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.

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The generation of heterosubtypic CD8 T cell responses is important for cross-protective immunity against unrelated strains of influenza. The need to maintain tolerance in the lung, however, limits the overall breadth and duration of CD8 T cell responses, warranting a better understanding of mechanisms of immunoregulation at this site. Influenza infection induces pulmonary expression of the tryptophan catabolizing enzyme IDO. Depletion of tryptophan results in suppression of T cell expansion or effector function, T cell anergy, or deletion. We hypothesized that ablation of IDO activity during CD8 T cell priming would enhance the subsequent CD8 T cell memory pool. To test this in vivo, we conditionally ablated IDO activity during the priming phase using the inhibitor 1-methyl tryptophan (1MT). 1MT-treated animals challenged with a lethal dose of a heterosubtypic influenza virus generated a more robust Th1 response, with enhanced migration to the lung airways. Interestingly, the immunodominance hierarchy was also shifted to favor subdominant CD8 T cell epitopes in both 1MT-treated and IDO-deficient animals, likely a result of observed decreased regulatory T cell function. While 1MT treatment did not affect cytotoxicity or viral clearance, pulmonary pathology was reduced in the absence of IDO. Together these data provide evidence that modulation of IDO activity in the context of influenza infection could be exploited in vaccine development to enhance memory CD8 T cell responses.

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