Immunomodulatory role of indoleamine 2, 3-dioxygenase during acute influenza infection

Abstract

Influenza virus is a worldwide concern causing significant morbidity and mortality. Although vaccines are available to prevent infection, the vaccine is targeted toward homologous strains of influenza virus providing limited heterologous protection. The majority of the cross-protection is derived from T cell immunity which is directed primarily at the conserved internal proteins of influenza virus. Enhancing the T cell response during vaccination could provide better cross-protection and perhaps reduce the need for seasonal vaccines. We hypothesized that modulating the activity of indoleamine 2, 3-dioxygenase (IDO) during influenza virus infection could enhance the immune response augmenting T cell memory to the vaccine. IDO has been shown to suppress the immune response through depletion of tryptophan and production of kynurenine metabolites. Pharmacological inhibition of IDO during acute influenza infections resulted in enhanced Th1-type response and memory T cell responses. Assessment of early immune time-points following infection revealed IDO inhibition enhanced cytokine production, and IDO activity was induced in alveolar epithelial cells through IFN-λ stimulation. 1MT treatment increased the pro-inflammatory response with increased expression of TNF-α and IL-6 following influenza virus infection. The enhanced pro-inflammatory response with IDO inhibited was modulated by the alveolar macrophage population residing in the lung airways. Together, these finding show a role for IDO during influenza virus infections and provide insight into the potential use of IDO modulation for vaccine and therapeutic designs.