The IDO–AhR Axis Controls Th17/Treg Immunity in a Pulmonary Model of Fungal Infection

Abstract

In infectious diseases, the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) that catalyzes the tryptophan (Trp) degradation along the kynurenines (Kyn) pathway has two main functions, the control of pathogen growth by reducing available Trp and immune regulation mediated by the Kyn-mediated expansion of regulatory T (Treg) cells via aryl hydrocarbon receptor (AhR). In pulmonary paracoccidioidomycosis (PCM) caused by the dimorphic fungus Paracoccidioides brasiliensis, IDO1 was shown to control the disease severity of both resistant and susceptible mice to the infection; however, only in resistant mice, IDO1 is induced by TGF-β signaling that confers a stable tolerogenic phenotype to dendritic cells (DCs). In addition, in pulmonary PCM, the tolerogenic function of plasmacytoid dendritic cells was linked to the IDO1 activity. To further evaluate the function of IDO1 in pulmonary PCM, IDO1-deficient (IDO1−/−) C57BL/6 mice were intratracheally infected with P. brasiliensis yeasts and the infection analyzed at three postinfection periods regarding several parameters of disease severity and immune response. The fungal loads and tissue pathology of IDO1−/− mice were higher than their wild-type controls resulting in increased mortality rates. The evaluation of innate lymphoid cells showed an upregulated differentiation of the innate lymphoid cell 3 phenotype accompanied by a decreased expansion of ILC1 and NK cells in the lungs of infected IDO1−/− mice. DCs from these mice expressed elevated levels of costimulatory molecules and cytokine IL-6 associated with reduced production of IL-12, TNF-α, IL-1β, TGF-β, and IL-10. This response was concomitant with a marked reduction in AhR production. The absence of IDO1 expression caused an increased influx of activated Th17 cells to the lungs with a simultaneous reduction in Th1 and Treg cells. Accordingly, the suppressive cytokines IL-10, TGF-β, IL-27, and IL-35 appeared in reduced levels in the lungs of IDO1−/− mice. In conclusion, the immunological balance mediated by the axis IDO/AhR is fundamental to determine the balance between Th17/Treg cells and control the severity of pulmonary PCM.

<p>Dendritic Cells Promote Treg Expansion but Not Th17 Generation in Response to <em>Talaromyces marneffei</em> Yeast Cells</p>

“…10, 38,39 Th17 and Treg cells always play opposing roles in fungal infection. 12,27,40 An impaired balance of Th17/Treg is associated with disease progression, while the inhibition or depletion of Treg cells could potentially rescue Th1/Th17 immunity and improve prognosis. 12,27,40 Foxp3 could inhibit RORγt and down-regulate the expression of RORγt-mediated IL-17.…”

“…12,27,40 An impaired balance of Th17/Treg is associated with disease progression, while the inhibition or depletion of Treg cells could potentially rescue Th1/Th17 immunity and improve prognosis. 12,27,40 Foxp3 could inhibit RORγt and down-regulate the expression of RORγt-mediated IL-17. 41 Therefore, the dominance of Treg cells could be associated with the down-regulation of RORγt expression and the suppression of Th17 cells.…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…Administration of the statin group of drugs reduces IL-6 production but increases IL-10 and kynurenine (178). This expected opposite movement of IL-10 and IL-6 has been observed in IDO1-deficient DCs in which there is the anticipated loss of AHR activity and reduced levels of IL-10, but increased IL-6 and TNF-α production (179); conversely both IL-6 and IL-10 were increased after surgery (180). Kynurenine itself suppresses IL-6 release but kynurenic acid has been reported to increase it.…”

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…Activation of GCN2 further promotes the generation of regulatory phenotypes (T reg ) in naive CD4 + T cells (137). Activation of AhR by its endogenous ligand Kyn results in reduced T helper 17 (Th17) cell differentiation, while promoting the generation of T reg cells (138,139). T reg cells, in turn, induce IDO1 expression in DCs, thus expanding their own population and forming a positive regulatory feedback loop (137).…”