Indoleamine 2,3-Dioxygenase (IDO) Activity During the Primary Immune Response to Influenza Infection Modifies the Memory T Cell Response to Influenza Challenge

Abstract

The generation of a heterosubtypic memory T cell response is important for cross-protective immunity against unrelated strains of influenza virus. One way to facilitate the generation of the memory T cell population is to control the activity of immune modulatory agents. The enzyme, indoleamine 2,3-dioxygenase (IDO), is upregulated during influenza infection by the interferon response where IDO activity depletes tryptophan required in T cell response. In this study, IDO activity was pharmacologically inhibited with 1-methyl-tryptophan (1MT) during the primary response to influenza virus infection and the effect on the memory T cell response was evaluated. 1MT treatment improved the memory T cell response to influenza virus challenge by increasing interferon gamma expression by CD4 and CD8 T cells, and numbers of lung virus-specific CD8 + T cells, and increased the Th1 response as well as modifying the immunodominance hierarchy to increase the number of subdominant epitope specific CD8 + T cells, a feature which may be linked to decreased regulatory T cell function. These changes also accompanied evidence of accelerated lung tissue repair upon virus challenge. These findings suggest that modulation of IDO activity could be exploited in influenza vaccine development to enhance memory T cell responses and reduce disease burden.

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

“…Similar to our findings with lung epithelial A549 cells, in neuronal cells IFN-␥ strongly induced IDO expression, causing inhibition of HSV replication, which could be rescued by Trp (54). Interaction of IDO with several other viruses, such as HIV, cytomegalovirus, RSV, hepatitis virus, and influenza A virus, has been unraveled recently, but mainly in the context of T cell responses and induced immunity (52,(55)(56)(57)(58). The effect of IDO on PIV3, however, was appreciated in nonimmune cells; it is thus representative of a cellintrinsic mechanism that directly inhibits viral gene expression.…”

Role of indoleamine 2,3-dioxygenase in health and disease

“…In murine influenza, inhibition of IDO1 activity in wild-type mice with 1-DL-MT or infection of IDO1 −/− mice, enhanced the primary immune response to infection by increasing the production of macrophage-derived pro-inflammatory cytokines, promoting CD4 + and CD8 + T-cell function, as well as Th1 responses [529,530]. Secondary immune responses are also affected, as 1-DL-MT treatment or Ido1 gene deficiency also resulted in elevated effector CD4 + Th1 and Th17 responses, increased the number of effector memory CD8 + T-cells, altered the memory CD8 + T-cell repertoire and decreased numbers of CTLA-4-expressing Tregs [529,530,553]. IDO1 inhibition is also associated with improved tissue repair in influenza [553].…”

“…Secondary immune responses are also affected, as 1-DL-MT treatment or Ido1 gene deficiency also resulted in elevated effector CD4 + Th1 and Th17 responses, increased the number of effector memory CD8 + T-cells, altered the memory CD8 + T-cell repertoire and decreased numbers of CTLA-4-expressing Tregs [529,530,553]. IDO1 inhibition is also associated with improved tissue repair in influenza [553]. However, despite these clear enhancements of primary and secondary immune responses, there is no apparent difference in lung viral burden or morbidity recorded between untreated and 1-DL-MT-or 1-D-MT-treated wild-type mice [529,530,553], although infected IDO1 −/− mice exhibit improved survival and more rapid recovery from influenza virus infection [530].…”

“…IDO1 inhibition is also associated with improved tissue repair in influenza [553]. However, despite these clear enhancements of primary and secondary immune responses, there is no apparent difference in lung viral burden or morbidity recorded between untreated and 1-DL-MT-or 1-D-MT-treated wild-type mice [529,530,553], although infected IDO1 −/− mice exhibit improved survival and more rapid recovery from influenza virus infection [530]. These discrepant lethality results between the 1-MT and IDO1 −/− studies may be reconciled by the fact that, although the level of replicating virus in the lung declines by day 6 and is below the level of detection by day 7, 1-MT treatment does not inhibit IDO1 activity, as indexed by the Kyn/L-Trp ratio, until day 10 post-infection [529].…”

5-Hydroxytryptophan, a major product of tryptophan degradation, is essential for optimal replication of human parainfluenza virus

“…However, IDO was originally shown to inhibit the replication of the unicellular protozoan parasite Toxoplasma gondii in immune cells (Dai et al, 1994; Mehraj and Routy, 2016; Mellor and Munn, 2003). It is only recently that the relationship of IDO with viral pathogenesis and the antiviral role of IDO have been appreciated, notably with measles virus, herpes simplex virus, hepatitis B virus, influenza virus and respiratory syncytial virus (Adams et al, 2004; Huang et al, 2013; Mao et al, 2011; Obojes et al, 2005; Rabbani et al, 2016; Sage et al, 2014). The majority of these studies were conducted in cells of immune origin, such as macrophages and dendritic cells (DC), or in the live animal, which indicated a role of IDO in regulating adaptive immunity (Mellor and Munn, 2003; Schmidt and Schultze, 2014).…”