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.
Highlights
Cells expressing IDO suppress innate and adaptive immunity in a range of clinically relevant syndromes including autoimmune, allergic and infectious diseases, cancer, pregnancy, and transplantation [1]
To evaluate IDO enzyme activity during influenza infection B6 mice were infected with sub-lethal doses (50 PFU/mouse, i/n) of influenza A/PR/8/34 (PR8) virus and levels of the tryptophan catabolite kynurenine (Kyn) released by cells expressing functional IDO enzyme activity were assessed in lungs and mediastinal lymph nodes (msLNs) by performing HPLC analysis on tissue homogenates
In this study we show that influenza infection stimulated rapid increase in IDO activity in lungs and lung-associated lymph nodes that persisted long after virus was eliminated from lungs
Summary
Cells expressing IDO suppress innate and adaptive immunity in a range of clinically relevant syndromes including autoimmune, allergic and infectious diseases, cancer, pregnancy, and transplantation [1]. Splenic CD19+ DCs expressed IDO and mediated IDO-dependent T cell suppression when mice were treated with soluble CTLA4 (CTLA4-Ig), relatively high doses of TLR9 ligands (CpG oligonucleotides) and DNA nanoparticles delivered systemically [10,11,12,13,14,15]. In these and other settings of inflammation, induced IDO activity in DCs caused naıve CD4 T cells to convert into Foxp3-lineage regulatory T cells (Tregs) and stimulated preformed, resting Tregs to acquire potent regulatory phenotypes that attenuated effector T cell responses [16,17,18,19]. Tumor cells and some stromal cell types such as epithelial cells and fibroblasts can express IDO at sites of inflammation, and these cells may promote local T cell regulation
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