title: Induction and role of indoleamine 2,3 dioxygenase in mouse models of influenza a virus infection.
abstract: Influenza infection stimulates protective host immune responses but paradoxically enhances lung indoleamine 2,3 dioxygenase (IDO) activity, an enzyme that suppresses helper/effector T cells and activates Foxp3-lineage regulatory CD4 T cells (Tregs). Influenza A/PR/8/34 (PR8) infection stimulated rapid elevation of IDO activity in lungs and lung-draining mediastinal lymph nodes (msLNs). Mice lacking intact IDO1 genes (IDO1-KO mice) exhibited significantly lower morbidity after sub-lethal PR8 infection, and genetic or pharmacologic IDO ablation led to much faster recovery after virus clearance. More robust influenza-specific effector CD8 T cell responses manifested in lungs of PR8-infected IDO1-KO mice, though virus clearance rates were unaffected by IDO ablation. Similar outcomes manifested in mice infected with a less virulent influenza A strain (X31). IDO induction in X31-infected lungs was dependent on IFN type II (IFNγ) signaling and was restricted to non-hematopoietic cells, while redundant IFN type 1 or type II signaling induced IDO exclusively in hematopoietic cells from msLNs. Memory T cells generated in X31-primed IDO1-KO mice protected mice from subsequent challenge with lethal doses of PR8 (100×LD50). However recall T cell responses were less robust in lung interstitial tissues, and classic dominance of TCR Vβ8.3 chain usage amongst memory CD8(+) T cells specific for influenza nucleoprotein (NP366) did not manifest in IDO1-KO mice. Thus, influenza induced IDO activity in lungs enhanced morbidity, slowed recovery, restrained effector T cell responses in lungs and shaped memory T cell repertoire generation, but did not attenuate virus clearance during primary influenza A infection.
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Lingqian
authors.initials: L
authors.lastname: Li
authors.forename: Kim D
authors.initials: KD
authors.lastname: Klonowski
authors.forename: S Mark
authors.initials: SM
authors.lastname: Tompkins
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Tripp
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000276:immunology; D007156:Immunologic Memory; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D009980:Influenza A virus / Q000276:immunology*; D007372:Interferons / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology; D008482:Mediastinum; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007372:Interferons