Induction and Role of Indoleamine 2,3 Dioxygenase in Mouse Models of Influenza A Virus Infection

Lei Huang, Lingqian Li, Kim D. Klonowski, S. Mark Tompkins, Ralph A. Tripp, Andrew L. Mellor

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere66546
JournalPloS one
Volume8
Issue number6
DOIs
StatePublished - Jun 13 2013

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Indoleamine-Pyrrole 2,3,-Dioxygenase
T-cells
Influenza A virus
Virus Diseases
Viruses
influenza
Human Influenza
T-lymphocytes
animal models
lungs
Lung
T-Lymphocytes
mice
infection
Ablation
Infection
Data storage equipment
viruses
lymph nodes
morbidity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Huang, L., Li, L., Klonowski, K. D., Tompkins, S. M., Tripp, R. A., & Mellor, A. L. (2013). Induction and Role of Indoleamine 2,3 Dioxygenase in Mouse Models of Influenza A Virus Infection. PloS one, 8(6), [e66546]. https://doi.org/10.1371/journal.pone.0066546

Induction and Role of Indoleamine 2,3 Dioxygenase in Mouse Models of Influenza A Virus Infection. / Huang, Lei; Li, Lingqian; Klonowski, Kim D.; Tompkins, S. Mark; Tripp, Ralph A.; Mellor, Andrew L.

In: PloS one, Vol. 8, No. 6, e66546, 13.06.2013.

Research output: Contribution to journalArticle

Huang, L, Li, L, Klonowski, KD, Tompkins, SM, Tripp, RA & Mellor, AL 2013, 'Induction and Role of Indoleamine 2,3 Dioxygenase in Mouse Models of Influenza A Virus Infection', PloS one, vol. 8, no. 6, e66546. https://doi.org/10.1371/journal.pone.0066546
Huang, Lei ; Li, Lingqian ; Klonowski, Kim D. ; Tompkins, S. Mark ; Tripp, Ralph A. ; Mellor, Andrew L. / Induction and Role of Indoleamine 2,3 Dioxygenase in Mouse Models of Influenza A Virus Infection. In: PloS one. 2013 ; Vol. 8, No. 6.
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