Adaptive immunity
  • Contact hypersensitivity
  • Inflammation
  • Tolerance

ASJC Scopus subject areas

  • Immunology

Cite this

Metz, R., Smith, C., DuHadaway, J. B., Chandler, P., Baban, B., Merlo, L. M. F., ... Prendergast, G. C. (2014). IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. International Immunology, 26(7), 357-367. https://doi.org/10.1093/intimm/dxt073

IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. / Metz, Richard; Smith, Courtney; DuHadaway, James B.; Chandler, Phillip; Baban, Babak; Merlo, Lauren M F; Pigott, Elizabeth; Keough, Martin P.; Rust, Sonja; Mellor, Andrew L.; Mandik-Nayak, Laura; Muller, Alexander J.; Prendergast, George C.

In: International Immunology, Vol. 26, No. 7, 01.01.2014, p. 357-367.

Research output: Contribution to journalArticle

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 2014, 'IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation', International Immunology, vol. 26, no. 7, pp. 357-367. https://doi.org/10.1093/intimm/dxt073
Metz, Richard ; Smith, Courtney ; DuHadaway, James B. ; Chandler, Phillip ; Baban, Babak ; Merlo, Lauren M F ; Pigott, Elizabeth ; Keough, Martin P. ; Rust, Sonja ; Mellor, Andrew L. ; Mandik-Nayak, Laura ; Muller, Alexander J. ; Prendergast, George C. / IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. In: International Immunology. 2014 ; Vol. 26, No. 7. pp. 357-367.
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