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New Insights into IDO Biology in Bacterial and Viral Infections.

Schmidt SV, Schultze JL - Front Immunol (2014)

Bottom Line: Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance.In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C.Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn , Bonn , Germany.

ABSTRACT
Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.

No MeSH data available.


Related in: MedlinePlus

Schematic summary of immunosuppressive functions of indoleamine-2,3-dioxygenase (IDO) during HIV infection. Direct induction of IDO in antigen-presenting cells (APC) by viral Tat protein is established via an intracellular signaling cascade including kinases (JakI, PI3K) or CTLA-4-B7 interaction on regulatory T (Treg)-cells with B7 co-receptor on the APC, which leads in consequence to a breakdown of tryptophan (Trp) into kynurenine (Kyn). Diminished anti-viral immune responses during chronic HIV infection is caused by an impaired T-cell response, the lack of potent IFNγ secreting DC, and the induction of immunosuppressive IDO+ APC. pDC, plasmacytoid DC; mDC, myeloid DC.
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Figure 1: Schematic summary of immunosuppressive functions of indoleamine-2,3-dioxygenase (IDO) during HIV infection. Direct induction of IDO in antigen-presenting cells (APC) by viral Tat protein is established via an intracellular signaling cascade including kinases (JakI, PI3K) or CTLA-4-B7 interaction on regulatory T (Treg)-cells with B7 co-receptor on the APC, which leads in consequence to a breakdown of tryptophan (Trp) into kynurenine (Kyn). Diminished anti-viral immune responses during chronic HIV infection is caused by an impaired T-cell response, the lack of potent IFNγ secreting DC, and the induction of immunosuppressive IDO+ APC. pDC, plasmacytoid DC; mDC, myeloid DC.

Mentions: Infection with HIV causes a severe impairment of T-cell responses by loss of proliferative capacity of T-cells accompanied by a depletion of functionally competent CD4+ T helper cells and by induction of regulatory T-cells (Treg) during the chronic phase of HIV infection (Figure 1). The exact T-cell impairing mechanism is still not completely understood, but inhibitory molecules on T-cell function have been investigated intensely [reviewed elsewhere (26)]. Elevated serum levels of IFNγ (27, 28) and Kyn (29) in HIV patients pointed toward a participation of IDO in suppression of T-cell function, yet molecular mechanisms were unknown. Further support came from increased IDO mRNA levels measured in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients (30). In vitro infection of PBMC led to the secretion of IFNα and IFNβ by plasmacytoid dendritic cells (pDC) (31). While both CD4+ and CD8+ T-cells expressed the activation markers CD69 and CD38, they failed to proliferate and were insensitive to T-cell receptor stimulation, a status described as division arrest anergy (32). While CD4+ T-cells were arrested in G1/S phase, CD8+ T-cells downregulated the costimulatory receptor CD28. When the enzymatic activity of IDO was inhibited by 1-methyl tryptophan (1-MT), CD4+ and CD8+ T-cells regained their ability to proliferate (30, 31). In monocyte-derived DC (moDC), the N-terminal domain of HIV-1 transactivator regulatory protein (Tat) induced IFNγ and IDO expression and therefore further led to a suppression of T-cell proliferation. Here, 1-MT was also able to reconstitute T-cell proliferation (33). IDO expression was initially induced by Tat and followed by the induction of IFNγ leading to a feed forward loop. Interestingly, IFNγ signaling pathways leading to IDO expression could be blocked by JAKs and PI3K inhibitors but Tat-induced IDO expression could not be inhibited, suggesting a novel so far not characterized mechanism of IDO induction by Tat proteins in HIV infection (33).


New Insights into IDO Biology in Bacterial and Viral Infections.

Schmidt SV, Schultze JL - Front Immunol (2014)

Schematic summary of immunosuppressive functions of indoleamine-2,3-dioxygenase (IDO) during HIV infection. Direct induction of IDO in antigen-presenting cells (APC) by viral Tat protein is established via an intracellular signaling cascade including kinases (JakI, PI3K) or CTLA-4-B7 interaction on regulatory T (Treg)-cells with B7 co-receptor on the APC, which leads in consequence to a breakdown of tryptophan (Trp) into kynurenine (Kyn). Diminished anti-viral immune responses during chronic HIV infection is caused by an impaired T-cell response, the lack of potent IFNγ secreting DC, and the induction of immunosuppressive IDO+ APC. pDC, plasmacytoid DC; mDC, myeloid DC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128074&req=5

Figure 1: Schematic summary of immunosuppressive functions of indoleamine-2,3-dioxygenase (IDO) during HIV infection. Direct induction of IDO in antigen-presenting cells (APC) by viral Tat protein is established via an intracellular signaling cascade including kinases (JakI, PI3K) or CTLA-4-B7 interaction on regulatory T (Treg)-cells with B7 co-receptor on the APC, which leads in consequence to a breakdown of tryptophan (Trp) into kynurenine (Kyn). Diminished anti-viral immune responses during chronic HIV infection is caused by an impaired T-cell response, the lack of potent IFNγ secreting DC, and the induction of immunosuppressive IDO+ APC. pDC, plasmacytoid DC; mDC, myeloid DC.
Mentions: Infection with HIV causes a severe impairment of T-cell responses by loss of proliferative capacity of T-cells accompanied by a depletion of functionally competent CD4+ T helper cells and by induction of regulatory T-cells (Treg) during the chronic phase of HIV infection (Figure 1). The exact T-cell impairing mechanism is still not completely understood, but inhibitory molecules on T-cell function have been investigated intensely [reviewed elsewhere (26)]. Elevated serum levels of IFNγ (27, 28) and Kyn (29) in HIV patients pointed toward a participation of IDO in suppression of T-cell function, yet molecular mechanisms were unknown. Further support came from increased IDO mRNA levels measured in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients (30). In vitro infection of PBMC led to the secretion of IFNα and IFNβ by plasmacytoid dendritic cells (pDC) (31). While both CD4+ and CD8+ T-cells expressed the activation markers CD69 and CD38, they failed to proliferate and were insensitive to T-cell receptor stimulation, a status described as division arrest anergy (32). While CD4+ T-cells were arrested in G1/S phase, CD8+ T-cells downregulated the costimulatory receptor CD28. When the enzymatic activity of IDO was inhibited by 1-methyl tryptophan (1-MT), CD4+ and CD8+ T-cells regained their ability to proliferate (30, 31). In monocyte-derived DC (moDC), the N-terminal domain of HIV-1 transactivator regulatory protein (Tat) induced IFNγ and IDO expression and therefore further led to a suppression of T-cell proliferation. Here, 1-MT was also able to reconstitute T-cell proliferation (33). IDO expression was initially induced by Tat and followed by the induction of IFNγ leading to a feed forward loop. Interestingly, IFNγ signaling pathways leading to IDO expression could be blocked by JAKs and PI3K inhibitors but Tat-induced IDO expression could not be inhibited, suggesting a novel so far not characterized mechanism of IDO induction by Tat proteins in HIV infection (33).

Bottom Line: Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance.In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C.Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn , Bonn , Germany.

ABSTRACT
Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.

No MeSH data available.


Related in: MedlinePlus