Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure.
Indoleamine 2,3-dioxygenase (IDO) suppresses the functions of CD4(+) T cells through its ability to metabolize the essential amino acid tryptophan. Although the activity of IDO is required for the immunosuppression of allergic airway disease by the Toll-Like-Receptor 9 (TLR9) agonist, oligonucleotides comprised of cytosine and guanine nucleotides linked by phosphodiester bonds (CpG) DNA, it is unclear whether IDO expression by resident lung epithelial cells is sufficient to elicit these effects. Therefore, we created a transgenic mouse inducibly overexpressing IDO within nonciliated airway epithelial cells. Upon inhalation of formalin-fixed Aspergillus fumigatus hyphal antigens, the overexpression of IDO from airway epithelial cells of these mice reduced the number of CD4(+) T cells within the inflamed lung and impaired the capacity of antigen-specific splenic CD4(+) effector T cells to secrete the cytokines IL-4, IL-5, IL-13, and IFN-γ. Despite these effects, allergic airway disease pathology was largely unaffected in mice expressing IDO in airway epithelium. In support of the concept that dendritic cells are the major cell type contributing to the IDO-inducing effects of CpG DNA, mice expressing TLR9 only in the airway epithelium did not augment IDO expression subsequent to the administration of CpG DNA. Furthermore, the systemic depletion of CD11c(+) cells rendered mice incapable of CpG DNA-induced IDO expression. Our results demonstrate that an overexpression of IDO within the airway epithelium represents a novel mechanism by which the number of CD4(+) T cells recruited to the lung and their capacity to produce cytokines can be diminished in a model of allergic airway disease, and these results also highlight the critical role of dendritic cells in the antiasthmatic effects of IDO induction by CpG DNA.
Paveglio
Sara A
SA
Vermont Lung Center, and Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, 149 Beaumont Ave., Burlington, VT 05405, USA.
Allard
Jenna
J
Foster Hodgkins
Samantha R
SR
Ather
Jennifer L
JL
Bevelander
Mieke
M
Campbell
Jana Mayette
JM
Whittaker LeClair
Laurie A
LA
McCarthy
Sean M
SM
van der Vliet
Albert
A
Suratt
Benjamin T
BT
Boyson
Jonathan E
JE
Uematsu
Satoshi
S
Akira
Shizuo
S
Poynter
Matthew E
ME
D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D055732:Pulmonary Aspergillosis / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D051381:Rats; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism
D000946:Antigens, Fungal; C408982:CPG-oligonucleotide; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009838:Oligodeoxyribonucleotides; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019382:Human Growth Hormone; D007737:Kynurenine; D014598:Uteroglobin